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Relation between serum sodium concentration and the hemodynamic and clinical responses to converting enzyme inhibition with captopril in severe heart failure
Abstract
The relation between pretreatment serum sodium concentration and the early and late effects of captopril was examined in 77 consecutive patients with severe chronic heart failure, in whom cardiac catheterization was performed during initiation of treatment and after 2 to 8 weeks. Two groups of patients were defined: 37 patients had hyponatremia (serum sodium less than 135 mEq/liter, group A) and 40 patients had a normal serum sodium concentration (greater than or equal to 135 mEq/liter, group B). With first doses of captopril, patients in group A showed more marked hemodynamic responses than did patients in group B (p less than 0.02). The changes in mean arterial pressure and left ventricular filling pressure seen with first doses of the drug varied linearly and inversely with the pretreatment serum sodium concentration (r = -0.58 and r = -0.53, respectively); this was likely related to the finding that, before administration of captopril, the serum sodium concentration varied linearly and inversely with the logarithm of the plasma renin activity (r = -0.78). However, the pretreatment serum sodium concentration did not predict the long-term hemodynamic or clinical responses to converting enzyme inhibition. Symptomatic hypotension occurred early in the course of therapy (within 24 hours of initiating captopril therapy) in 9 (12%) of the 77 patients; 8 of these 9 had severe hyponatremia (serum sodium less than 130 mEq/liter) and comprised 53% of the 15 patients in our study with such low serum sodium concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)
... In this subtype of worsening HF, in addition to the response to lower blood pressure, the RAAS tends to be over activated due to positive tubuloglomerular feedback resulting from a decreased supply of filtered chloride to the macula densa, but the RAAS activation to increase reabsorption of filtered solutes would be ineffective because the supply of these solutes is reduced in the urinary tubules of HF patients with no increase in the serum chloride concentration. It is speculated that a substantial number of the clinical features of this type of worsening of HF overlaps with those of advanced HF patients with hyponatremia [49][50][51][52][53]. ...
... The RAAS is basically involved in the development and progression of HF [18][19][20]35]. Activation of the RAAS ultimately results in increased afterload and body fluid retention, leading to a vicious cycle of decompensated HF [49][50][51]54]. Many previous studies concordantly reported an inverse association between the serum sodium concentration and plasma renin activity in populations of HF patients with various disease severities [51,[55][56][57][58]. ...
... Activation of the RAAS ultimately results in increased afterload and body fluid retention, leading to a vicious cycle of decompensated HF [49][50][51]54]. Many previous studies concordantly reported an inverse association between the serum sodium concentration and plasma renin activity in populations of HF patients with various disease severities [51,[55][56][57][58]. ...
We recently proposed a unifying hypothesis of the "chloride theory" for Heart Failure (HF) pathophysiology, which states that changes in the serum chloride concentration are the primary determinant of changes in the plasma volume and neurohormonal activity under worsening HF and its resolution. The proposed hypothesis is based on speculative interactions between changes in the serum chloride concentration and neurohormonal systems, but it has been unclear whether these interactions are physiologically applicable to clinical HF states. Thus, here we review the current literature to provide scientific rationale for the " chloride theory " to explain the activity of neurohormonal systems, mainly the renin-angiotensin-aldosterone system and the antidiuretic hormone axis. Many published clinical studies provide support for the "chloride theory" in real-world HF pathophysiology during both HF worsening ant recovery.
... In this subtype of worsening HF, in addition to the response to lower blood pressure, the RAAS tends to be over activated due to positive tubuloglomerular feedback resulting from a decreased supply of filtered chloride to the macula densa, but the RAAS activation to increase reabsorption of filtered solutes would be ineffective because the supply of these solutes is reduced in the urinary tubules of HF patients with no increase in the serum chloride concentration. It is speculated that a substantial number of the clinical features of this type of worsening of HF overlaps with those of advanced HF patients with hyponatremia [49][50][51][52][53]. ...
... The RAAS is basically involved in the development and progression of HF [18][19][20]35]. Activation of the RAAS ultimately results in increased afterload and body fluid retention, leading to a vicious cycle of decompensated HF [49][50][51]54]. Many previous studies concordantly reported an inverse association between the serum sodium concentration and plasma renin activity in populations of HF patients with various disease severities [51,[55][56][57][58]. ...
... Activation of the RAAS ultimately results in increased afterload and body fluid retention, leading to a vicious cycle of decompensated HF [49][50][51]54]. Many previous studies concordantly reported an inverse association between the serum sodium concentration and plasma renin activity in populations of HF patients with various disease severities [51,[55][56][57][58]. ...
... The treatment strategy of hyponatremia in HF patients includes improvement of hemodynamics, fluid restriction, and the recent use of vasopressin receptor antagonists [5,[13][14][15]. ACEi and ARBs reduce the afterload and improve the hemodynamics [16,17], cardiac output, neurohumoral parameters [18], serum sodium levels, and survival [16,17,19]. ...
... The treatment strategy of hyponatremia in HF patients includes improvement of hemodynamics, fluid restriction, and the recent use of vasopressin receptor antagonists [5,[13][14][15]. ACEi and ARBs reduce the afterload and improve the hemodynamics [16,17], cardiac output, neurohumoral parameters [18], serum sodium levels, and survival [16,17,19]. ...
... Hyponatremic HF patients are more susceptible to the hypotensive and azotemic effects of ACEi, possibly because they are more dependent on neurohormones to sustain BP. Therefore the initiation or up-titration of ACEi is particularly difficult in these patients [17]. However, hyponatremia identifies a high-risk population that may benefit from intensive medical treatment, and every effort should be made to ensure that all eligible patients receive evidence-based therapy. ...
Hyponatremia is a well-known risk factor for poor outcomes in Western studies of heart failure (HF) patients. We evaluated the predictive value of hyponatremia in hospitalized Asian HF patients.
The Clinical Characteristics and Outcomes in the Relation with Serum Sodium Level in Asian Patients Hospitalized for Heart Failure (the COAST) study enrolled hospitalized patients with systolic HF (ejection fraction < 45%) at eight centers in South Korea, Taiwan, and China. The relationship between admission sodium level and clinical outcomes was analyzed in 1,470 patients.
The mean admission sodium level was 138 ± 4.7 mmol/L, and 247 patients (16.8%) had hyponatremia defined as Na(+) < 135 mmol/L. The 12-month mortality was higher in hyponatremic patients (27.9% vs. 14.6%, p < 0.001), and hyponatremia was an independent predictor of 12-month mortality (hazard ratio, 1.72; 95% confidence interval, 1.12 to 2.65). During hospital admission, 57% of hyponatremic patients showed improvement without improvement in their clinical outcomes (p = 0.620). The proportion of patients with optimal medical treatment was only 26.5% and 44.2% at admission and discharge, respectively, defined as the combined use of angiotensin-converting-enzyme inhibitor/angiotensin receptor blocker and β-blocker. Underuse of optimal medical treatment was more pronounced in hyponatremic patients.
In hospitalized Asian HF patients, hyponatremia at admission is common and is an independent predictor of poor clinical outcome. Furthermore, hyponatremic patients receive less optimal medical treatment than their counterparts.
... Sequential nephron blockade may be accompanied by inappropriate fluid loss, electrolyte imbalance (hyponatremia or hypokalemia), and worsening renal function [46, 80,83]. If residual congestion persists or progressively worsens despite higher doses of conventional diuretics, adherence to such decongestive therapy may promote a vicious cycle of HF worsening and RAAS activation [85][86][87][88], leading to worsening HF with a decreased serum Cl concentration as shown in the right half of Fig. 1; such a patient with worsening HF might present with progressive hypochloremia, extravasated fluid retention, intravascular volume contraction, hypotension, and worsening renal function. It should be noted that, besides advanced cardiac and renal dysfunction [89], an important cause of diuretic resistance may be the inappropriate use of conventional diuretics for different HF states with various serum electrolyte abnormalities. ...
... Accordingly, RAAS blockers increase renal blood flow and decrease proximal tubular sodium reabsorption. Therefore, it is not surprising that they are among the first agents demonstrated to be effective in hypotonic dilutional hyponatremia, perhaps including dilutional hypochloremia, in patients with HF [44, [85][86][87][88]. RAAS blockades should always be titrated up in this case if there are no contraindications, such as coexisting renal dysfunction, hypotension, and HF with preserved ejection fraction [17,44,121]. ...
Currently, diuretic therapy for heart failure (HF) pathophysiology is primarily focused on the sodium and water balance. Over the last several years, however, chloride (Cl) has been recognized to have an important role in HF patho-physiology, as both a prognostic marker and a possible central factor regulating the body fluid status. I recently proposed a unifying hypothesis for HF pathophysiology, called the ''chloride theory'', during HF worsening and recovery, as follows. Chloride is the key electrolyte for regulating both reabsorption of tubular electrolytes and water in the kidney through the renin-an-giotensin-aldosterone system and distributing body fluid in each compartment of the body. As changes between the serum Cl concentration and plasma volume are intimately associated with worsening HF and its recovery after decongestive therapy, modulation of the serum Cl concentration by careful selection and combination of various diuretics and their doses could become an attractive therapeutic option for HF. In this review, I will propose a new classification and practical use of diuretics according to their effects on the serum Cl concentration. Diuretic use according to this classification is expected to be a useful strategy for the treatment of patients with HF.
... No wonder intracellular Mg 2+ and K + concentrations increase while ventricular arrhythmia decreases as the consequence of ACE inhibitor therapy (329,330). ACE inhibitors do not only have a beneficial effect on the distribution of K + ad Mg 2+ but also that of Na + , as indicated by the hemodynamic improvement in hyponatremic patients suffering from congestive heart failure, as the serum Na + level was also increased (331,332). By contrast, in the end stage (NYHA IV) of heart failure, enalapril did not increase the low concentrations of K + and Mg 2+ in skeletal muscles; nor did it reduce high IC Na + concentrations (333). ...
... Enalapril did not increase low ATP or CrP contents in the same conditions (334). Giving ACE inhibitors to hyponatremic patients increased the frequency of adverse reactions (331,335,336). The rate of creatinine clearance decreased in hyponatremic patients as a result of ACE inhibitor treatment was particularly high in patients who also suffered from diabetes mellitus and received high doses of loop diuretics in addition to enalapril (336). ...
This article was updated, see :
https://www.researchgate.net/publication/338140567_Part_1_A_Theory_for_Modelizing_the_Cytoplasm_and_Diseases
With several decades of work, the author attempted to create a simple cytoplasm model for animal/human cells. The judgment of cytoplasm's dynamic work (anabolism vs. catabolism) leads us to a closer look at the pathophysiology of some diseases; for example, it presents diabetes into a new point of view. The author, with the help of this model, later (in other publications) concluded that CO2 plays a prominent role in the pathophysiology of several disorders/group of diseases; also in the development of civilization diseases and functional diseases. (Elsewhere) The author separates functional disorders from the organic ones, based on the model. Finally, he concluded that acute hypocapnia is an independent pathogenetic entity, which can often be the direct cause of death.
... Ezért nem meglepõ, ha ACE-inhibitor terápiában nõ az intracelluláris Mg 2+ -és K + -koncentráció és csökken a ventricularis aritmia (329,330). Az ACEinhibitorok nemcsak a K + és Mg 2+ , de többnyire a Na +megoszlást is kedvezõen befolyásolják, amennyiben pangásos szívelégtelenségben szenvedõ hyponatraemiás betegeken általában nemcsak hemodinamikai javulás következett be adásukra, de nõtt a szérum Na + -szint is (331,332). Ezzel szemben végstádiumú (NYHA IV.) szívelégtelenségben enalapril kezelésre nem nõtt a harántcsíkolt izom alacsony K + -és Mg 2+ -koncentrációja és nem csökkent a magas IC Na + -koncentráció (333), valamint nem nõtt az alacsony ATP-és CrP-koncentráció sem ugyanott (334). Másrészt viszont ACEinhibitor adására gyakrabban alakult ki szövõdmény hyponatraemiás betegeknél (331,335,336). ...
... Ezzel szemben végstádiumú (NYHA IV.) szívelégtelenségben enalapril kezelésre nem nõtt a harántcsíkolt izom alacsony K + -és Mg 2+ -koncentrációja és nem csökkent a magas IC Na + -koncentráció (333), valamint nem nõtt az alacsony ATP-és CrP-koncentráció sem ugyanott (334). Másrészt viszont ACEinhibitor adására gyakrabban alakult ki szövõdmény hyponatraemiás betegeknél (331,335,336). A kreatinin clearence csökkenésének rátája hyponatraemiás páciensek ACE-inhibitor kezelése esetén különösen magas volt, ha egyúttal diabetes mellitus is fennállt és/vagy az enalapril mellé nagy adag kacsdiuretikumot is kaptak a páciensek (336). ...
The favorite cytoplasm model of the author is the "Cytoplasmic Ions-ATP-Protein Model" which is capable to reveal the mechanism of several fundamental pathological processes (such as anabolism and catabolism) and to draw logical conclusions.
It was published in Hungarian (Cardiologia Hungarica) in 2007.
It was also translated to English.
... Data from the TRACE study have shown that treatment with ACE-I did not predispose to worsening renal dysfunction or hypotension in patients with hyponatremia [17]. A few studies have demonstrated that treatment with ACE-I in patients with HF and hyponatremia results in a more marked increase in CI and a decrease in CVP, mean arterial pressure, and left ventricular filling pressures than in patients with normal p-Na [18]. However, there is a further need for clinical trials to assess the risks or benefits initiation and treatment with ACE-I in hyponatremic patients with HFrEF. ...
Hyponatremia is associated with worse outcomes in patients with chronic heart failure (HF) and reduced ejection fraction (HFrEF). However, it is unclear whether the worse prognosis is driven by hemodynamic derangement and how this potentially could be associated with hyponatremia. The study included 502 patients with HFrEF evaluated for advanced HF therapies, who underwent a right heart catheterization (RHC). Hyponatremia was defined as p-Na≤136 mmol/L. The risk of all-cause mortality and a composite endpoint including mortality, left ventricular assist device (LVAD) implantation, implantation of total artificial heart (TAH) or heart transplantation (HTx) was evaluated using Cox regression analyses and Kaplan-Meier models. Included patients were predominantly men (79%) and had a median age of 54 years (IQR; 43-62). A third (165) of the patients had hyponatremia. In both univariate and multivariate regression analyses, p-Na was associated with increased central venous pressure (CVP), pulmonary capillary wedge pressure (PCWP) and mean pulmonary artery pressure (mPAP) but not with cardiac index. Hyponatremia was significantly associated with the combined endpoint (HR; 1.36 [95% CI 1.07 – 1.74]; P=0.01), but not all-cause mortality in adjusted Cox models. In stable HFrEF patients evaluated for advanced HF therapies, lower p-Na was associated with more deranged invasive hemodynamic measurements. Hyponatremia remained significantly associated with the combined endpoint but not all-cause mortality in adjusted Cox models. The study suggests that the increased mortality associated with hyponatremia in HFrEF patients could partly be driven by hemodynamic derangement.
... Some studies have shown increased levels of renin, angiotensin II, aldosterone, epinephrine, norepinephrine, and dopamine in patients with HF and hyponatremia compared to those with HF and normonatremia. [16][17][18][19] Hyponatremia may also be a predictor of higher neurohormonal activation that suggests HF severity. 4 Diuretics, especially thiazides, often result in hyponatremia, which promotes water retention due to enhanced AVP activation in the distal tubules. ...
Resumo Fundamento A coexistência de hiponatremia e fibrilação atrial (FA) aumenta a morbidade e mortalidade em pacientes com insuficiência cardíaca (IC). No entanto, não está estabelecido se a hiponatremia está relacionada à FA ou não. Objetivo O objetivo do nosso estudo foi buscar a possível associação de hiponatremia com FA em pacientes que apresentam IC com fração de ejeção reduzida (ICFrE). Métodos Este estudo observacional, transversal e unicêntrico incluiu 280 pacientes ambulatoriais consecutivos com diagnóstico de ICFr com 40% ou menos. Com base nas concentrações de sódio ≤135 mEq/L ou superior, os pacientes foram classificados em hiponatremia (n=66) e normonatremia (n=214). Um valor de p
... 11,12 In addition, hyponatraemia is associated with longer hospital stay, and predicts higher rates of early rehospitalization and death. 3,4,13,14 . Therapeutic approaches to hyponatraemia have traditionally included fluid restriction, hypertonic saline, and loop diuretics. ...
AIMS: Arginine vasopressin (AVP) V(2) receptor antagonism is a new approach to the management of hyponatraemia in congestive heart failure (CHF). The aim of this study was to investigate the efficacy and safety of satavaptan, an oral AVP V(2)-receptor antagonist, in patients with dilutional hyponatraemia.
METHODS AND RESULTS: A total of 118 patients (90 with CHF) with dilutional hyponatraemia (serum sodium 115-132 mmol/L) were randomized to double-blind treatment with placebo or to 25 or 50 mg/day of satavaptan for 4 days, followed by non-comparative open-label satavaptan therapy for up to 343 days. The response rate (sodium ≥ 135 mmol/L and/or an increase in ≥ 5 mmol/L above baseline) was significantly higher with satavaptan 50 mg than with placebo (61.0 vs. 26.8%; P= 0.0035), with a trend towards significance with satavaptan 25 mg (48.6%, P= 0.0599). Median times to response were 3.30 and 2.79 days with satavaptan 25 and 50 mg/day, respectively, both shorter than placebo (>4 days; P= 0.0278 and P= 0.0004, respectively). Satavaptan therapy was effective in CHF patients, with response rates higher with both satavaptan 25 mg/day (53.6%) and 50 mg/day (57.1%) than with placebo (23.5%; P= 0.019 and P= 0.009, respectively). Sodium responses were maintained during open-label therapy after a temporary study drug discontinuation period. Higher rates of adverse events occurred with the 50 mg/day dose, including rapid correction of hyponatraemia.
CONCLUSIONS: In patients with dilutional hyponatraemia, V(2) receptor antagonism with satavaptan was effective in increasing serum sodium concentrations. The long-term open-label treatment results demonstrate sustained efficacy of satavaptan in maintaining normal sodium levels. Trial Registration clinicaltrials.gov Identifier: NCT00274326.
... The SNS activation helps to maintain circulatory homeostasis and perfusion to vital organs by increasing inotropy and chronotropy of the failing myocardium and by modulating vascular reaction. In the long term, these mechanisms as well as the RAAS activation are maladaptive and responsible for disease progression [14][15][16]. ...
Electrolyte and acid-base abnormalities are a frequent and potentially dangerous complication in subjects with congestive heart failure. This may be due either to the pathophysiological alterations present in the heart failure state leading to neurohumoral activation (stimulation of the renin-angiotensin-aldosterone system, sympathoadrenergic stimulation), or to the adverse events of therapy with diuretics, cardiac glycosides, and ACE inhibitors. Subjects with heart failure may show hyponatremia, magnesium, and potassium deficiencies; the latter two play a pivotal role in the development of cardiac arrhythmias. The early identification of these alterations and the knowledge of the pathophysiological mechanisms are very useful for the management of these patients.
... From large studies of sodium concentrations and heart failure, it is known that hyponatremia is more common in severe heart failure [33e35]. Low serum sodium levels have been repeatedly described as a predictor of adverse short-term outcomes [4e6, 35,36]. Hyponatremia is a predictor of hospital mortality in patients with heart failure. ...
Background
Dysnatremia is a frequent finding in patients with community acquired pneumonia (CAP) and a predictor of mortality. We studied the relation between dysnatremia, comorbidities and CT-pro-AVP and MR-proANP.
Methods
We enrolled 2138 patients (60 ± 18 years, 55% male) with CAP from the CAPNETZ database. Pro-atrial natriuretic peptide (proANP), pro-vasopressin (proAVP), serum sodium and CRB-65 score were determined on admission. Patients were followed up for 28 days. Sodium concentration on admission was examined as a function of mortality at 28 days. Hyponatremia (HypoN) was defined as admission serum sodium <136 mmol/L, hypernatremia (HyperN) as admission serum sodium > 145 mmol/L.
Results
HypoN was diagnosed in 680 (31.8%) patients, HyperN in 29 (1.4%) patients. Comorbidities were associated with sodium levels, and CT-pro-AVP and MR-proANP were inversely related to sodium levels. Patients with HypoN were older, had a higher CRB-65 score and higher values of CT-proAVP and MR-proANP (all p< 0.05). When examined as a function of sodium values, a U-shaped association was found between sodium levels and 28 day mortality. In multivariate Cox proportional hazards analysis, HypoN and HyperN were independent predictors of 28 day mortality. Sodium levels added to the predictive potential of proAVP and proANP.
Conclusion
HypoN is common at admission among CAP patients and is independently associated with mortality. HyperN is rare at admission among CAP patients but is also independently associated with mortality. The combination of sodium and CT-pro-AVP and MR-proANP levels achieved the highest prediction of mortality.
... In agreement with the above mechanisms patients with heart failure and hyponatremia have higher levels of plasma renin, angiotensin Ⅱ, aldosterone, epinephrine, norepinephrine, and dopamine compared with patients with normal sodium levels [40,53,54] . It has been shown that heart failure patients exhibit increased AVP production and generally a dysregulation of AVP characterised by an elevation of its levels despite the presence of volume overload, atrial distension and low plasma osmolality [55][56][57][58][59][60][61] . ...
The present review analyses the mechanisms relating heart failure and hyponatremia, describes the association of hyponatremia with the progress of disease and morbidity/mortality in heart failure patients and presents treatment options focusing on the role of arginine vasopressin (AVP)-receptor antagonists. Hyponatremia is the most common electrolyte disorder in the clinical setting and in hospitalized patients. Patients with hyponatremia may have neurologic symptoms since low sodium concentration produces brain edema, but the rapid correction of hyponatremia is also associated with major neurologic complications. Patients with heart failure often develop hyponatremia owing to the activation of many neurohormonal systems leading to decrease of sodium levels. A large number of clinical studies have associated hyponatremia with increased morbidity and mortality in patients hospitalized for heart failure or outpatients with chronic heart failure. Treatment options for hyponatremia in heart failure, such as water restriction or the use of hypertonic saline with loop diuretics, have limited efficacy. AVP-receptor antagonists increase sodium levels effectively and their use seems promising in patients with hyponatremia. However, the effects of AVP-receptor antagonists on hard outcomes in patients with heart failure and hyponatremia have not been thoroughly examined.
... Blood pressure declines without symptoms in nearly every patient treated with an ACEI, so hypotension is generally a concern only if it is accompanied by postural symptoms, worsening renal function, blurred vision, or syncope. Hypotension is seen most frequently during the first few days of initiation of increments in therapy, particularly in patients with hypovolemia, a recent marked diuresis, or severe hyponatremia (serum sodium concentration less than 130 mmol per liter) (212). Should symptomatic hypotension occur with the first doses, it may not recur with repeated administration of the same doses of the drug. ...
... 33 In addition, hyponatraemia identifies patients with intense activation of neurohormonal systems that directly affect renal haemodynamics. 31,34,35 Neurohormonal activation serves to preserve renal function in low-flow states, because angiotensin II has a direct constrictor effect on post-glomerular efferent arterioles which acts to increase the filtration fraction. 8 Moreover, in hyponatraemic patients, the responses of neurohormones and regional blood flow to orthostatic stress are greatly attenuated, 31 suggesting that neurohormonal pathways are already maximally challenged. ...
The acute (type 1) cardio-renal syndrome (CRS) refers to an acute worsening of heart function leading to worsening renal function (WRF), and frequently complicates acute decompensated heart failure (ADHF) and acute myocardial infarction (AMI). The aim of this study was to investigate whether hyponatraemia, a surrogate marker of congestion and haemodilution and of neurohormonal activation, could identify patients at risk for WRF.
We studied the association between hyponatraemia (sodium <136 mmol/L) and WRF (defined as an increase of >0.3 mg/dL in creatinine above baseline) in two separate cohorts: patients with ADHF (n = 525) and patients with AMI (n = 2576). Hyponatraemia on admission was present in 156 patients (19.7%) with ADHF and 461 patients (17.7%) with AMI. Hyponatraemia was more frequent in patients who subsequently developed WRF as compared with patients who did not, in both the ADHF (34.6% vs. 22.2%, P = 0.0003) and AMI (29.7% vs. 21.8%, P<0.01) cohorts. In a multivariable logistic regression model, the multivariable adjusted odds ratio for WRF was 1.90 [95% confidence interval (CI) 1.25-2.88; P = 0.003] and 1.56 (95% CI 1.13-2.16; P = 0.002) in the ADHF and AMI cohorts, respectively. The mortality risk associated with hyponatraemia was attenuated in the absence of WRF.
Hyponatraemia predicts the development of WRF in two clinical scenarios that frequently lead to the type I CRS. These data are consistent with the concept that congestion and neurohormonal activation play a pivotal role in the pathophysiology of acute cardio-renal failure.
... 12 These beneficial effects of ACE inhibitor or ARB therapy are seen as long as cardiac output remains adequate for renal perfusion. In this regard, hyponatremic patients with HF are typically more susceptible to the hypotensive and azotemic effects of ACE inhibitors, 3,8 probably because they are both more ill and are overly dependent on the markedly activated RAAS for maintenance of systemic blood pressure (BP) and renal perfusion. Thus, when these RAAS-inhibiting drugs are used, mean arterial pressure should be kept >60-65 mm Hg and even higher if significant renal arterial disease is present. ...
Hyponatremia as it occurs in the heart failure patient is a multifactorial process. The presence of hyponatremia in the heart failure patient correlates with both the severity of the disease and its ultimate outcome. The therapeutic approach to the treatment of hyponatremia in heart failure has traditionally relied on attempts to improve cardiac function while at the same time limiting fluid intake. In more select circumstances, hypertonic saline, loop diuretics, and/or lithium or demeclocycline have been used. The latter two compounds act by retarding the antidiuretic effect of vasopressin but carry with their use the risk of serious renal and/or cardiovascular side effects. Alternatively, agents that selectively block the type 2 vasopressin receptor increase free water excretion without any of the adverse consequences of other therapies. Conivaptan, lixivaptan, and tolvaptan are three such aquaretic drugs. Vasopressin receptor antagonists will redefine the treatment of heart failure-related hyponatremia and may possibly evolve as adjunct therapies to loop diuretics in diuretic-resistant patients.
The first dedicated multidisciplinary heart failure program in the US was founded as the Division of Circulatory Physiology at the Columbia University College of Physicians & Surgeons in 1992. The Division was administratively and financially independent of the Division of Cardiology and grew to 24 faculty members at its peak. Its administrative innovations included (1) a comprehensive full-integrated service line, with two differentiated clinical teams, one devoted to drug therapy and the other to heart transplantation and ventricular assist devices; (2) a nurse specialist/physician assistant-led clinical service; and (3) a financial structure independent of (and not supported by) other cardiovascular medical or surgical services. The Division had three overarching missions: (1) to promote a unique career development path for each faculty member to be linked to recognition in a specific area of heart failure expertise; (2) to change the trajectory and enhance the richness of intellectual discourse in the discipline of heart failure, so as to foster an understanding of fundamental mechanisms and to develop new therapeutics; and (3) to provide optimal medical care to patients and to promote the ability of other physicians to provide optimal care. The major research achievements of the Division included: (1) the development of beta-blockers for heart failure, from initial hemodynamic assessments to proof-of-concept studies to large-scale international trials; (2) the development and definitive assessment of flosequinan, amlodipine and endothelin antagonists; (3) initial clinical trials and concerns with nesiritide; (4) large-scale trials evaluating dosing of angiotensin converting-enzyme inhibitors and the efficacy and safety of neprilysin inhibition; (5) identification of key mechanisms in heart failure, including neurohormonal activation, microcirculatory endothelial dysfunction, deficiencies in peripheral vasodilator pathways, noncardiac factors in driving dyspnea, and the first identification of subphenotypes of heart failure and a preserved ejection fraction; (6) the development of a volumetric approach to the assessment of myocardial shortening; (7) conceptualization and early studies of cardiac contractility modulation as a treatment for heart failure; (8) novel approaches to the identification of cardiac allograft rejection and new therapeutics to prevent allograft vasculopathy; and (9) demonstration of the effect of left ventricular assist devices to induce reverse remodeling, and the first randomized trial showing a survival benefit with ventricular assist devices. Above all, the Division served as an exceptional incubator for a generation of leaders in the field of heart failure.
Methodology has been developed to evaluate the efficacy and toxicity of two angiotensin converting enzyme (ACE) inhibitors when either was used as an adjuvant to digoxin and diuretic therapy in the treatment of frail elderly heart failure patients. In an open study of enalapril only 11/17 patients mean (SD) age 83 (5) y tolerated its cautious introduction (1 patient died despite uneventful introduction of enalapril). Compliance (pill counts) was excellent in the 9/10 patients continued in the trial. When the functional ability was assessed in a symptom limited walking test (SWT), there was nearly a three-fold increase in distance walked and a two-fold increase in walking speed within one week of starting enalapril. Although performance was maintained at this level for at least 3 months, the patients actually reported a worsening of some of their symptoms. Furthermore, beyond 3 months 8/10 patients experienced adverse effects which necessitated the withdrawal of enalapril. The benefits of captopril an ACE inhibitor with a shorter plasma half-life were examined in a randomised, placebo-balanced, crossover trial. Twenty-six patients, mean (SD) age 82 (6) were recruited. Adverse effects led to withdrawal of captopril in 6 patients in the pre-trial period. Compliance (monitored "pill box") was excellent in the remaining 20 patients who were entered into the trial. This consisted of 3 treatment periods, a twice daily dosage of captopril established during a titration period, once daily captopril (half the above), and the placebo, each treatment period lasting for 3 weeks. Functional ability was assessed by gait analysis (GA) and SWT. Walking tended to be best on the once daily captopril treatment and worst on placebo. When the effects of serum ACE activity and blood pressure were taken into account in a linear model a statistically significant (P=0.04) treatment effect on SWT distance was revealed. No such effect was observed on oxygen consumption or ventilation volume in a tailored exercise protocol. Plasma atrial natriuretic factor (ANF) reflects the degree of cardiac compromise. An analytical method was developed to measure ANF in human plasma. Pre-exercise levels of ANF were significantly lower on the captopril treatments than on placebo, but still remained four-fold higher in patients than in 11 healthy age-matched subjects. Furthermore, unlike the control group, there was no apparent increase in ANF response to exercise in the patients. On completing the crossover study patients entered an open study on twice daily captopril. A slight deterioration in gait was observed in these patients after 3 months. Captopril appeared to be relatively well tolerated during the trial: only 3/20 patients (1 during the crossover, 2 during the open study), experienced adverse effects which led to the withdrawal of captopril.
Objectives:
Hyponatremia and atrial fibrillation (AF) have been established as strong predictors for worse clinical outcomes for patients with heart failure (HF). However, less is known about the hyponatremia in relation to the occurrence of AF. This study aims to investigate the possible relationship between hyponatremia and AF in patients with chronic HF and reduced ejection fraction (HFrEF).
Methods:
Turkish research team-HF (TREAT-HF) is a network that has been undertaking multicenter, observational cohort studies in HF. A total of 880 patients who had plasma sodium measurement in TREAT-HF dataset were included in this study. Hyponatremia was defined as a plasma sodium level of ≤135 mmol/L. The patients were classified into hyponatremia (n=213) or normonatremia (n=667) based on the sodium level.
Results:
The rate of AF was found 33.3% in patients with hyponatremia and 18.8% in patients with normonatremia (p<0.001). Univariate analysis demonstrated an association between hyponatremia and AF. Furthermore, in multivariate logistic regression model, hyponatremia was also found to be significantly and independently associated with occurrence of AF (OR=2.457, 95% CI= 1.586-3.806, p<0.001) in addition to other well-known risk factors for AF.
Conclusion:
The results of this study showed that AF was more prevalent in HFrEF outpatients with hyponatremia than those with normonatremia. These results also suggest that hyponatremia is independently associated with occurrence of AF.
When undertaken in the setting of an intensive care unit (ICU), the therapeutic goals for patients suffering from severe heart failure are to immediately increase cardiac output without exacerbating or precipitating myocardial ischemia and to distribute the enhanced cardiac output to the kidneys, heart and brain.
When cardiac output falls after an insult to the myocardium, several neurohormonal mechanisms are activated in an attempt to preserve circulatory homeostasis. These mechanisms include both endogenous vasoconstrictor systems (sympathetic nervous system, reninangiotensin system, and vasopressin) that act to increase systemic blood pressure and expand intravasular volume, and endogenous vasodilator systems (atrial natriuretic peptide and prostaglandins) that limit the pressor, antinatriuretic, and antidiuretic effects of the vasoconstrictor systems.1 The hemodynamic and metabolic abnormalities in heart failure result in large part from the complex interplay of these neurohormonal forces, which regulate systemic and regional blood flow as well as salt and water balance.
The medical management of patients with chronic congestive heart failure (CHF) has evolved considerably over the last two decades. In addition to the availability of new agents with proven clinical efficacy, we now know a great deal more about where and when to use (or sometimes avoid) traditional drugs like digoxin and diuretics. It is not happenstance that changes in therapeutics were preceded by and, in some instances developed in tandem with, advances in our understanding of the pathogenesis of myocardial dysfunction and the integrated series of events that give rise to the clinical syndrome of CHF. In addition, within the past 5 yr the results of a remarkable series of well designed clinical trials have provided guidelines for the medical management of a wide variety of patients with left ventricular (LV) dysfunction. Although CHF remains an extremely serious illness, the advances in our understanding of the pathophysiology and treatment described in this text have resulted in both longer and more enjoyable lives for patients who suffer from this syndrome.
The treatment of congestive heart failure is a challenge for modern medicine. Despite the fact that digitalis was introduced into therapy 200 years ago and vasodilators have been used for the last 15 years, the outcome of overt heart failure is still bad [1]. Therefore, many efforts have been undertaken in order to develop new inotropes, but only in recent years have a number of promising compounds emerged. The present article reviews the different action of new inotropic compounds on the myocardium, and the results of first clinical trials are presented.
Ischaemic heart disease is the commonest cause of death in developed countries, and is among the most frequent causes of morbidity. This remains true despite the decline in cardiovascular mortality during the last two decades in certain countries of the world. Since 1968, declining trends have been observed in some industrialized countries, such as the United States, Australia and Finland.1,2. Other countries, notably England and Wales, have not shown a decline until 1979 when a cautious downward trend appeared3. Recent papers from Sweden indicate an increase in coronary mortality4,5.
Die Herzinsuffizienz ist nach wie vor eine therapeutische Herausforderung. Die Herausforderung besteht darin, daß der Zustand der Herzinsuffizienz vielfältig ausgeprägt sein kann und die Krankheit individuell sehr variable verläuft. Der Therapeut muß diejenigen Faktoren erkennen, die eventuell korrigiert werden können, wobei vorrangig die Erhaltung der Integrität des Myokards steht. Er hat ferner zu beachten, daß jeder Zustand einer chronischen Herzinsuffizienz den Keim zur Progredienz in sich trägt, gleichgültig, welche Ursache die zugrundeliegende Herzerkrankung hat.
Despite many years of use and numerous investigations regarding its clinical efficacy, the utility of prazosin in the management of severe chronic heart failure remains undefined. Initial reports indicated that the drug produced marked increases in cardiac output and decreases in left ventricular filling pressure and systemic vascular resistance [11], and these benefits were accompanied by long-term amelioration of dyspnea and fatigue [1]. Unfortunately, these initial reports largely evaluated only the hemodynamic effects of first doses of prazosin; subsequent reports indicated that repeated administration of the drug was accompanied by a rapid loss of hemodynamic efficacy, such that there was no notable effect seen after 48h of continuous administration [12]. The importance of this short-term hemodynamic “tachyphylaxis” remained largely unknown, however, since numerous reports indicated that the drug produced long-term hemodynamic and clinical benefits [1, 3, 5, 8, 9]. These investigators, however, did not keep the dose of concomitantly administered diuretics constant and thus could not distinguish between the hemodynamic benefits attributable to prazosin from those resulting from changes in diuretic therapy. Previous reports also did not generally withdraw prazosin at the end of the trial in order to determine whether or not the drug exerted persistent long-term effects.
The angiotensin converting enzyme (ACE) inhibitors constitute a major breakthrough in the medical management of congestive heart failure. The incidence of side effects with these agents is surprisingly low when they are used in the appropriate dosage. They produce sustained beneficial hemodynamic and symptomatic improvement in most patients with congestive heart failure and may produce greater symptomatic benefit than digoxin when given as second-line therapy to patients with heart failure on diuretics. Their neurohumoral effects generally are advantageous, resulting in normalization of sodium and potassium balance and a reduction in ventricular arrhythmias. The ACE inhibitors may improve survival in patients with congestive heart failure, and recent data suggest that they may prevent or delay the development of left ventricular dilatation and overt heart failure in patients with asymptomatic left ventricular dysfunction
The treatment of congestive heart failure (CHF) has undergone significant changes in recent years.1 This has occurred as a result of both our improved understanding of the hemodynamic and neurohormonal alterations that underlie the pathophysiology of CHF and the availability of new therapeutic agents. In particular, heart failure is now recognized as a complex syndrome, involving the central and peripheral circulations, neuro-hormonal responses, and alterations of renal and skeletal muscle function, rather than a simple hemodynamic derangement.2 In this chapter we review the neuroendocrine changes that characterize CHF and focus on the use of angiotensin-converting enzyme (ACE) inhibition in its treatment. This discussion is limited to CHF resulting from left ventricular systolic dysfunction, characterized by reduced indices of contractility and left ventricular dilatation. CHF resulting from left ventricular diastolic dysfunction, although now more commonly recognized than previously, is beyond the scope of this chapter.
The presence of hyponatremia has been perceived to increase the risk of adverse events on initiation of treatment with angiotensin-converting enzyme inhibition in heart failure patients. The aim of this study was to investigate if baseline hyponatremia (plasma Na(+) <135 mmol/L) predicts development of hypotension and renal impairment in patients with myocardial infarction (MI) and left ventricular dysfunction (LVD) treated with angiotensin-converting enzyme inhibitors.
A retrospective analysis was performed with data from the Trandolapril Cardiac Evaluation (TRACE) a double-blind randomized study. Plasma sodium levels were available in 1,731 patients, who were considered as the study population. Patients 3-7 days after MI with left LVD (LVEF ≤0.35), were randomized to trandolapril (n = 876) or placebo (n = 873). Baseline hyponatremia did not predict development of hypotension or worsening renal function after 1 month in patients treated with trandolapril compared with placebo (122 ± 19.1 mm Hg vs 123.2 ± 20.4 mm Hg [P = .84]; and creatinine clearance 57.4 ± 21.4 mL/min vs 55.2 ± 21.0 mL/min [P = .8]). There was no interaction between hyponatremia and the effect of trandolapril (P = .68).
Mild hyponatremia was not a contraindication for the initiation of treatment with angiotensin-converting enzyme inhibitors in patients with post-MI heart failure.
Despite its detrimental effects on cardiac function, the renin-angiotensin system plays a pivotal role in some patients with severe heart failure. Although many patients will benefit from long-term converting enzyme inhibition, others may be quite susceptible to interference with an important mechanism that has evolved to preserve cerebral and renal function and electrolyte balance. Identification of patients with heart failure who are at greatest risk of developing adverse effects from captopril and enalapril is a worthwhile goal, but clinical experience has not provided the means to do so. Although hyponatremia identifies those patients most likely to experience symptomatic hypotension during the initiation of therapy, there are no means of predicting who will develop symptomatic hypotension, worsening azotemia or hyperkalemia during long-term converting enzyme inhibition, probably because changes in diuretic therapy and in dietary sodium intake continually modify each patient's dependence on angiotensin II in maintaining circulatory homeostasis. Consequently, patients treated with captopril and enalapril need to be advised about the risk of symptomatic hypotension and require periodic biochemical evaluation to detect drug-related azotemia and hyperkalemia; if such adverse events are observed, patients should be instructed to reduce the dose of diuretic drugs or avoid sources of supplemental potassium (salt substitutes). In this regard, converting enzyme inhibitors that are short-acting may have an important advantage over longer-acting agents, because long-term hemodynamic and clinical improvement does not appear to require continuous angiotensin II suppression, but the frequency and severity of adverse effects (hypotension, azotemia and hyperkalemia) may be reduced by permitting brief restoration of the homeostatic actions of the renin-angiotensin system. There is a price for interfering with evolution. Trying to interrupt the detrimental hemodynamic actions of the renin-angiotensin system while simultaneously striving to preserve its beneficial circulatory functions may become an exacting challenge for the clinician treating the individual patient with congestive heart failure, a challenge that requires the continuous reevaluation of dietary sodium intake, dose of diuretic drug and dose and type of converting enzyme inhibitor. For some patients, amelioration of dyspnea can only be achieved at the cost of worrisome hypotension and considerable (albeit usually asymptomatic) deterioration of renal function.
Approximately 5 million people in the United States have heart failure (HF), with an additional 500,000 getting diagnosed with HF each year. 1 Nearly a million people were hospitalized with HF as the primary diagnosis in 1999, with up to twice the number being hospitalized with HF as a secondary diagnosis. 2 Despite recent declines, the HF hospitalization rate remains >2000/100,000 person-years among Medicare beneficiaries as of 2008, with a 1-year mortality of 29.6%. 3 Many of these patients will present to the operating room, presenting challenges to the anesthesiologists, as HF is one of the major clinical predictors of perioperative adverse cardiac events.4 This article reviews nonsurgical therapy for HF and specifically addresses medication therapy, cardiac resynchronization, and the use of implantable cardioverter-defibrillator (ICD) in HF patients.
The pathophysiology of congestive heart failure (CHF) includes conditions (e.g., activation of the renin-angiotensin-aldosterone system) which, when combined with CHF therapies, make patients afflicted with this syndrome quite susceptible to electrolyte disturbances. The most commonly encountered are hyponatremia, hypokalemia, and hypomagnesemia. These derangements are of vast clinical importance; their development not only represents an immediate threat to the CHF patient (e.g., dysrhythmias secondary to hypokalemia), but are also indicative of underlying pathophysiologic events, an unfavorable clinical course, and occasionally an adverse therapeutic response. The optimal care of the CHF patient includes the recognition and management of these electrolyte disturbances.
Heart failure is a clinical syndrome characterized by exertional fatigue, exertional dyspnea, or both related to cardiac dysfunction.1 It is commonly accompanied by circulatory congestion manifested by edema in the lungs or extremities and by ventricular arrhythmias
(Fig. 62.1). Heart failure may be precipitated by acute events that disturb the structure or function of the ventricular chambers
or by chronic cardiac disease that eventuates in the clinical syndrome. The distinction between cardiac and noncardiac causes
of the symptomatology depends on the clinical demonstration of altered cardiac structure or impaired cardiac function. This
may be accomplished at the bedside, sometimes with assistance from a blood test for natriuretic hormone level, in the cardiac
catheterization laboratory, or by the use of a variety of imaging techniques. Since the clinical syndrome is often preceded
by months or years of relatively asymptomatic cardiac dysfunction, it is appropriate to encompass the preclinical phase with
consideration of the overall syndrome, as has been done in recent guidelines. Thus semantic rigor mandates confining the diagnosis
of heart failure to the symptomatic state, but recognition of the functional and structural cardiac disorder that leads to
the syndrome provides an opportunity for prevention rather than treatment.
The elderly are at risk of developing hyponatraemia because of age related changes in renal function and body composition. Factors regulating sodium and water balance in the elderly are reviewed with emphasis on iatrogenic factors. Since rapid reversal of hyponatraemia may cause neurological damage in some patients, the optimum rate of correction is discussed.
Heart failure due to a decline in cardiac performance initiates compensatory neurohormonal mechanisms in an effort to maintain
systemic perfusion. Ongoing neurohormonal activation may have deleterious consequences for cardiac performance, ventricular
remodeling, myocardial function, and heart failure progression. The fundamental objective of modern medical therapy for heart
failure is to relieve symptoms (largely through relief of volume overload) and to stall (or even reverse) disease progression
through combined utilization of neurohormonal antagonists that help to restore normal hemodynamics, maintain normal plasma
volume, and prevent ventricular enlargement. This chapter focuses on the key elements of medical therapy for heart failure.
Key WordsHeart failure-Medical therapy-Neurohormones-Renin– angiotensin system-Digitalis-Systolic dysfunction-Remodeling-Hemodynamics
Congestive heart failure is a lethal condition that affects an increasing number of patients. In recent years a great amount of data have accumulated on the pathophysiology and medical and surgical therapy of this condition. In spite of the advances in its management and the great number of patients affected, common errors are still made by internists and cardiologists in the use of drugs and therapeutic strategies. Digitalis has only recently been shown to affect hemodynamics, exercise capacity, and clinical symptoms, but the effects on survival still have to be demonstrated. Loop diuretics, eventually combined with thiazides and antialdosterone drugs in patients with clinical signs and symptoms of fluid retention, are the mainstays of therapy of congestive heart failure. In order to make diuretic therapy efficacious, moderate salt and water intake restriction is mandatory. Angiotensin-converting enzyme (ACE) inhibitors are now considered unavoidable drugs in the management of heart failure, and an attempt to reach the doses that have been shown to be efficacious for survival in the large trials has to be made in every patient with this condition. Other vasodilators, such as hydralazine and nitrates, which show a less pronounced effect on survival but more effective hemodynamic actions than ACE inhibitors, may be used to control mitral insufficiency or to improve hemodynamics in very sick patients. Hemodynamic instability refractory to increasing doses of vasodilators and diuretics is a severe condition that requires hospital admission to administer drugs parenterally. These patients are usually treated with the combination of catecholamines and phosphodiesterase inhibitors associated with intravenous diuretics until clinical stability is again achieved and oral therapy is resumed and restructured. The use of aggressive pharmacological therapy and phosphodiesterase inhibitors has reduced the need for assisted circulatory support in these patients. Beta-blockers have shown promising results when administered to patients with heart failure, although a definitive demonstration of their effects on survival is still lacking. Other additional measures that need to be considered in patients with end-stage congestive heart failure are the use of antiarrhythmic drugs and anticoagulation.
The major electrolyte disorders of CHF are hyponatremia, hypokalemia and hypomagnesemia. The pathophysiology of CHF itself fosters the development of these disorders, and diuretic therapy, required in the management of most CHF patients, greatly enhances the prevalence and severity of these electrolyte disturbances. In addition to reflecting important underlying pathophysiologic processes (eg, intense neurohormonal activation), the clinical relevance of the major electrolyte disorders in CHF resides in their association with a less favorable cardiac-hemodynamic status and clinical course and in their role of provoking severe or catastrophic events (eg, syncope, sudden death). In the life-threatening milieu of CHF (eg, diseased myocardium, high sympathetic tone), the recognition and treatment of hyponatremia, hypokalemia and hypomagnesemia represent important aspects in the optimal management of this condition. Although electrolyte abnormalities represent just one aspect of the management of CHF, more research is needed in this area. Information is not complete in human CHF regarding the mechanisms for their development, their full clinical significance and so forth. In addition, the metabolism, status, role and clinical significance of other ions (eg, calcium, iron, trace elements) are virtually unexplored in human CHF.
Electrolyte disturbances are a common complication of CHF. CHF provides a perfect milieu for the development of these disturbances; renal dysfunction, elevation of neurohormonal substances, activation of the renin-angiotensin-aldosterone axis, and diuretic therapy represent the major contributory factors. Hyponatremia is closely aligned with an unfavorable clinical course. Hypokalemia is associated with increased ventricular dysrhythmias. Hypomagnesemia noted in advanced CHF can be accompanied by arrhythmias and refractory hypokalemia. CHF also offers the ideal milieu (diseased, ischemic, and arrhythmogenic myocardium; elevated catecholamines; and arrhythmogenic drugs) for the threatening clinical consequences (clinical deterioration, dysrhythmias, or death) of these disturbances. These consequences underscore the importance of the recognition, appreciation, and management of these electrolyte abnormalities.
Hyponatraemia has been reported to be a potent predictor of poor outcome in patients hospitalized for heart failure (HF). The aim of the study was to determine the prevalence and prognostic significance of hyponatraemia in a large cohort of HF outpatients followed in clinics participating in the Danish Heart Failure Clinics Network.
The study population consisted of consecutive patients referred for HF management in 18 Danish heart failure clinics. Overall, 2863 patients (83%) had a normal plasma sodium (p-sodium) level and 602 patients (17%) had hyponatraemia with a p-sodium level <136 mmol/L. Outcome data were obtained from a validated, national registry. Patients were elderly with a mean age of 68 years. The mean P-[Na+] was 139.6 ± 2.4 mmol/L among patients with normonatraemia and 132.4 ± 3.2 mmol/L among patients with hyponatraemia. In multivariate Cox Proportional Hazard Models adjusted for confounders (age, gender, hospitalization within the last 90 days, loop diuretics, creatinine level, systolic blood pressure, New York Heart Association class III-IV, left ventricular ejection fraction <0.46, ischaemic heart disease and diabetes) hyponatraemic patients had increased risk of hospitalization or death [hazard ratio (HR) 1.2 (95% confidence interval (CI) 1.0-1.4, P = 0.011)]. Hyponatraemia was also an independent predictor of all-cause mortality [HR 1.5 (95% CI 1.2-1.9, P< 0.001)]. There was no interaction between hyponatraemia and the covariables on outcome in the multivariable models.
The presence of hyponatraemia in outpatients with HF is associated with increased risk of hospitalization or death.
Arginine vasopressin (AVP) V(2) receptor antagonism is a new approach to the management of hyponatraemia in congestive heart failure (CHF). The aim of this study was to investigate the efficacy and safety of satavaptan, an oral AVP V(2)-receptor antagonist, in patients with dilutional hyponatraemia.
A total of 118 patients (90 with CHF) with dilutional hyponatraemia (serum sodium 115-132 mmol/L) were randomized to double-blind treatment with placebo or to 25 or 50 mg/day of satavaptan for 4 days, followed by non-comparative open-label satavaptan therapy for up to 343 days. The response rate (sodium ≥ 135 mmol/L and/or an increase in ≥ 5 mmol/L above baseline) was significantly higher with satavaptan 50 mg than with placebo (61.0 vs. 26.8%; P= 0.0035), with a trend towards significance with satavaptan 25 mg (48.6%, P= 0.0599). Median times to response were 3.30 and 2.79 days with satavaptan 25 and 50 mg/day, respectively, both shorter than placebo (>4 days; P= 0.0278 and P= 0.0004, respectively). Satavaptan therapy was effective in CHF patients, with response rates higher with both satavaptan 25 mg/day (53.6%) and 50 mg/day (57.1%) than with placebo (23.5%; P= 0.019 and P= 0.009, respectively). Sodium responses were maintained during open-label therapy after a temporary study drug discontinuation period. Higher rates of adverse events occurred with the 50 mg/day dose, including rapid correction of hyponatraemia.
In patients with dilutional hyponatraemia, V(2) receptor antagonism with satavaptan was effective in increasing serum sodium concentrations. The long-term open-label treatment results demonstrate sustained efficacy of satavaptan in maintaining normal sodium levels. Trial Registration clinicaltrials.gov Identifier: NCT00274326.
Hypervolemia and hyponatremia resulting from activation of the neurohormonal system and impairment of renal function are prominent features of decompensated heart failure. Both conditions share many pathophysiologic and prognostic features and each has been associated with increased morbidity and mortality. When both conditions coexist, therapeutic options are limited.
This review presents a concise digest of the pathophysiology, clinical significance, and pharmacological therapy of hyponatremia complicating heart failure with a special emphasis on vasopressin antagonists and their aquaretic effects in the absence of neurohormonal activation along with their ability to correct hyponatremia.
Hypervolemia and hyponatremia share many pathophysiologic and prognostic features in heart failure. Vasopressin antagonists provide a viable option for their management and a potentially unique role when both conditions coexists.
To determine whether renal prostaglandins participate in the regulation of renal blood flow during acute reduction of cardiac output, cardiac venous return was decreased in 17 anesthetized dogs by inflating a balloon placed in the thoracic inferior vena cava. This maneuver decreased cardiac output from 3.69+/-0.09 liters/min (mean+/-SEM) to 2.15+/-0.19 liters/min (P < 0.01) and the mean arterial blood pressure from 132+/-4 to 111+/-5 mm Hg (P < 0.01) and increased total peripheral vascular resistance from 37.6+/-2.5 to 57.9+/-4.8 arbitrary resistance units (RU) (P < 0.01). In marked contrast, only slight and insignificant decreases in the renal blood flow from 224+/-16 to 203+/-19 ml/min and renal vascular resistance from 0.66+/-0.06 to 0.61+/-0.05 arbitrary resistance units (ru) were observed during inflation of the balloon. Concomitant with these hemodynamic changes, plasma renin activity and plasma norepinephrine concentration increased significantly in both the arterial and renal venous bloods. Plasma concentration of prostaglandin E(2) in renal venous blood increased from 34+/-6 to 129+/-24 pg/ml (P < 0.01). The subsequent administration of indomethacin or meclofenamate had no significant effect on mean arterial pressure, cardiac output, and total peripheral vascular resistance, but reduced renal blood flow from 203+/-19 to 156+/-21 ml/min (P < 0.01) and increased renal vascular resistance from 0.61+/-0.05 to 1.05+/-0.21 ru (P < 0.01). Simultaneously, the plasma concentration of prostaglandin E(2) in renal venous blood fell from 129+/-24 to 19+/-3 pg/ml (P < 0.01). Administration of indomethacin to five dogs without prior obstruction of the inferior vena cava had no effect upon renal blood flow or renal vascular resistance. The results indicate that acute reduction of cardiac output enhances renal renin secretion and the activity of the renal adrenergic nerves as well as renal prostaglandin synthesis without significantly changing renal blood flow or renal vascular resistance. Inhibition of prostaglandin synthesis during acute reduction of cardiac output results in an increased renal vascular resistance and reduced renal blood flow. Accordingly, that data provide evidence that renal prostaglandins counteract in the kidney the vasoconstrictor mechanisms activated during acute reduction of cardiac output.
The factors that might activate the renin-angiotensin system in treated heart failure were explored. Serum Na+ correlated inversely with plasma renin activity. The degree of congestive heart failure measured by right atrial pressure, pulmonary capillary wedge pressure, cardiac index, and systemic vascular resistance did not correlate with plasma renin activity. Similarly, renal function as measured by blood urea nitrogen, creatinine, and urinary Na+ excretion did not correlate with plasma renin activity. In a prospectively screened group, seven patients with congestive heart failure who were found to be hyponatraemic had plasma renin activities greater than 15 ng/ml per h. Serial determinations in one patient showed plasma renin activity to vary inversely with the serum Na+. It is concluded that serum sodium can be used to identify those patients with congestive heart failure who have a high plasma renin activity. The value of identifying these high renin heart failure patients was seen in their response in four cases to specific therapy with a converting enzyme inhibitor.
This work was supported by the Squibb Institute for Medical Research, Princeton, New Jersey and in part by the U.S. Public Health Service (Grant HL 14148) and the Medical Research Service, Veterans Administration, Washington, D.C.
The antidiuretic hormone arginine vasopressin could contribute to both the vasoconstriction and impaired water handling frequently found in patients with congestive heart failure. In order to determine basal levels for vasopressin in this condition, plasma vasopressin was measured by radioimmunoassay in a group of 31 patients with advanced congestive heart failure. At the same time, plasma norepinephrine, plasma renin activity and numerous hemodynamic variables were also measured. In a subgroup of patients, the response of vasopressin to hemodynamic changes induced by nitroprusside infusion and to inhibition of the renin-angiotensin system with captopril was studied. The basal vasopressin levels in the patients were compared with those obtained from 51 comparably aged normal subjects. The mean vasopressin level (± standard error of the mean) in the patients was 9.5 ± 0.89 pg/ml as compared with 4.7 ± 0.66 (probability [p] < 0.001) in the normal subjects. Serum sodium was 137 ± 0.56 mEq/liter. The vasopressin level did not correlate with any hemodynamic variable and was increased to the same degree in patients with both low and normal cardiac index. The vasopressin level failed to correlate with serum sodium, and was similarly increased in patients with low and normal serum sodium. There was no correlation of vasopressin and plasma norepinephrine, but vasopressin did correlate modestly with plasma renin activity (r = 0.53, p < 0.02). Acute hemodynamic changes induced by nitroprusside did not influente vasopressin levels, nor did comparable changes aceompanied by inhibition of the renin-angiotensin system with captopril.Thus, vasopressin levels measured under steady state conditions are usuallv increased in patients with congestive heart failure. The increase is not dependent on reduced cardiac index. There appears to be an abnormality in the relation between vasopressin and serum sodium in some persons and vasopressin does not respond to acute hemodynamic changes with or without the inhibition of the renin-angiotensin system. The mechanisms causing increased vasopressin levels and their biologic importance in congestive heart failure remain to be defined.
The role of the renin-angiotensin-aldosterone system in the development of congestive failure has been assessed in the conscious dog by use of the nonapeptide converting enzyme inhibitor. Constriction of the pulmonary artery or thoracic inferior vena cava was maintained for 2 wk while daily measurements were made of plasma renin activity, plasma aldosterone, plasma volume, hematocrit, serum sodium and potassium concentrations, sodium and water balance, body weight, and arterial, caval, and atrial pressures. The initial response to constriction was a reduction in blood pressure, a rise in plasma renin activity, plasma aldosterone, and water intake, and nearly complete sodium retention. In the days after moderate constriction plasma volume and body weight increased (with development of ascites and edema); blood pressure, sodium excretion, plasma renin acvitity, and plasma aldosterone returned to normal. In animals in which blood pressure was not restored, plasma renin activity and plasma aldosterone remained elevated throughout the period of constriction. Single injections of converting enzyme inhibitor reduced blood pressure when plasma renin activity was elevated. Chronic infusion of the inhibitor in dogs with thoracic inferior vena caval constriction prevented the restoration of blood pressure and suppressed the rise in plasma aldosterone; sodium retention and volume expansion were less than in control experiments. Thus the renin-angiotensin-aldosterone system plays an essential role in the maintenance of blood pressure during the genesis of congestive failure. Initially, the restoration of blood pressure is dependent upon circulating angiotensin II; in the later stages, blood pressure is dependent upon the increase in plasma volume.
The cardiovascular pharmacology of SQ 14,225 (D-3-mercapto-2-methylpropanoyl-L-proline), a new orally effective inhibitor of angiotensin-coverting enzyme (ACE) was investigated in conscious normotensive rabbits. Intravenous administration of SQ 14,225 (3.1-310.0 microgram/kg) resulted in a dose related inhibition of the pressor responses to 310 ng/kg, i.v. of angiotensin I (AI) without diminishing the pressor responses to 100 ng/kg, i.v. of angiotensin II (AII). In fact, the responsiveness of the rabbits to AII was significantly enhanced by higher doses of SQ 14,225. This enhancement of the pressor effects of AII was found to be related to the inhibition of ACE and the resulting decrease in the levels of endogenous AII. In addition, SQ 14,225 (1.0 mg/kg, i.v.) markedly potentiated the magnitude and duration of the vasodepressor responses elicited by bradykinin (1.0 microgram/kg. i.v.). At a dose of 1.0 mg/kg. i.v., SQ 14,225 had no effect on the vasodepressor effects of intravenously administered isoproterenol (0.4 microgram/kg), acetylcholine (1.0 microgram/kg) or prostaglandin E2 (3.0 microgram/kg, i.v.). The pressor responses to norepinephrine (3.0 microgram/kg, i.v.) were similarly unaffected by SQ 14,225 (1.0 mg/kg, i.v.). In normal rabbits SW 14,225 (1.0 mg/kg, i.v.) caused a small but significant decrease in arterial pressure; it had no such effect in anephric rabbits. The observation of this study indicate that SQ, 14,225 is a specific inhibitor of ACE in conscious rabbits.
The renin-angiotensin system is thought to maintain elevated systemic vascular resistance in heart failure. The hemodynamic effects of captopril (SQ 14225), an oral inhibitor of angiotensin-converting enzyme, were measured in 10 patients with stable congestive heart failure poorly controlled by digitalis and diuretics. At single daily doses of 25 to 150 mg, the cardiac index rose from 1.75 +/- 0.18 to 2.27 +/- 0.39 (mean +/- S.D.) liters per minute per square meter (P less than 0.001), and pulmonary-wedge pressure fell from 26.5 +/- 7.5 to 17.3 +/- 6.1 mm Hg (P less than 0.01). Systemic vascular resistance decreased from 2006 +/- 300 to 1393 +/- 238 dyne seconds per centimeter (P less than 0.001), and mean arterial pressure fell from 83.7 +/- 7.0 to 70.3 +/- 9.9 mm Hg (P less than 0.001) (mean +/- S.D.). Heart rate did not change appreciably. Hemodynamic alterations peaked at 90 minutes and persisted for three to four hours. Control plasma renin activity ranged from 1.1 to 7.3 ng per milliliter per hour and did not correlate with changes in hemodynamic values. Three patients on long-term treatment maintained clinical improvement. Although its mechanism of action has not been completely elucidated, captopril may prove useful in the treatment of chronic congestive heart failure.
The oral effectiveness of 10 mg followed by 20 mg of isosorbide dinitrate in 21 patients with acute mycardial infarction was studied over a period of 13 hours. The patients were grouped according to initial left ventricular filling pressure: group I, pressure less than 20 mm Hg, and group II, pressure more than 20 mm Hg. Patients in group II had left ventricular failure. In both groups isosorbide dinitrate resulted in a significant decrease in pulmonary arterial pressure. The left ventricular filling pressure decreased in group I from 13.6 +/- 4.0 to 7.1 +/- 2.6 mm Hg (mean +/- 1 standard deviation) and in group II from 26.9 +/- 4.6 to 19.0 +/- 3.6 mm Hg (P less than 0.001). Cardiac output decreased in group I from 5.1 +/- 1.0 to 4.5 +/- 0.9 liters/min, whereas in group II it increased significantly from 3.5 +/- 0.8 to 4.1 to 0.9 liters/min (P less than 0.001). In both groups, peripheral arterial blood pressure decreased (P less than 0.60). Heart rate remained constant. Whether cardiac output increased or decreased was found to be dependent on the initial left ventricular filling pressure. In patients with an initially high value (above 20 mm Hg), the increase in cardiac output is probably due to the reduction of afterload. An additional factor may be the decrease in left ventricular filling pressure, which leads to an improved blood supply in the affected mural segments as a result of the decrease in the extravascular component of the coronary resistance. Significant changes in cardiac output and left ventricular filling pressure were achieved 3 to 5 hours after oral administration of isosorbide dinitrate. Clinical signs of failure were less pronounced. Isosorbide dinitrate is, therefore, a therapeutic agent in the treatment of left ventricular failure due to acute myocardial infarction.
Both the isolated perfused rabbit heart and kidney are capable of synthesizing prostaglandin (PG) I(2). The evidence that supports this finding includes: (a) radiochemical identification of the stable end-product of PGI(2), 6-keto-PGF(1alpha), in the venous effluent after arachidonic acid administration; (b) biological identification of the labile product in the venous effluents which causes relaxation of the bovine coronary artery assay tissue and inhibition of platelet aggregation; and (c) confirmation that arachidonic acid and its endoperoxide PGH(2), but not dihomo-gamma-linolenic acid and its endoperoxide PGH(1), serve as the precursor for the coronary vasodilator and the inhibitor of platelet aggregation. The rabbit heart and kidney are both capable of converting exogenous arachidonate into PGI(2) but the normal perfused rabbit kidney apparently primarily converts endogenous arachidonate (e.g., generated by stimulation with bradykinin, angiotensin, ATP, or ischemia) into PGE(2); while the heart converts endogenous arachidonate primarily into PGI(2). Indomethacin inhibition of the cyclo-oxygenase unmasks the continuous basal synthesis of PGI(2) by the heart, and of PGE(2) by the kidney. Cardiac PGI(2) administration causes a sharp transient reduction in coronary perfusion pressure, whereas the intracardiac injection of the PGH(2) causes an increase in coronary resistance without apparent cardiac conversion to PGI(2). The perfused heart rapidly degrades most of the exogenous endoperoxide probably into PGE(2), while exogenous PGI(2) traverses the heart without being metabolized. The coronary vasoconstriction produced by PGH(2) in the normal perfused rabbit heart suggests that the endoperoxide did not reach the PGI(2) synthetase, whereas the more lipid soluble precursor arachidonic acid (exogenous or endogenous) penetrated to the cyclooxygenase, which apparently is tightly coupled to the PGI(2) synthetase.
Recent reports have indicated that vascular responsiveness can be altered by exogenously administered or endogenously released prostaglandins. Furthermore, in certain tissues inhibitors of prostaglandin synthesis have been shown to limit the increase in blood flow in response to bradykinin and to enhance the reduction in blood flow in response to angiotensin and norepinephrine. These findings suggest an important local circulatory role for prostaglandins. We attempted to implicate further prostaglandins in local blood flow regulation by examining the effects of indomethacin (IND) and 5,8,11,14-eicosatetraynoic acid (ETA), inhibitors of prostaglandin synthesis, on microvascular arteriolar responses to bradykinin, prostaglandin E1 (PGE1), prostaglandin E2 (PGE2), histamine, norepinephrine, and angiotensin. Male Wistar rats were anesthetized with sodium pentobarbital, and their cremaster muscle was exteriorized and prepared for in vivo microscopic observation of microvessels. Changes in arteriolar luminal diameters in response to topical administration of vasoactive agents were quantified with an image-shearing measuring eyepiece in conjunction with a television microscope and recorder. Local administration of IND or ETA significantly reduced the arteriolar dilation elicited by bradykinin, whereas the responses to PGE1 and PGE2 remained unaltered. Responses to histamine, although somewhat reduced, were not significantly different from control. Vasoconstrictor responses of arterioles elicited by norepinephrine and angiotensin were potentiated by IND or ETA administration. These results indicate that prostaglandins synthetized in skeletal muscle microcirculation in situ (1) mediate, in part, vasodilator responses to bradykinin and (2) modulate vasoconstrictor responses to angiotensin and norepinephrine. Thus, these findings support the hypothesis that prostaglandins are local regulators of microvascular responsiveness.
1. Intravenous infusion of angiotensin causes rats which are in water balance to drink water.
2. The mean amount of angiotensin needed to initiate drinking was 29·1 ± 4·6 μg/kg ( S.E. of mean) in twenty normal rats, and 15·7 ± 2·1 μg/kg in thirty‐four nephrectomized rats.
3. The nephrectomized rat is therefore more sensitive to this action of angiotensin than the rat with intact kidneys.
4. The rates of infusion (0·05–3·0 μg/kg ⁻¹ min ⁻¹ ) which cause drinking are comparable to those used to produce other effects in rats.
5. Angiotensin restores the drinking response of the nephrectomized rat subjected to caval ligation to a value similar to that obtained in the uninfused normal rat subjected to caval ligation.
6. The effects of angiotensin and hypertonic saline on drinking are additive when both substances are administered to nephrectomized rats.
7. These experiments provide further support for the view that the renin—angiotensin system is concerned in extracellular thirst.
The hydrolysis of bradykinin and its higher homologues by angiotensin-converting enzyme has been investigated by using an automated ninhydrin technique. The results show an inverse relationship of hydrolysis rate with size and charge of the peptide, which parallels the inactivation in the pulmonary circulation and offers an explanation for the selectivity of metabolism of these kinins by the lungs.
Persistent secretion of vasopressin and/ or diminished distal fluid delivery have been proposed to explain the impaired water excretion associated with low-output cardiac failure. In the present investigation cardiac output (CO) was diminished in anesthetized dogs undergoing a water diuresis by constriction of the thoracic inferior vena cava (TIVC). In intact animals (group I) acute TIVC constriction decreased CO from 3.5 to 2.2 liters/min (P < 0.005) as urinary osmolality (U(osm)) increased from 103 to 543 mosmols/ kg (P < 0.001) and free water clearance (C(H2o)) decreased from 2.1 to -0.6 ml/min (P < 0.001). This antidiuretic effect was disassociated from changes in renal arterial and venous pressures, glomerular filtration rate, solute excretion, and renal innervation. To examine the role of vasopressin in this antidiuresis, studies (group II) were performed in acutely hypophysectomized, steroid-replaced animals. In these animals TIVC constriction decreased CO to a similar degree from 3.4 to 2.1 liters/min (P < 0.001). However, the effects on U(osm) (87-104 mosmols/kg) and C(H2o) (2.1-1.6 ml/min) were significantly less than in intact dogs. In another group of hypophysectomized animals, (group III) renal arterial and venous pressures were not controlled, and the effect of TIVC constriction on U(osm) was not significant (65-79 mosmols/kg) although C(H2o) decreased from 3.3 to 1.9 ml/min (P < 0.001). In both the group II and III studies, there were linear correlations between the changes in C(H2o) and the urine flow. Studies were also performed in baroreceptor-denervated animals with intact hypothalamo-neurohypophyseal tracts, and acute TIVC constriction altered neither U(osm) nor C(H2o) when renal arterial pressure was controlled. These results therefore indicate that the effect of TIVC constriction on U(osm) is primarily vasopressin mediated while the effect on C(H2o) is mediated both by vasopressin release and diminished distal fluid delivery. A decrease in renal arterial pressure, or some consequence thereof, seems to be an important determinant of the latter effect.
SUMMARY Mutants of Pseudomonas aeruginosa 8602 were isolated which, unlike the wild-type strain, utilized butyramide as a growth substrate. One group produced amidases with altered substrate specificities, indicating that the mutations may be in the amidase structural gene. The second group of butyramide-utilizing mutants produced wild-type enzyme and were all con- stitutive. It was concluded that such mutants possessed mutations in an amidase regulator gene which allowed them to synthesize large amounts of amidase in the presence of butyramide. Induction of amid ase synthesis by N-acetylacetamide in the wild-type strain was repressed in a competitive manner by butyramide and other amide analogues, e.g. cyanoacetamide. The constitutive mutant c I I, which could not utilize butyramide for growth, was subject to severe repression of amidase synthesis by butyramide and cyanoacetamide. The regulator mutants which were able to grow on butyramide were all less sensitive to repression by butyramide. Mutant CB 2, a butyramide-utilizing regulator mutant, was relatively insensitive to repression of amidase synthesis by cyanoacetamide whereas strain B 6, a butyramide-utilizing mutant producing an altered enzyme, was as sensitive to repression by cyanoacetamide as its parent strain the constitutive mutant c I I. The contribution of mutations in structural and regulator genes to utilization of novel growth substrates is discussed.
Renin concentration was measured in 155 plasma samples from 79 patients with congestive cardiac failure, 23 samples being obtained from 21 patients before the start of treatment. Before treatment, renin was variously subnormal, high, and within the normal range. Initially normal renin levels might become high with diuretic therapy; conversely, in other patients high pretreatment values subsided to normal with therapy. In yet other instances renin remained within the normal range throughout. In both untreated and treated patients, plasma renin concentration was closely related inversely to plasma sodium and directly to plasma urea concentration. Before treatment, plasma renin was found to be closely related inversely to plasma tCO2, and directly, but rather less closely, to plasma potassium. Neither of these relationships remained significant when treated patients were considered. Renin-mediated intrarenal vasoconstriction is considered as the possible cause of the typically reduced renal blood flow, with a relatively high filtration fraction, of cardiac failure. In particular, a hypothesis is put forward in which a renin-mediated selective reduction of renal inner-medullary blood flow in cardiac failure might be responsible for the disproportion between the high urinary osmolality in relation to that of plasma, and for oliguria, uremia, and hyponatremia. It is proposed that the retarded renal inner-medullary blood flow enhances countercurrent exchange, and thus also limits the extent of urea retention, while simultaneously tending to build up osmolality in the inner medulla and so inhibit water excretion. Renin is further considered as a possible contributor to diuretic resistance.
The acute haemodynamic effects of low doses of the oral converting-enzyme inhibitor, captopril, were studied in 18 patients with severe chronic heart failure. The effects of long-term therapy were also evaluated. Increasing doses (1 mg, 2.5 mg, 6.25 mg, 12.5 mg, and 25 mg) of captopril were given at 2 h intervals with haemodynamic monitoring. Graded haemodynamic improvement (increased stroke-volume index and reduced mean pulmonary capillary wedge pressure) was noted from 1 hand was closely associated with reduction of blood pressure. Maximal haemodynamic improvement for the group was seen at 6 h and 7 h after the 6.25 mg and 12.5 mg doses, when stroke-volume index had risen 35% and mean pulmonary capillary wedge pressure had fallen 40% from control. Captopril 12.5-50 mg every 8 h was continued long term but was withdrawn in 2 patients with symptomatic hypotension and 1 patient with altered taste. 4 patients died and 1 was noncompliant with therapy. At 3 months, 10 patients showed significant improvement in symptoms, treadmill-exercise duration, and echocardiographic indices of left-ventricular size and function. Repeat haemodynamic measurements were similar to optimum measurements obtained during the initial study.
The ability of the kidney to release prostacyclin (PGI2) under direct stimulation with exogenous angiotensin II was studied in the pentobarbital-anesthetized dog. We assayed for prostacyclin-like activity in systemic arterial blood by continuously monitoring platelet aggregation in vivo and with the blood-bathed bovine coronary artery, which relaxes to prostacyclin. This parallel bioassay allows detection of small amounts of prostacyclin-like activity released into the systemic circulation. Angiotensin II, infused at a rate of 10 or 20 ng/kg/min into the renal artery inhibited latelet aggregation in 8 out of 18 dogs, relaxed the bovine coronary artery in 13 of 16 dogs, and lowered systemic arterial blood pressure 5-10 mm Hg in all but 3 animals. These effects of antiotensin II could be blocked by treating the animal with indomethacin (2 mg/kg, i.v.) and mimicked by administration of exogenous prostacyclin. Infusion of the same dose of angiotensin II (10 or 20 ng/kg/min) intravenously did not release prostacyclin; blood pressure increased during intravenous infusion, and platelet aggregation remained unchaged. These data are consistent with the hypothesis that prostacyclin, of renal origin in these experiments, can act as a circulating hormone. Prostacyclin should not be regarded only as an antiaggregatory substance, but also as a potentially important modulator of blood pressure.
Captopril is the first angiotensin-converting enzyme inhibitor for oral administration. In combination with continued digitalis and diuretic therapy it has been demonstrated to be effective in the management of severe heart failure refractory to optimal digitalis, diuretic and, in many patients, vasodilator treatment. Most studies to date have been open trials of several weeks or months duration, but a number of patients have received continued treatment, with sustained benefit, for up to 1 year or more. A placebo-controlled trial in a limited number of patients with less severe heart failure has confirmed the results of open trials. Captopril administration improves cardiac performance as a result of a reduction in systemic vascular resistance (afterload) and the various determinants of left ventricular filling pressure (preload). Improvements in exercise tolerance and functional classification, with associated reduction of clinical symptomatology, occur with simultaneous decreases in myocardial oxygen consumption. At present, captopril is worthy of a trial in patients refractory to more traditional medical management. Whether it should be considered a 'first-line' agent after failure of optimal digitalis and diuretic therapy, and before instituting other vasodilator therapy, is less clear. In patients with severe or resistant heart failure, a response to captopril is usually accompanied by a general improvement in the quality of life. The effect of captopril treatment on 1- and 2-year survival rates in patients with severe heart failure appears similar to that reported for other vasodilators. Most patients tolerate captopril treatment well, but hypotension, reduced renal function, skin rash, dysgeusia, and neutropenia have been reported.
The hemodynamic effects of an oral angiotensin-converting enzyme inhibitor, captopril, were evaluated in 10 symptomatic patients with chronic congestive heart failure. In all patients there was a significant increase in cardiac output (average 28%), stroke volume (49%), and stroke work index (26%), along with a decrease in pulmonary capillary wedge pressure (48%), indicating improved left ventricular function. Modest decreases in heart rate and arterial pressure were also observed. In seven patients maintained on captopril therapy, repeat hemodynamic studies at 2 months revealed sustained effects. These beneficial hemodynamic effects were accompanied by clinical improvement and improved exercise tolerance during maintenance therapy. These findings suggest that captopril may be a useful therapeutic adjunct for the long-term management of patients with chronic congestive heart failure.
Eight patients with severe congestive heart failure refractory to conventional therapy, including vasodilators, were given captopril (seven patients) or teprotide (one patient). All had dyspnea, edema, elevated pulmonary wedge pressure (28.0 +/- 2.6 mm Hg), low cardiac index (1.6 +/- 0.1 liters per minute per square meter), and elevated levels of serum creatinine (2.3 +/- 0.2 mg per deciliter [203.3 +/- 17.7 mumol per liter]), blood urea nitrogen (48 +/- 5 mg per deciliter [17.1 +/- 1.8 mmol of urea per liter]), plasma renin activity (21 +/- 7 ng of angiotensin I per milliliter per hour), plasma angiotensin II (271 +/- 51 pg per milliliter), and plasma aldosterone (65 +/- 14 ng per deciliter). After one week of therapy, all indexes improved. Creatinine and p-aminohippurate clearances were also increased (P less than 0.01). Improvement was sustained (more than six months) and was associated with a statistically significant increase in the cardiac ejection fraction (12 +/- 3 to 26 +/- 7 per cent). With a mean follow-up of seven months, the New York Heart Association Functional Class has been reduced from IV to II, and the number of days of hospitalization to less than 10 per cent of that before captopril therapy. We conclude that captopril reduces afterload in advanced congestive heart failure and induces sustained improvements in clinical status and renal function.
Captopril (SQ 14,225), an oral angiotensin converting-enzyme inhibitor, was administered to 11 patients with severe congestive heart failure (CHF). Peak effect was observed at 1.5 hours after administration. At peak effect right atrial pressure fell from 3.4 to 0.0 mm Hg, pulmonary capillary wedge pressure (PCW) fell from 22.7 to 12.3 mm Hg, mean arterial pressure (MAP) fell from 79.5 to 62.1 mm Hg, systemic vascular resistance (SVR) fell from 1989 to 1370 dyn-sec-cm-5, pulmonary vascular resistance fell from 843 to 523 dyn-sec-cm-5, and cardiac index (CI) rose from 1.96 to 2.43 l/min/m2. These were all statistically significant. Control plasma renin activity (PRA) was elevated (25.9 ng/ml/hr) and correlated with resting PCW (r=0.65). The acute hemodynamic response was related to PRA: a fall in MAP (r=0.74), a fall in PCW (r=0.80), a fall in SVR (r=0.45) and a rise in CI (r=0.45). Eight patients were placed on chronic captopril therapy. After 2 or more months, their exercise time was significantly increased, from 6.8 to 11.7 minutes. Their cardiothoracic ratios showed a significant decrease, from 0.55 to 0.52, and most patients reported symptomatic improvement. Chronic response was not predicted by acute hemodynamic response. Captopril is therefore a vasodilator with both arterial and venous effects that are at least partially caused by inhibition of the renin-angiotensin system. It may be useful for the treatment of CHF.
To evaluate the therapeutic efficacy of oral angiotensin-converting inhibition (ACE) with captopril in chronic normotensive congestive heart failure (CHF), acute and cardiocirculatory actions were determined by cardiac catheterization and forearm plethysmography, and ambulatory effects were assessed by echocardiography, nuclear angiography, treadmill exercise, and clinical symptomatology in 10 severe CHF patients. Captopril (90 mg) produced marked (peak 1 hour) and sustained (5 hours) left ventricular filling pressure (23 to 15 mm Hg), systemic vascular resistance decreases, and cardiac index increase (1.99 to 2.41 L/min/m2), while mean blood pressure declined mildly (87 to 80 mm Hg) without heart rate change. Both forearm venous tone and vascular resistance decreased considerably. After 1 week of ambulatory therapy (90 mg three times daily), nuclear angiographic ejection and echocardiogram shortening fractions increased, and exercise duration (341 to 453 sec) and New York Heart Association functional class (3.6 to 2.2) improved. Thus ACE-induced vasodilation by oral captopril improved cardiac performance and clinical status in refractory CHF.
To determine whether prostaglandins contribute to the depressor response to the converting enzyme inhibitor, captopril, we measured the plasma prostaglandin levels by radioimmunoassy before and after captopril administration, and then examined the effect of prostaglandin synthetase inhibition on captopril's antihypertensive effect. When a single oral captopril dose (25-100 mg) was given to 31 sodium-restricted patients with essential hypertension, the levels of the stable transformation product of prostacyclin remained unmeasurable and that of thromboxane A2 did not change, while the metabolite of PGE2 (PGE-M) increased by 53% (34 +/- 4pg/ml pre-captopril, 52 +/- 5 pg/ml after; p less than 0.001). As expected, blood pressure (BP) and angiotension II (AII levels fell, and kinin levels rose (all changes p less than 0.001). We then blocked prostaglandin synthesis in 18 of these subjects for 24 hours with either indomethacin (n = 10) or aspirin (n = 8) before repeating the captopril dose, to assess the importance of these PGE-M increments. The PGE-M responses to captopril were effectively blocked in nine of 10 subjects receiving indomethacin and four of eight receiving aspirin. In these 13 patients, the depressor response to captopril was significantly blunted (-20 +/- 3mm Hg pre-synthetase inhibition vs - 13 +/- 2 mm Hg post; p less than 0.05). When these agents did not block the PGE-M response to captopril, the BP response was also unchanged (-15 +/- 4mm Hg pre, -18 +/- 5mm Hg post). Neither indomethacin nor aspirin changed the AII or kinin responses to captopril. We conclude that the prostaglandins may be important mediators of captopril's antihypertensive effect in the sodium-restricted state.
Prostaglandin E2 antagonizes vasopressin-stimulated adenylate cyclase activity and water flow in isolated epithelial membranes in vitro and in the intact kidney in vivo. Paradoxically, vasopressin stimulates PGE2 synthesis by these same tissues, thus simultaneously stimulating adenylate cyclase and the synthesis of an inhibitor of vasopressin-stimulated adenylate cyclase activity. The apparent significance of this relationship is that PGE2 serves as a modulating hormone in vivo for the vasopressin-mediated increase in renal collecting tubule water permeability and water reabsorption. The significance of the interaction between these two substances in vivo is evident by virtue of the changes in water permeability and reabsorption after prostaglandin synthesis inhibition with nonsteroidal anti-inflammatory agents or with sulfonylurea compounds, such as chlorpropamide. Of particular note is the fact that the administration of ACTH to sodium-depleted normal subjects who had previously received indomethacin evokes an experimental model of the syndrome of inappropriate antidiuretic hormone secretion; under these conditions prostaglandins clearly contribute to the prevention of the inappropriate reabsorption of water by the kidney. On the other hand, excessive renal production of PGE2 might account for the resistance to vasopressin exhibited by patients who have acquired or inherited nephrogenic diabetes insipidus. Although PGE2 currently is thought to be only a minor factor in the regulation of pituitary vasopressin release, abnormalities of vasopressin release might be secondary to changes in PGE2 synthesis by the brain.
We studied the effect of a converting enzyme inhibitor (CEI), Captopril SQ 14,225 50 mg p.o. in eight supine normal subjects under a high sodium (150 mEq/d) and low sodium (25 mEq/d) diet. On high sodium, plasma renin (PRA) and aldosterone were basal and Saralasin did not lower mean blood pressure. However, CEI induced an 11.4 +/- 3.2 mm fall in blood pressure (p less than 0.02) and either indomethacin 50 mg or ibuprofen 800 mg (PI), when given simultaneously on another day abolished the blood pressure response (2.5 +/- 0.9 mm Hg, p greater than 0.5). In contrast, on a low salt diet where renin was increased, CEI induced a drop in blood pressure which was not significantly altered by PI (12.8 +/- 1.1 vs. 10.0 +/- 3.1 mm Hg, p greater than 0.5). CEI increased plasma renin on both diets (1.7 +/- 0.5 to 3.5 +/- 0.8 and 2.8 +/- 0.6 to 12.5 +/- 3.1 ng/ml/hr respectively both p less than 0.05). Aldosterone did not change (high Na+) or fell (low Na+). Inhibition of Prostaglandin synthesis did not significantly block the renin rise from CEI suggesting that the direct angiotensin II negative feedback is relatively independent of acute prostaglandin release. Our studies suggest that CEI has a dual hypotensive action. In a low renin state, the hypotensive action appears to be mediated through vascular prostaglandins.
To determine whether prostaglandins contribute to the depressor response of angiotensin-converting enzyme inhibitors, plasma prostaglandin levels were measured by radioimmunoassay in normo- and hypertensive subjects on both sodium-restricted and sodium-loaded diets before and after captopril administration. On the sodium-restricted diet, the hypotensive response to captopril was accompanied by significant increments in the metabolite of prostaglandin E2 (PGE2-M) and bradykinin and by significant decrements in angiotensin II. The high sodium diet suppressed the response of the renin-angiotensin and kinin systems to captopril but the hypotensive response persisted. Furthermore, the decrease in blood pressure correlated significantly with increments in prostaglandin E2-metabolite. Prostaglandin synthesis was then inhibited in the sodium-restricted hypertensive patients by pretreatment with indomethacin. This maneuver completely eliminated the captopril-induced prostaglandin E2-metabolite increment without changing bradykinin or angiotensin II responses but significantly attenuating the hypotensive response. Finally, when patients were studied on a high sodium intake, similar effects were observed except now indomethacin completely abolished the blood pressure response to captopril. These studies therefore support the hypothesis that increased production of vasodilator prostaglandins in a major mediator of the hypotensive response to captopril. Whether the change in prostaglandin release is a direct effect of the drug or secondary to increased kinin levels is uncertain.
Although many studies have shown acute hemodynamic improvement in patients with congestive heart failure treated with vasodilating drugs, long-term controlled studies with both hemodynamic and exercise capacity measurements are not available. We studied the converting-enzyme inhibitor captopril in 16 ambulatory patients in New York Heart Association functional class II-IV heart failure who were clinically stable on digoxin and diuretics. The acute response to open-label captopril was quantified by blood pool scintigraphy, right-heart catheterization at rest and during exercise, and measurements of exercise capacity. The patients were then randomized to maintenance therapy with captopril or matching placebo and were restudied after 3 months. The two groups were similar in their clinical characteristics and pretreatment rest and exercise hemodynamic measurements. Both displayed similar acute beneficial responses to captopril at rest, with a mean reduction in left ventricular filling pressure from 24 ± 9 to 14 ± 6 mm Hg (p<0.001) and increases in cardiac index, from 2.1 ± 0.5 to 2.5 ± 0.61/min/m2 (p<0.01), and stroke index, from 25 ± 8 to 34 ± 8 ml/m2 (p<0.001). Directionally similar hemodynamic improvement was noted during exercise. After 3 months, these beneficial hemodynamic changes were sustained only in the patients randomized to captopril. Concomitantly, the captopril patients increased their exercise capacity as measured by the duration of bicycle exercise (9.0 ± 2.2 vs 11.7 ± 1.4 min, p<0.01), maximal work load (360 ± 80 vs 460 ± 50 kpm/min, p<0.005) and oxygen consumption (12.9 ± 2.3 vs 15 ± 1.8 ml/kg/min). The placebo group showed either no change or a worsening over the 3 months compared to their pretreatment measurements. These findings demonstrate that captopril is an effective adjunctive agent for the treatment of chronic heart failure and that it produces long-term hemodynamic improvement together with an increase in exercise capacity.
A correlation between hyponatremia and increased plasma renin activity (PRA) has been reported in patients with severe congestive heart failure (CHF), implying both clinical and pathophysiologic significance. To determine the impact of diuretic therapy on this relation, we evaluated the correlation of serum sodium, prerenal azotemia (blood urea nitrogen/creatinine ratio [BUN/Cr] ), and PRA in 44 patients with severe CHF who were maintained on diuretic therapy. Serum sodium level was inversely related to PRA (r = -0.389, p less than 0.02). However, a significant correlation also existed between the BUN/Cr ratio and PRA (r = 0.365, p less than 0.025) and an inverse correlation between serum sodium level and the BUN/Cr ratio (r = 0.332, p less than 0.025). Multiple regression analysis of the 3 variables yielded significant interdependence (p less than 0.01). To evaluate the effect of diuretic therapy, 12 patients with severe CHF discontinued diuretic therapy and received, for 1 week each, 10 and 100 mEq sodium diets in balance studies. PRA ranged from 0.14 to 16 ng/ml/h. Despite this range, there was no significant correlation between either serum sodium or BUN/Cr ratio and PRA. It is concluded that the presence of marked hyponatremia and prerenal azotemia in patients with diuretic-treated CHF may suggest increased PRA. However, substantial patient-to-patient variability limits the predictive value of these correlations. Although some clinical value may be derived from such correlations, they should not be used to draw major inferences regarding the severity of CHF or the pathophysiology of water balance in CHF.
To determine the relationship between the early and late hemodynamic effects of captopril in patients with severe heart failure, we performed serial right heart catheterizations in 51 such patients who were treated with the drug for 2 to 8 weeks. Four hemodynamic patterns of response were observed. Nine patients had minimal responses initially (type I); six failed to improve during long-term treatment, but three showed delayed hemodynamic benefits. Twenty-eight patients had initial beneficial drug effects that were sustained after 48 hr and after 2 to 8 weeks (type II). In seven patients, first doses of captopril produced marked beneficial responses, but these became rapidly attenuated after 48 hr; nevertheless, continued therapy for 2 to 8 weeks was accompanied by spontaneous restoration of the hemodynamic effects of first doses of the drug, i.e., triphasic response (type III). In the remaining seven patients, attenuation of initial response was not reversed by prolonged captopril therapy; hemodynamic variables after 2 to 8 weeks had returned to their pretreatment values, i.e., drug tolerance (type IV). Plasma renin activity was lower in patients with minimal responses (0.6 +/- 0.2 ng/ml/hr) and was higher in patients with triphasic responses (9.4 +/- 2.5 ng/ml/hr) than in patients with types II and IV response patterns (4.4 +/- 0.7 and 2.8 +/- 0.5 ng/ml/hr, respectively; both p less than .05). Although first-dose effects of captopril are frequently sustained, the occurrence of delayed, attenuated, and triphasic responses indicates that a complex and variable relationship may exist between the early and late hemodynamic effects of vasodilator drugs in patients with severe heart failure.
Supine and upright hemodynamic measurements were performed in 10 patients with chronic congestive heart failure, before and during vasodilator therapy with hydralazine and isosorbide dinitrate. This combination of drugs produced significant improvement in supine hemodynamic measurements, with the pulmonary capillary wedge pressure decreasing from 26 +/- 5 to 18 +/- 5 mm Hg (mean +/- SD, p less than 0.01) and stroke volume index increasing from 25 +/- 6 to 39 +/- 6 ml/m2 (p less than 0.01), without any significant change in heart rate (HR) or mean arterial pressure (MAP). However, with the patients upright, HR rose significantly (87 +/- 17 to 99 +/- 17 beats/min, p less than 0.05) and MAP fell (84 +/- 10 to 66 +/- 11 mm Hg, p less than 0.001) compared with measurements before treatment. These patients also exhibited potentially deleterious postural changes in HR, MAP, cardiac output, stroke volume index and stroke work index during therapy with the combination of hydralazine and isosorbide dinitrate. Although diuretic therapy (which had been withheld for 12 hours in eight subjects but only for 6 hours in two others) may have played a role in producing these changes, postural hypotension or tachycardia was not noted before vasodilator therapy or during therapy with nitrates or hydralazine. Repeat catheterization after 3 months in six patients revealed a lessening of the postural effects. These findings indicate the need to perform upright as well as supine hemodynamic measurements during the initiation of vasodilator therapy and suggest the need for particular caution in patients with ischemic heart disease.
We assessed the hemodynamic and hormonal response to tilt and the baroreceptor response in 12 patients in sinus rhythm with severe chronic congestive heart failure. We also assessed the response to acute (n = 12) and chronic (n = 8) converting-enzyme inhibition with captopril. The control tilt was characterized by high cardiac filling pressures, absence of significant peripheral pooling and apparent absence of afferent stimuli for hemodynamic and hormonal response. After acute captopril, the hemodynamic response to tilt was improved, but not normalized. The chronic response was characterized by the absence of a reflex increase of systemic vascular resistance on tilt despite peripheral pooling. Five patients developed orthostatic hypotension, but responded to acute infusion of 0.9% sodium chloride. Efferent sympathetic activity (response to cold pressor) was abnormal during the control study, but indistinguishable from normal subjects by the time of chronic captopril therapy. This paralleled an improved responsiveness of plasma catecholamines during chronic tilt. The Valsalva maneuver remained abnormal. There was a distinct absence of the normally anticipated heart rate increase on tilt, suggesting a parasympathetic abnormality.
The status of the renin-angiotensin-aldosterone system (RAAS) in congestive heart failure (CHF) varies in many reports, in part because of the heterogeneity of the clinical status of the patients studied. To relate the RASS to clinical state, we studied 23 patients with severe CHF (New York Heart Association functional classes III-IV): five had recent onset of severe pump failure with pulmonary edema (group 1), nine had recent cardiac decompensation superimposed on chronic CHF (group 2) and nine had chronic stable CHF (group 3). The severity of cardiac dysfunction in patients in group 3 was comparable to that in the other two groups (cardiac index, 1.6 ± 0.2 l/min/m2; ejection fraction, 19.3 ± 3%). Pulmonary wedge pressure was similar in all groups (29 ± 3,28 ± 2 and 29 ± 5 mm Hg). Groups 1 and 2 had reduced mean blood pressure (71 ± 4 and 79 ± 4 mm Hg), increased plasma renin activity (PRA) (65 ± 12 and 29 ± 4 ng A I/ml/hour), plasma aldosterone (117 ± 19 and 59 ± 11 ng/dl) and serum creatinine (2.5 ± 0.5 and 3.0 ± 0.3 mg/dl). Serum sodium concentration was reduced only in group 2 (131 ± 2 mEq/l). These variables were normal in group 3. PRA and mean systemic blood pressure were inversely correlated in all patients (r = -0.48, p < 0.05), as were PRA and serum sodium concentration in patients in groups 2 and 3 (r = -0.51, p < 0.05). In four patients in group 2 who were followed longitudinally, PRA fell from 13.5 ± 1.3 to 3.9 ± 1.0 ng/ml/hour, plasma angiotensin II level from 177 ± 76 to 25 ± 11 pg/ml as their CHF was stabilized. In nine patients with an acute, apparently uncomplicated myocardial infarction, PRA was normal (5.0 ± 2.1 ng/ml/hour). The RAAS is markedly activated during decompensated cardiac failure but returns to normal with stabilization, even though evidence for severe cardiac dysfunction persists. A major stimulus for the activation of the RAAS in acute decompensation appears to be a decrease in systemic blood pressure associated with a decrease in cardiac output.
The hemodynamic mechanism by which patients with chronic congestive heart failure (CHF) maintain their blood pressure (BP) in the upright posture is distinct from that of normal and hypertensive individuals. There are little data regarding the effects of chronic vasodilator therapy on the mechanisms controlling this response, especially in the presence of diuretic therapy. Therefore, 10 consecutive patients with severe chronic CHF underwent hemodynamic tilt study following acute and chronic captopril therapy. One patient developed orthostatic hypotension following first-dose captopril, but 6 of 10 had a mean BP decrease of 70 +/- 6 to 56 +/- 3 mm Hg on tilt following chronic captopril. This associated with significant reduction of plasma aldosterone, and was abolished on re-tilt following acute saline infusion. Therefore, during chronic captopril therapy of CHF, a reduction of diuretic dosage may be necessary to prevent orthostatic hypotension.
The contribution of sympathetic tone and the renin-angiotensin system to the pathogenesis of chronic heart failure was evaluated. In 20 paired studies of the same 10 patients, the baseline hemodynamic and humoral correlates of congestive heart failure, and the response to alpha adrenergic blockade (prazosin) and angiotensin converting enzyme inhibition (captopril) were assessed. Despite the extent of failure, baseline plasma renin activity ranged from normal to very high. In contrast, baseline plasma catecholamine levels were always elevated. Baseline plasma norepinephrine reflected the severity of heart failure, correlating inversely with baseline cardiac index before administration of both drugs. Comparable improvement in left ventricular function was noted after acute therapy. Baseline renin and norepinephrine did not predict the response to prazosin, but baseline renin did predict the response to captopril: pulmonary wedge pressure (r=-0.776, p less than 0.01), stroke index (r=0.752, p less than 0.02), systemic vascular resistance (r=-0.673, p less than 0.05). In summary, elevated levels of plasma norepinephrine were inversely correlated with baseline cardiac function but norepinephrine levels did not change despite improved hemodynamics with specific prazosin therapy. The renin-angiotensin system exhibited a wide spectrum of activity and hemodynamic improvement with captopril was related to this activity. Absence of a correlation between plasma norepinephrine and plasma renin activity suggested that their contributions to vasoconstriction were not interdependent. Increased sympathetic tone was consistent in severe heart failure, whereas renin-angiotensin activity differed widely. The response to captopril can be used to identify a subset of patients with severe heart failure and adverse angiotensin-mediated vasoconstriction.
In advanced heart failure, severe edema develops associated with hyponatremia. In 20 patients with severe congestive heart failure, we studied plasma antidiuretic hormone (ADH) concentrations related to hemodynamics and plasma osmolality. Prazosin was used to test the acute response to changes in atrial receptors and hemofiltration to test the response to changes in volume receptors. One group of the patients had inappropriately high ADH values (14.5 +/- 8.8 pg/ml) in relation to their plasma osmolality, which was well below normal values (276 +/- 23 mosmol/kg water) with no apparent osmoregulatory control. The other group showed a normal relationship of ADH and plasma osmolality (3.9 +/- 1.0 pg/ml; 289 +/- 8 mosmol/kg water), Only in the normal regulating group did lowering of left atrium pressure by prazosin result in a rise in ADH related to the decrease in pressure. Inappropriately high ADH secretion could be reversed by hemofiltration. This suggests that the syndrome of "dilutional hypo-osmolality" in severe congestive heart failure may be caused by an inappropriately high ADH secretion in which the osmoreceptor system is dominated by nonosmolar stimuli; however, it cannot be ruled out that associated hemodynamic effects in the kidney or other intrarenal or hormonal factors contribute to this mechanism.
The systemic administration of angiotensin II or its precursors will result in increased water intake. Several manipulations that result in hypovolemia and/or hypotension (extracellular thirst challenges) are known to activate the peripheral renin-angiotensin system and also produce drinking. Although there are without question multiple mediators of thirst associated with extracellular thirst challenges, one of the major factors responsible for water intake has been hypothesized to be the action of angiotensin II. In the experimental analysis of thirst, several types of hypovolemic-hypotensive manipulations have been employed. However, there is a paucity of data available that characterize the systematic changes of angiotensin II levels following such challenges. The present studies determined plasma angiotensin II levels and drinking responses after isoproterenol administration, caval ligation, and subcutaneous polyethylene glycol treatment. The experimental protocols for treatment of the animals closely approximated conditions commonly employed in the experimental analysis of thirst. The results indicated that endogenous levels of angiotensin II increase after these treatments to levels that in all likelihood are sufficient to make a substantial contribution to the drinking response.
We used a sensitive radioimmunoassay technique to measure AVP in 37 patients with congestive heart failure and associated hyponatremia. AVP levels were detectable in 30 of the 37 patients; 11 of the 30 had never received diuretics. The degree of hyponatremia and hypo-osmolality was more severe and renal function more impaired in the 30 patients with detectable AVP levels than in the seven patients with undetectable AVP levels. Although our results implicate 'inappropriate' release of vasopressin in the mechanism of hyponatremia in congestive heart failure, they do not exclude a contribution by intrarenal factors.
Interaction of arginine vasopressin with renal prostaglandins in regulating renal blood flow (abstr).
- JA Oliver
- G LeCren
- Cannon PJ Sciacca
- JA Oliver
- G LeCren
- Cannon PJ Sciacca
Enhanced prostaglandin E excretion during vasopressin escape (abstr)
- PA Craven
- FR DeRubertis
- PA Craven
- FR DeRubertis
Altered regional blood flow and hormonal responses to orthostasis in congestive heart failure (abstr)
- Lilly Ls Dzau
- Williams Gh Vj
- Hollenberg
- Nk
Lilly LS, Dzau VJ, Williams GH, Hollenberg NK. Altered regional blood flow and hormonal responses to orthostasis in congestive heart failure (abstr). Circulation 1982;66(suppllI):II-249.
Role of endogeneous pros-taglandins in circulatory homeostasis in human heart failure (abstr)
- Dzau
- Lilly L Vj
- S Swartz
- Packer
Dzau VJ, Lilly L. Swartz S, Packer M. Role of endogeneous pros-taglandins in circulatory homeostasis in human heart failure (abstr).
Panel discussion. The role of captopril in the treatment of heart failure
- Levine
Levine TB. Panel discussion. The role of captopril in the treatment of heart failure. Br J Clin Pharmacol 1982;14:247S-52S.