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Influence of autonomic neuropathy upon LV dysfunction in insulin-dependent diabetic patients
Clinical Cardiology
Abstract
Diabetic cardiomyopathy is a well-defined complication of diabetes that occurs in the absence of ischemic, vascular, and hypertensive disease.
The study was undertaken to test the relationship among autonomic neuropathy (AN), 24-h blood pressure (BP) profile, and left ventricular function.
Nineteen type-1 diabetic patients underwent autonomic tests and echocardiographic examination. Patients were divided according to the presence (AN+) or absence (AN-) of AN.
In the AN+ group (n = 8), the E/A ratio at echo was lower than in the AN- group (n = 11) (1.1 +/- 0.3 vs. 1.6 +/- 0.3; p < 0.005). Systolic and diastolic BP reductions during sleep were smaller in the AN+ than in the AN- group (6.6 +/- 6.6 vs. 13.0 +/- 4.3%; p < 0.03 for systolic and 12.8 +/- 6.8 vs. 20.0 +/- 4.0% for diastolic BP reduction; p < 0.03, respectively). Considering all patients, the E/A ratio correlated inversely with awake diastolic BP (r - 0.63; p = 0.005); sleep systolic BP (r - 0.48; p = 0.04), and sleep diastolic BP (r - 0.67; p = 0.002). The AN correlated with diastolic interventricular septum thickness (r 0.57; p = 0.01), sleep systolic BP (r 0.45; p = 0.05), sleep diastolic BP (r 0.54; p = 0.02), and correlated inversely with systolic and diastolic sleep BP reduction (r - 0.49; p = 0.03 and r - 0.67; p = 0.002, respectively). Finally, E/A ratio and AN score correlated between themselves (r - 0.6; p = 0.005).
Our results suggest that left ventricular diastolic dysfunction may be detected very early in type-1 diabetic patients with AN. Parasympathetic lesion and nocturnal elevations in BP could be the link between AN and diastolic ventricular dysfunction.
... Moreover, the spectrum of left ventricular (LV) functional abnormalities characterizing this syndrome is not well defined. CAN has been related to altered LV filling patterns in the presence of preserved systolic function in patients with type 1 (7)(8)(9)(10)(11) as well as T2DM (12). However, these findings may simply reflect the parallel development of diabetic complications with poor metabolic control, and the independence of the association has not been investigated relative to factors with known involvement in DCM. ...
... The parallel association of reduced Em with global CAN based on clinical assessment and myocardial uptake of 123 I-MIBG, in addition to the independent regional association in the free wall (mid-anterior and lateral walls) suggests that the diastolic impairment central to autonomic cardiopathy is linked to cardiac sympathetic denervation. These results concur with previously reported correlations between CAN and altered LV filling patterns, mainly in type 1 diabetes mellitus (7)(8)(9)(10)(11) but also in T2DM (12), in addition to associations of global sympathetic denervation with diastolic dysfunction in type 1 diabetes mellitus (25,26). The present study builds on previous findings by defining regional associations accompanying the independent global association in T2DM, for which the pathophysiology of LV dysfunction may be markedly different compared with type 1 diabetes mellitus due to increased contributions from insulin resistance, obesity, and hypertension. ...
The purpose of this study was to investigate the independent association between global cardiac autonomic neuropathy (CAN) and left ventricular (LV) dysfunction in addition to regional associations of LV dysinnervation and function, in patients with type 2 diabetes mellitus (T2DM).
CAN represents a potential mechanism in the etiology of nonischemic diabetic cardiomyopathy.
Clinical measures of CAN based on total spectral power of heart rate variability and cardiac reflex testing and echocardiographic assessment of LV function were performed in 118 patients with type 2 diabetes mellitus. Systolic and diastolic function were defined at rest and peak exercise using peak systolic and peak early diastolic (Em) tissue velocities, calculated in 6 basal- and mid-segments using color tissue Doppler. Iodine 123-metaiodobenzylguanidine imaging was performed in 33 patients to directly quantify global (heart/mediastinum ratio) and regional LV sympathetic integrity.
Patients with CAN demonstrated higher resting heart rate, systolic and mean blood pressures, aortic stiffness, hemoglobin A(1c), and urine albumin/creatinine ratio, in addition to lower peak heart rate, chronotropic index, and exercise capacity. Diastolic function (Em) was associated with CAN, evidenced by total spectral power (r = 0.42, p < 0.001) and heart/mediastinum ratio (r = 0.41, p = 0.017). Diastolic function (Em) at rest and systolic function (peak systolic tissue velocity) at rest and exercise were significantly reduced in patients with CAN. Furthermore, total spectral power was associated with Em independent of age, hypertension, metabolic factors, and other relevant contributors to LV dysfunction (β = 0.20, p = 0.035). Relative regional tracer deficits indicative of local denervation were predominant in the anterior and lateral walls (p < 0.001). Associations with regional Em, independent of global iodine 123-metaiodobenzylguanidine uptake, were identified exclusively in mid-anterior (β = 0.45, p = 0.01) and mid-lateral walls (β = 0.34, p = 0.03). However, no association was found between regional denervation and systolic or diastolic dyssynchrony.
The diastolic dysfunction of type 2 diabetes mellitus shows associations with both regional markers of sympathetic integrity and clinical markers of autonomic neuropathy.
... Abnormal systolic blood pressure response to standing was significantly correlated with a reduced mitral E/A ratio. Other studies have related parasympathetic neuropathy with LV diastolic dysfunction [53, 59, 60]. Uusitupa et al. [53] found a significantly lower mean heart rate variation during deep breathing in diabetic subjects with abnormal diastolic peak filling rate than in those with normal filling. ...
... Uusitupa et al. [53] found a significantly lower mean heart rate variation during deep breathing in diabetic subjects with abnormal diastolic peak filling rate than in those with normal filling. Monteagudo et al. [59] found a lower mitral E/A ratio at echocardiography (1.1 vs. 1.6, p < 0.005) in the group of patients with autonomic neuropathy compared to those without; furthermore, a significant correlation between E/A ratio and autonomic neuropathy (r = – 0.6, p = 0.005) was also found. ...
The existence of a diabetic cardiomyopathy has been proposed as evidence has accumulated for the presence of myocardial dysfunction in diabetic patients in the absence of ischemic, valvular or hypertensive heart disease. Diastolic dysfunction has been described as an early sign of this diabetic heart muscle disease preceding the systolic damage. Abnormalities in diastolic performance have been first demonstrated by cardiac catheterisation and subsequently by mainly using echocardiography. The pathogenesis of this left ventricular dysfunction is not clearly understood. Microangiopathy, increased extracellular collagen deposition, or abnormalities in calcium transport alone or in combination are considered to be associated with this dysfunction. The relationship between diastolic dysfunction and glycemic control is still a matter of debate. Some epidemiological and clinical arguments suggest that diastolic abnormalities may contribute to the high morbidity and mortality among diabetic patients. However, the prognostic importance of subclinical diastolic dysfunction and the possibilities for intervention are not fully known. Eventually, despite numerous studies, evidence of an intrinsic diastolic dysfunction in diabetes mellitus remains questionable. Indeed, quite contradictory results have been reported. They have been obtained in small, inhomogeneous populations, with sometimes confounding factors, using various echocardiographic indices with known limitations. Also, further studies using more refined techniques for the evaluation of diastolic function are needed, as a prerequisite, to unequivocally relate diabetes mellitus to a specific cardiomyopathy.
... The increase in cardiovascular morbidity and mortality is mainly due to accelerated atherosclerosis in Type 2 diabetic patients, presumably augmented by a specific diabetic cardiomyopathy and autonomic neuropathy [1,2]. These factors could induce changes in cardiac function, including impairment of diastolic filling as an early consequence [3]. ...
... Previous studies in patients with hypertension have in general demonstrated an increased LV mass [1,4,5] and impaired systolic as well as diastolic dysfunction [1][2][3][4][5] in diabetic as compared with non-diabetic patients. However, whether the impairment in cardiac function is independent of the concomitant increase in LV mass has not been extensively studied. ...
Type 2 diabetic patients with hypertension have an increased left ventricular (LV) mass and impaired cardiac function compared to hypertensive patients without diabetes. However, it is unknown if the impaired cardiac function can be explained solely by LV hypertrophy, or is independently related to diabetes. The aim of the present study was to compare LV function between diabetic and non-diabetic hypertensive patients with electrocardiographic LV hypertrophy.
In 937 patients participating in the LIFE echocardiographic substudy, all echocardiograms were centrally evaluated by a core reading centre measuring LV mass, systolic and diastolic LV function. Known diabetes was present in 105 patients.
Left ventricular mass was similar in diabetic and non-diabetic patients. Endocardial systolic LV function, estimated by LV ejection fraction, was reduced and indices of midwall systolic LV function were impaired in the diabetic patients. Diastolic LV filling pattern was impaired and arterial stiffness, measured by pulse pressure/stroke index, was increased in diabetic patients.
Systolic and diastolic LV function in hypertensive patients with electrocardiographic LV hypertrophy and diabetes are impaired independent of LV mass, most likely reflecting the adverse effects of diabetes per se.
... Cardiac Autonomic Neuropathy (CAN) is defined by the Toronto Consensus Panel on Diabetic Neuropathy (2011) [12] as "impaired cardiovascular autonomic control in patients with established diabetes after excluding other causes". It has been proposed to be associated with alterations in coronary flow and cardiac function, contributing to impaired diastolic function [13][14][15]. Attenuation of heart rate with respiration, Valsalva maneuver, reduced heart rate variability and reduced heart rate recovery after exercise [16] indicate the presence of NAC. Cardiac Autonomic Reflex Tests (CARTs) are proposed as the gold standard by the Toronto Consensus Panel on Diabetic Neuropathy (2011) to diagnose the presence of CAP. ...
... Studies also reflect an association between parasympathetic and cardiac dysfunction as evidenced by the association between significantly lower mean heart rate variation during deep breathing, and abnormal diastolic peak filling rate in diabetic patients (Uusitupa et al., 1988). The mitral E/A ratio have been shown to be significantly reduced in patients with autonomic neuropathy and a significant correlation was observed between the E/A ratio and autonomic neuropathy (Monteagudo et al. 2000). ...
Review paper about the pathological aspects of cardiovascular disease.
... In T2DM patients both systolic and diastolic dysfunction was related to altered sympathetic function [53]. Several studies also show an association between parasympathetic and cardiac dysfunction with decreased mean heart rate variation [54]. ...
Evidence from clinical trials repeatedly confirms the association of diabetes with heart failure, independent of hypertension, atherosclerosis, coronary artery disease and valvular heart disease. However, the importance of coexistence of diabetes and heart failure is not universally recognized, despite the fact that it may significantly contribute to morbidity and mortality of the diabetic population. It seems that prevention of heart failure, early diagnosis, and appropriate management could improve the outcome. Unfortunately, the etiology of heart failure in diabetic patients is still to be elucidated. It is multifactorial in nature and several cellular, molecular and metabolic factors are implicated. Additionally, there are still no definite guidelines on either the diagnosis and treatment of heart failure in diabetic patients or on the therapy of diabetes in subjects with heart failure. This review focuses on the pathophysiology, diagnosis, and prevention of heart failure in the diabetic population as well as management of both comorbidities.
... Ventricular filling abnormalities are also prevalent in diabetic patients with autonomic neuropathy independent of duration of diabetes, presence of retinopathy, HbA1, or blood glucose levels [44]. A significant correlation has been described between the E/A ratio and autonomic neuropathy [45]. ...
Diabetic cardiomyopathy is defined as the presence of myocardial dysfunction in patients with diabetes in the absence of coronary artery disease, hypertension, or other known cardiac disease. Diabetes has been shown to affect the heart through various cellular mechanisms leading to enhanced myocardial fibrosis, left ventricular hypertrophy, systolic and diastolic dys-function. With increasing incidence of type II diabetes mellitus, it has continuously rising health and financial implications in both developed and developing countries. Hyperglycaemia seems to be the main deriving force, and careful glycaemic control as well as early administration of neurohormonal antagonists currently remains the mainstay of therapy. Many newer treatment targets are currently being explored. Here we present a brief review of its pathophysiology, association with heart failure symptoms, and management strategies.
... Studies also reflect an association between parasympathetic and cardiac dysfunction as evidenced by the association between significantly lower mean heart rate variation during deep breathing, and abnormal diastolic peak filling rate in diabetic patients (Uusitupa et al., 1988). The mitral E/A ratio have been shown to be significantly reduced in patients with autonomic neuropathy and a significant correlation was observed between the E/A ratio and autonomic neuropathy (Monteagudo et al. 2000). ...
ARTICLE INFO ABSTRACT Fatal and non-fatal Coronary Artery Diseases (CAD) are increased 2-4 fold in patients with diabetes and autopsy as compared to non-diabetic patients with Coronary Heart Disease (CHD). Immediate and long-term post-Myocardial Infarction (MI) mortality is increased 1.5-2 fold among diabetic patients. Despite a comparably small infarct size, diabetic patients have a far greater risk of developing highly fatal post-MI complications when compared to non diabetic patients. Following MI, the surviving myocardium of non-diabetic patients becomes hyperkinetic to compensate for non-viable infarcted myocardium in an attempt to maintain cardiac output. However, in diabetic patients, these areas of myocardium cannot achieve this compensatory enhancement in function due to a complex set of intra-and extra-myocardial factors superimposed on an already reduced coronary artery flow reserve. Endomyocardial samples from diabetic patients show enhanced thickening of capillary basement membrane, myocellular atrophy and hypertrophy with myocardial and, interstitial fibrosis, which further reduces the function of the myocardium. In this review the author have looked into various cardiovascular complications in diabetic condition and the pathophysiological mechanisms lying behind each. Copyright © Dr. Pratima Tripathi. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
... In addition to abnormal diastolic filling, an abnormal systolic blood pressure in response to standing up was significantly associated with reduced mitral E/A ratio (ratio of early to late peak mitral filling wave velocities). The E/A ratio has been shown to be significantly reduced in patients with autonomic neuropathy, suggesting a significant correlation between E/A ratio and autonomic neuropathy [74]. Studies also revealed that parasympathetic dysfunction was associated with abnormal cardiac function. ...
Diabetes mellitus is one of the most common chronic diseases across the world. Cardiovascular complication is the major morbidity and mortality among the diabetic patients. Diabetic cardiomyopathy, a new entity independent of coronary artery disease or hypertension, has been increasingly recognized by clinicians and epidemiologists. Cardiac dysfunction is the major characteristic of diabetic cardiomyopathy. For a better understanding of diabetic cardiomyopathy and necessary treatment strategy, several pathological mechanisms such as impaired calcium handling and increased oxidative stress, have been proposed through clinical and experimental observations. In this review, we will discuss the development of cardiac dysfunction, the mechanisms underlying diabetic cardiomyopathy, diagnostic methods, and treatment options.
... Several authors have demonstrated cardiac sympathetic dysfunction in diabetic patients, even without myocardial perfusion abnormalities [126,177]. At the same time, others have described a correlation between myocardial sympathetic innervation derived from scintigraphy analysis and the E/A ratio in Doppler echocardiography, providing evidence that an abnormal sympathetic innervation of the heart may contribute to a disturbance in LV filling [136,138]. This effect was more severe in type 2 diabetes patients than that in type 1 patients, particularly involving inferoposterior segments of the heart [206]. ...
Diabetes mellitus is an important and prevalent risk factor for congestive heart failure. Diabetic cardiomyopathy has been defined as ventricular dysfunction that occurs in diabetic patients independent of a recognized cause such as coronary artery disease or hypertension. The disease course consists of a hidden subclinical period, during which cellular structural insults and abnormalities lead initially to diastolic dysfunction, later to systolic dysfunction, and eventually to heart failure. Left ventricular hypertrophy, metabolic abnormalities, extracellular matrix changes, small vessel disease, cardiac autonomic neuropathy, insulin resistance, oxidative stress, and apoptosis are the most important contributors to diabetic cardiomyopathy onset and progression. Hyperglycemia is a major etiological factor in the development of diabetic cardiomyopathy. It increases the levels of free fatty acids and growth factors and causes abnormalities in substrate supply and utilization, calcium homeostasis, and lipid metabolism. Furthermore, it promotes excessive production and release of reactive oxygen species, which induces oxidative stress leading to abnormal gene expression, faulty signal transduction, and cardiomyocytes apoptosis. Stimulation of connective tissue growth factor, fibrosis, and the formation of advanced glycation end-products increase the stiffness of the diabetic hearts. Despite all the current information on diabetic cardiomyopathy, translational research is still scarce due to limited human myocardial tissue and most of our knowledge is extrapolated from animals. This paper aims to elucidate some of the molecular and cellular pathophysiologic mechanisms, structural changes, and therapeutic strategies that may help struggle against diabetic cardiomyopathy.
... 63 A significant association between a decrease of the transmitral ratio of early to late peak mitral filling wave velocities and the augmentation of sympathetic myocardial neurosis has also been demonstrated. 64 This relationship has confirmed that in DCM, the abnormal cardiac sympathetic neurosis contributes to the abnormal LV filling. The transmitral ratio of early to late peak mitral filling has also been associated with orthostatic hypotension as a clinical manifestation of CAN. ...
Diabetic cardiomyopathy (DCM), although a distinct clinical entity, is also a part of the diabetic atherosclerosis process. It may be independent of the coexistence of ischemic heart disease, hypertension, or other macrovascular complications. Its pathological substrate is characterized by the presence of myocardial damage, reactive hypertrophy, and intermediary fibrosis, structural and functional changes of the small coronary vessels, disturbance of the management of the metabolic cardiovascular load, and cardiac autonomic neuropathy. These alterations make the diabetic heart susceptible to ischemia and less able to recover from an ischemic attack. Arterial hypertension frequently coexists with and exacerbates cardiac functioning, leading to the premature appearance of heart failure. Classical and newer echocardiographic methods are available for early diagnosis. Currently, there is no specific treatment for DCM; targeting its pathophysiological substrate by effective risk management protects the myocardium from further damage and has a recognized primary role in its prevention. Its pathophysiological substrate is also the objective for the new therapies and alternative remedies.
... 77 Autonomic dysfunction brings with it an adverse cardiovascular outlook,withincreasedmortality,leftventricular dysfunction, and risk of sudden death in diabetic patients with or without myocardial ischemia. [78][79][80][81][82][83] There may be several reasons for this finding. First, diabetic patients with autonomic dysfunction have a higher resting heart rate than nondiabetic patients, 84 whichmightlogicallyincrease myocardial oxygen requirements, reduce coronary blood flow (shortened diastole), and exacerbate myocardial ischemia. ...
With diabetes mellitus reaching epidemic proportions, mainly secondary to obesity, the impact of cardiovascular disease due to this combination makes it a dominant public health problem during the first quarter of the 21st century. The complex interaction that results in diabetic heart disease is created by overlapping mechanisms. There is a propensity to develop premature, diffuse atherosclerotic coronary disease, which is associated with adverse short- and long-term morbidity and mortality. There are structural and functional abnormalities of the microvasculature, autonomic dysfunction, and intrinsic failure of myocardial contraction (so-called diabetic cardiomyopathy). These changes are amplified by arterial hypertension and kidney disease. In this review, we consider the role of the renin-angiotensin-aldosterone system and how it is a crucial driver of most of the pathophysiologic mechanisms behind diabetic heart disease and why in the past 5 years blocking this system in diabetic patients has emerged as a critical therapeutic intervention.
Cardiovascular diseases account for a major component of the morbidity and mortality affiicting patients with diabetes. Nearly 77% of all hospitalizations attributable to medical complications in patients with diabetes are cardiovascular in nature. Cardiovascular disease event rates and mortality among patients with diabetes are on the rise, although they are decreasing in individuals without diabetes (1,2). The effect of diabetes on the heart includes a wide spectrum of abnormalities that extends from subtle subclinical findings to overt clinical manifestations that may be considered under three broad categories: (1) coronary atherosclerosis; (2) diabetic cardiomyopathy; and (3) diabetic autonomic neuropathy. There is growing evidence that an early and tailored management strategy can limit or slow down the progression of diabetic heart disease and may also potentially reduce the cardiovascular event rate in this group of patients (3). This underscores the need for early and accurate detection of the manifestations of heart disease in patients with diabetes. This chapter summarizes the various diagnostic tools that are available to the clinician for the diagnosis of diabetic heart disease, and their value and utility in clinical practice. This chapter does not attempt to consider independently the important differences among patients with type 1 and type 2 diabetes, but rather addresses patients with diabetes in general, specifically referring to either type when issues unique to them are discussed.
Cardiovascular autonomic neuropathy (CAN) is the most clinically important form of diabetic autonomic neuropathy. The reported prevalence of CAN is about 20% of diabetic patients. The most important factor in the development of diabetic neuropathy is hyperglycemia. It is a background of two major pathogenetic hypotheses: metabolic and vascular. Clinical symptoms of CAN occur late in the course of this complication and are nonspecific. Major clinical manifestations include: resting tachycardia, reduced heart rate variability orthostatic hypotension, exercise intolerance, loss of day-night rhythm of blood pressure, left ventricular dysfunction.
Vascular endothelial dysfunction is a basic etiologic factor for the development
of late clinical complications in patients with diabetes mellitus type 1, such as diabetic retinopathy,
diabetic nephropathy (which is characterized at the very beginning by microalbuminuria), and left
ventricular cardiac dysfunction. The aims of this study were to determine the prevalence of asymp-
tomatic left ventricular systolic dysfunction in patients with diabetes mellitus type 1 and with or wi-
thout diabetic retinopathy and microalbuminuria, and to correlate the duration of diabetes with the
dynamics of diabetic retinopathy, microalbuminuria and asymptomatic left ventricular dysfunction
development in these patients. One-hundred and twenty selected patients with diabetes mellitus
type 1 were examined by ophthalmologist and cardiologist. All patients underwent ergometric te-
sting and two-dimensional (2-d) echocardiography with pulsed doppler. Patients were divided into
three groups according to their fundus indings and microalbuminuria: (a) patients without diabetic
retinopathy and without microalbuminuria (n=40); (b) patients with diabetic retinopathy without
microalbuminuria (n=40); and (c) patients with diabetic retinopathy and microalbuminuria (n=40).
All three groups of patients with diabetes mellitus type 1 (with low cardiovascular risk, regulated
blood sugar, and without diabetic neuropathy) had echocardiographic values in the normal range.
We found no statistically signiicant correlation between the duration of diabetes mellitus type 1
and echocardiographic values.
Key words: Diabetes mellitus, type 1; Retinopathy; Albuminuria; Ventricular function, left
Patients with type 2 diabetes suffer from cardiac diseases more often than non-diabetics. Heart diseases in diabetes typically comprise heart failure, especially heart failure with preserved ejection fraction, coronary artery disease, diabetic cardiomyopathy and cardiac autonomic diabetic neuropathy. Physical exercise not only prevents the onset of these diseases, but also influences a variety of pathophysiological mechanisms. Guidelines recommend these patients to be physically active at least 150 min/week at moderate intensity. The mean intensity is defined as 50-70% of maximum heart rate, which was determined in a stress test. In addition, strength training is recommended two times per week. A major problem concerning the implementation of these recommendations is the long-term adherence of these patients. The results of numerous studies showed that positive changes with respect to cardiovascular risk factors, morbidity and mortality can only be achieved only through long-term training programs in the form of a combination of aerobic and strength training. Therefore, the implementation of a sufficiently large number of outpatient rehabilitation facilities and the formation of sports groups for patients with diabetes in urgently needed to make this effective, safe and inexpensive therapy available to every patient in need.
Cardiovascular autonomic neuropathy (CAN) is one of the most clinically significant complications of diabetes mellitus (DM), but one of the least frequently diagnosed. In this review, we discuss the major risk factors for the development and progression of CAN in patients with DM, the natural history of autonomic neuropathy and its impact on cardiovascular disease in DM, as well as the tests for the early diagnosis and staging of CAN in the clinical practice. The bibliographic research was based on two databases: Medline and Tripdatabase, with the following descriptors: diabetic cardiovascular autonomic neuropathy and cardiovascular autonomic neuropathy and diabetes. We selected English and German articles, written between 1998 and 2007. In its initial stages (early and intermediate), CAN may be diagnosed and reversed. However, in advanced cases (severe stage), the only treatment that remains is a symptomatic one. CAN is associated with higher cardiovascular morbidity and mortality rates and poor quality of life in diabetic individuals.
The world-wide estimated prevalence of diabetes mellitus for 2025 is of about 300 million, resulting from a higher prevalence of obesity and sedentary lifestyles in the developed world. The group of cardiovascular diseases is responsible for 80% of deaths among diabetic patients. Several authors have suggested that patients with diabetes mellitus have a predisposition to develop a form of cardiomyopathy, known as «diabetic cardiomyopathy», which is not related to ischemic heart disease or hypertension, and may progress to cardiac failure. Such condition is known to be associated with a poor prognosis in patients with diabetes mellitus. The prevalence appears to be high. Thus, tissue Doppler techniques added to conventional echocardiography assessment have estimated it to be as high as 75%. However, the use of echocardiography as a screening tool in the asymptomatic diabetic population is problematic. Biomarkers of cardiac dysfunction have been proposed for diagnosis. In this article, we have assessed the role of biomarkers in the diagnosis of this condition and proposed a diagnostic algorithm that may be useful for the assessment of asymptomatic patients with diabetes.
A mieloperoxidase (MPO) é uma enzima derivada de leucócitos que catalisa a formação de numerosas espécies reativas oxidantes. Além de integrantes da resposta imune inata, evidências têm comprovado a contribuição desses oxidantes para o dano tecidual durante inflamação. A MPO participa de atividades biológicas pró-aterogênicas relacionadas à evolução da doença cardiovascular, incluindo iniciação, propagação e as fases de complicação aguda do processo aterosclerótico. Dessa forma, a MPO e sua cascata inflamatória representam um alvo atrativo para investigação prognóstica e terapêutica na doença aterosclerótica cardiovascular. Nesta revisão, apresentamos o estado da arte no entendimento das ações biológicas às evidências clínicas da relação entre MPO e doença arterial coronariana. Vários estudos apontam para o efeito independente dos níveis de MPO na evolução da doença e ocorrência de eventos em pacientes com síndrome coronariana aguda. Entretanto, ainda não é consistente o valor preditivo adicional dos níveis de MPO na estratificação de risco cardiovascular para incorporá-la à prática clínica como sinalizadora de vulnerabilidade de placa. Estudos adicionais são necessários para confirmar seu papel nas diferentes formas de apresentação da cardiopatia isquêmica, além da padronização do ensaio, ponto fundamental para a transição desse marcador do ambiente de pesquisa para uso na rotina clínica.
This chapter describes the effects of autonomic denervation in diabetic patients. Autonomic neuropathy as defined by abnormal autonomic tests is common but symptoms are rare. However when present, they can be devastating. Cardiovascular autonomic neuropathy leads to an approximately five fold risk of mortality. Autonomic neuropathy can result in hemodynamic and structural changes in the arterial system. This chapter discusses the epidemiology, etiology, and pathology of autonomic neuropathy. It then describes the effect of autonomic neuropathy on the cardiovascular, gastrointestinal, genitourinary, and respiratory systems. It outlines the effects of autonomic denervation on sweating, pupillary reflexes, the response to hypoglycemia, and erythropoietin production. Finally it discusses the clinical associations of autonomic neuropathy and concludes with a summary of its natural history, mortality, and management. Autonomic neuropathy is an important complication of diabetes, resulting in increased patient morbidity and mortality.
Interactions of glucose metabolism and chronic heart failure have been confirmed by many epidemiologic studies. The association of HbA1c with an increasing risk of heart failure clearly underlines the connection between both diseases. Coronary artery disease (CAD), hypertension and diabetic cardiomyopathy are long-term complications of diabetes mellitus, resulting in diabetic heart failure. Dysfunction of many regulation systems leads to specific diabetic cardiomyopathy, which has been firstly described by Rubler. A reduction in the cardiac expression of the Na-Ca exchanger pump and SERCA2a protein results in an imbalance in cardiac calcium handling. The overactive renin angiotensin aldosteron system (RAAS) also contributes to the impairment of myocardial function. Hyperlipidaemia, hpyerinsulinaemia and hyperglycaemia directly trigger diabetic cardiomyopathy. Generally chronic heart failure is a clinical diagnosis verified by blood tests like NT-proBNP and cardiac ultrasound. Recommendations on treatment of diabetic heart failure are based on subgroup analysis of the large heart failure trials.
Prevalence of diabetes and heart failure are increasing exponentially worldwide. Diabetes is well-known to increase the risk of heart failure independent of other traditional risk factors and ischemia. Current evidence indicates the presence of several biochemical and molecular changes associated with diabetes that lead to diastolic dysfunction or American Heart Association stage B heart failure. Some, if not all, changes may also predate the development of frank diabetes. In this review, the authors present some of the epidemiologic evidence and a brief description of major mechanistic pathways that favor the development of heart failure in prediabetic and diabetic states.
Individuals with diabetes are at a significantly greater risk of developing cardioymyopathy and heart failure despite adjusting for concomitant risks such as coronary artery disease or hypertension. This has led to the increased recognition of a distinct disease process termed as "diabetic cardiomyopathy." In this article, we perform an extensive review of the pathogenesis and treatment of this disease. From a clinical perspective, physicians should be aware of this entity, and early screening should be considered because physical evidence of early diabetic cardiomyopathy could be difficult to detect. Early detection of the disease should prompt intensification of glycemic control, concomitant risk factors, use of pharmacologic agents such as β-blockers and renin-angiotensin-aldosterone system antagosists. From a research perspective, more studies on myocardial tissue from diabetic patients are needed. Clinical trials to evaluate the development of diabetic cardiomyopathy and fibrosis in early stages of the disease, as well as clinical trials of pharmacologic intervention in patients specifically with diabetic cardiomyopathy, need to be conducted.
Interactions of glucose metabolism and chronic heart failure have been confirmed by many epidemiologic studies. The association of HbA1c with an increasing risk of heart failure clearly underlines the connection between both diseases. Coronary artery disease (CAD), hypertension and diabetic cardiomyopathy are long-term complications of diabetes mellitus, resulting in diabetic heart failure. Dysfunction of many regulation systems leads to specific diabetic cardiomyopathy, which has been firstly described by Rubler. A reduction in the cardiac expression of the Na-Ca exchanger pump and SERCA2a protein results in an imbalance in cardiac calcium handling. The overactive renin angiotensin aldosteron system (RAAS) also contributes to the impairment of myocardial function. Hyperlipidaemia, hpyerinsulinaemia and hyperglycaemia directly trigger diabetic cardiomyopathy. Generally chronic heart failure is a clinical diagnosis verified by blood tests like NT-proBNP and cardiac ultrasound. Recommendations on treatment of diabetic heart failure are based on subgroup analysis of the large heart failure trials.
The pathophysiological mechanisms responsible for increased cardiovascular mortality in diabetic autonomic neuropathy (AN) are largely unknown. The aim was to determine the relative role of AN in the pathogenesis of cardiac diastolic dysfunction and left ventricular hypertrophy in Type 1 diabetes.
Ten Type 1 diabetic patients with AN, defined by cardiovascular tests (AN+) and 10 age- and sex-matched patients without neuropathy (AN-) as well as 10 healthy subjects (C) participated in the study. Left ventricular diastolic function was assessed by Doppler echocardiography, whilst systolic function was evaluated by cine magnetic resonance (MR) imaging.
Doppler echocardiography showed a significant decrease in E/A ratio, i.e. the ratio between peak Early transmitral filling velocity during early diastole (E-wave) and peak transmitral Atrial filling velocity during late diastole (A-wave), in AN+ compared with C (P < 0.01) [0.95 +/- 0.08 (mean +/- sem) (AN+); 1.19 +/- 0.09 (AN-); 1.33 +/- 0.10 (C)]. The E-wave deceleration time was significantly shorter in AN+ compared with AN- and C (P < 0.02) [178 +/- 7 ms (AN+); 203 +/- 9 ms (AN-); 205 +/- 9 ms (C)]. Cine MR imaging showed a significantly greater left ventricular mass index in AN+ compared with C [103 +/- 4 g/m(2) (AN+) vs. 98 +/- 7 (AN-) and 92 +/- 4 g/m(2) (C), P < 0.05].
Autonomic neuropathy is associated with left ventricular hypertrophy and diastolic dysfunction in Type 1 diabetic patients.
Diabetic cardiomyopathy is characterized by a prominent interstitial fibrosis. Postulated etiologies include microangiopathy, autonomic neuropathy, and metabolic factors. A common root of these pathologies is hyperglycemia or hyperinsulinemia, both of which are prominent in type 2 diabetes mellitus, which has the highest incidence of cardiovascular morbidity and mortality. The relative importance of each factor is a matter of debate; it is likely that both of these factors in addition to the concomitant risk factors seen in diabetics (dyslipidemias, hypertension, obesity, coagulation abnormalities) contribute to the spectrum of myocardial disease in diabetes. A discussion of these contributive pathologies and the hyperglycemia and hyperinsulinemia that underlie them is the subject of this review. Treatment methodologies to control the development of such pathology also are discussed.
Independent of the severity of coronary artery disease, diabetic patients have an increased risk of developing heart failure. This clinical entity has been considered to be a distinct disease process referred to as 'diabetic cardiomyopathy'. Experimental studies suggest that extensive metabolic perturbations may underlie both functional and structural alterations of the diabetic myocardium. Translational studies are, however, limited and only partly explain why diabetic patients are at increased risk of cardiomyopathy and heart failure. Although a range of diagnostic methods may help to characterize alterations in cardiac function in general, none are specific for the alterations in diabetes. Treatment paradigms are very much limited to interpretation and translation from the results of interventions in non-diabetic patients with heart failure. This suggests that there is an urgent need to conduct pathogenetic, diagnostic and therapeutic studies specifically in diabetic patients with cardiomyopathy to better understand the factors which initiate and progress diabetic cardiomyopathy and to develop more effective treatments.
In subjects without underlying cardiac disease dobutamine is known to enhance systolic LV function and LV relaxation. As end-systolic (ES) and end-diastolic (ED) volumes (V) can be derived from gated SPECT we intent to study these volumes and their response to dobutamine in order to have a better understanding of the mechanism by which stroke volume (SV) increases during dobutamine infusion. We intent to do this in normal controls and in young diabetic subjects.
After injection of sestamibi, serial gated SPECT were obtained at baseline, and during low doses of dobutamine infusion in 12 asymptomatic type I diabetic patients, and in 12 age matched controls. LV EDV, ESV, SV and EF were calculated with the QGS program.
Gated SPECT showed comparable LV EF and SV in both groups at rest. There was a significant increase in LVEF and SV during dobutamine infusion but in the diabetic patients the increase in SV was due to a decrease in ESV from 25+/-5 to 20+/-6 ml/m2 (p=0.002) and no change in EDV. In normal controls, the increase in EF was due to an increase in EDV from 69+/-10 to 73+/-12 ml/m2 (p=0.002) with no significant change in ESV.
These data confirm the presence of subclinical abnormalities of diastolic function in asymptomatic type I diabetic patients and show differences in adaptation to inotropic stimulation in order to preserve the increase in stroke volume and LV ejection fraction.
This study was designed to determine the effects of type 1 diabetes mellitus (T1DM) on left ventricular (LV) and particularly left atrial (LA) structure and function. We evaluated 88 non-obese subjects: 44 with T1DM, 44 age- and gender-matched normal controls (age 39 +/- 11 years). LV and LA structure and function were quantified using two-dimensional echocardiography, pulse-wave Doppler, and tissue Doppler imaging, including early and late diastolic myocardial velocities (Em global and Am global, respectively). The T1DM subjects averaged higher heart rate, relative wall thickness, and ejection fraction, and lower indexed end-systolic volume than normal controls (P < .001, P < .05, P = .01, and P < .05, respectively). T1DM was related to A wave velocity, Am global, A wave integral, LA ejection fraction, and LA systolic ejection fraction (P < .01, P < .05, P < .0005, P < .001, and P < .0005, respectively). In multivariate analyses, T1DM was an independent predictor of the A wave integral, LA ejection fraction, and LA systolic ejection fraction (P < .01, P < .01, and P < .005, respectively). Thus, despite increased relative wall thickness, LV systolic function is increased and early diastolic filling is normal in T1DM subjects; however, they possess changes in LA transport function suggesting increased reliance on LA contribution to LV filling.
This article focuses on advances in the understanding of the pathogenesis and treatment of diabetic cardiomyopathy. Patients with diabetes are at an elevated risk for heart failure, and comorbid heart failure confers an increased risk of morbidity and mortality. Diabetic cardiomyopathy is a distinctive syndrome that also confers high risk. Every effort should be made to diagnose patients with diabetic cardiomyopathy and to apply proven lifesaving therapies in all heart failure patients, including those with diabetes, in the absence of contraindications or intolerance.
Diabetes mellitus (DM) has been found to be associated with depressed left ventricular (LV) function. Right ventricular (RV) function in DM patients, however, has not been well studied. The goal of this study was to evaluate the occurrence of LV and RV dysfunction in patients with DM. A series of 157 patients underwent simultaneous measurement of LV ejection fraction (LVEF) and RV ejection fraction (RVEF). Four of 26 DM patients had RVEF <30% (15.4%) vs 4 of 126 controls (3.2%) (P=.01). Eleven of 27 (40.7%) patients with DM had LVEF <30% vs 9 of 128 controls (7%) (P<.0001). Using multivariate analysis, DM remained independently associated with severely decreased biventricular function (RVEF <30%; odds ratio, 5.7; confidence interval, 1.3-25.4 [P=.02] and LVEF <30%; odds ratio, 12.9; confidence interval, 3.8-43.7 [P<.0001]). These results suggest that diabetic cardiomyopathy involves both ventricles as an independent pathologic process.
Diabetic cardiomyopathy is a well-defined complication of diabetes that occurs in the absence of ischemic heart disease or hypertension. Moreover impaired circadian blood pressure (BP) variation has been associated with autonomic dysfunction. The aim of our study was to evaluate diurnal BP fluctuations and autonomic function and their association with left ventricular function in adolescents with Type 1 diabetes mellitus (T1DM). In 48 normotensive, normoalbuminuric diabetic adolescents, with a mean (+/-SD) age of 17.3 (+/-4.1) yr and a mean (+/-SD) diabetes duration of 8.5 (+/-3.3) yr, 24-h ambulatory BP was recorded. Moreover 24-h heart rate (HR) monitoring was performed. Myocardial structural parameters were studied by echocardiogram. Left ventricular end-diastolic (EDDLV) and end-systolic diameters (ESDLV) were estimated and left ventricular mass index (LVMI) was calculated using the Devereux formula. The patients were divided into 2 groups according to the absence of decrease (non-dippers) or the decrease (dippers) of nocturnal diastolic BP (DBP). The non-dippers showed, in comparison with the dippers, reduced mean 24-h HR (79.6 vs 84.0 beats/min, p=0.05) and reduced mean day-time HR (81.3 vs 86.0 beats/min, p=0.05). The nondippers also presented greater ESDLV (28.7 vs 25.9 mm, p=0.001) and EDDLV (47.8 vs 45.1 mm, p=0.040), and LVMI (90.2 vs 78.3 g/m2, p=0.044), in comparison with the dippers. During stepwise multiple regression, the most important variables affecting LVMI were mean HR (day): (b=-0.40, p=0.001), high frequency domain variable of HR variability (b=0.38, p=0.016) and glycosylated hemoglobin (b=0.67, p=0.001). In conclusion, we found that a group of normotensive diabetic adolescents with impaired nocturnal BP reduction, also had autonomic dysfunction, together with impaired left ventricular function. These findings suggest that there is a close relationship between autonomic function and left ventricular remodeling in patients with T1DM, which may be attributed to altered diurnal BP profile, autonomic neuropathy and poor glycemic control.
Left ventricular diastolic function was assessed by pulsed Doppler echocardiography in 21 subjects (mean age 48 yr) with insulin-dependent diabetes mellitus (IDDM) and without evidence of ischemic heart disease and in 21 healthy control subjects of similar age and sex distribution. The peak mitral valve flow velocities during the early rapid filling phase (E) and during late atrial filling (A) were measured, and the ratio of these peak flow velocities (E:A) was calculated. E was similar in both groups, but A was higher (P less than .01) in the diabetic group. Thus, E:A was lower (1.19 +/- 0.24 vs. 1.65 +/- 0.67; P less than .01) in the diabetic subjects than in the control subjects. On subgroup analysis, 6 patients with cardiac autonomic neuropathy had lower E:A than the patients with no such disorder (0.99 +/- 0.15 vs. 1.29 +/- 0.25; P less than .05). E:A was not related to the duration of diabetes, presence of retinopathy, HbA1, or blood glucose levels. In conclusion, the atrial contribution to left ventricular filling seems to be augmented in diabetic subjects. This finding indirectly supports the view that left ventricular compliance is already reduced in asymptomatic diabetic subjects.
To evaluate the relationship between autonomic neuropathy, nephropathy, and 24-h blood pressure (BP) pattern in insulin-dependent diabetes mellitus (IDDM).
We studied 30 normotensive IDDM patients without overt nephropathy, divided into two groups and matched for age, duration of diabetes, and HbA1, according to the presence of cardiovascular autonomic neuropathy. We simultaneously measured 24-h BP and urinary albumin excretion rate (UAE) on urine collections timed overnight and at 2-h intervals during the day.
Mean day and night systolic and diastolic BP values did not significantly differ between the groups. Mean night albuminuria was significantly higher in patients with autonomic neuropathy than in those without (61.4 +/- 104.6 [mean +/- SD] vs. 16 +/- 25.2 micrograms/min, P < 0.04). The percentages day-night changes in systolic BP, diastolic BP, and UAE were significantly lower in neuropathic patients (systolic BP: 2.4 +/- 7.7 vs. 9.6 +/- 4.2%, P < 0.001; diastolic BP: 8.4 +/- 6.9 vs. 15.5 +/- 5.4%, P < 0.002; UAE: -8 +/- 99.4 vs. 49.3 +/- 29.4%, P < 0.02) and were inversely related to autonomic score, index of autonomic neuropathy degree (r = -0.54, P < 0.002; r = -0.58, P < 0.001; and r = -0.53, P < 0.005, respectively). In patients with autonomic neuropathy, 2-h day periods and day and night UAE were more strongly related, respectively, to mean 2-h day periods (r = 0.58, P < 0.0001), day systolic BP (r = 0.67, P < 0.04), and night systolic BP (r = 0.69, P < 0.04) than in patients without autonomic neuropathy (2-h day periods: r = 0.32, P < 0.001; day: r = 0.37, NS; night: r = 0.35, NS).
Autonomic neuropathy in IDDM patients is associated with reduced nocturnal falls in BP and UAE and with a stronger relationship of UAE to systolic BP. We suggest a pathogenetic role of autonomic neuropathy in the development of diabetic nephropathy through changes in nocturnal glomerular function and by enhanced kidney vulnerability to hemodynamic effects of BP.
In diabetic autonomic neuropathy, abnormal circadian patterns of blood pressure and sympathovagal balance with reduced fall of blood pressure and prevalence of sympathetic activity during the night have been described. To correlate the abnormalities of blood pressure to those of sympathovagal balance, we simultaneously performed 24-h noninvasive monitoring of blood pressure and ECG in 25 diabetic patients (45.6 +/- 13.6 yr of age with a 17.6 +/- 9.1 yr duration of diabetes) with various degrees of cardiovascular reflex impairment. Autoregressive power spectrum analysis of RR interval variability was applied to 24-h ECG recordings to obtain for day and night periods the mean power of low- (0.03-0.15 Hz) and high-frequency (0.18-0.40 Hz) components, which are relative markers of sympathetic and vagal activity, respectively, and their ratio (low frequency/high frequency), assumed as index of sympathovagal balance. Diabetic patients showed a lower percentage of day-night change in systolic blood pressure (9 +/- 5.48 vs. 11.6 +/- 4.78%, P < 0.037), a lower day low frequency (5.9 +/- 0.81 vs. 6.62 +/- 0.73 In-ms2, P < 0.001), a lower night high frequency (6.06 +/- 0.71 vs. 6.52 +/- 0.85 In-ms2, P < 0.05), a lower day low frequency:high frequency ratio (1.82 +/- 1.77 vs. 3.05 +/- 1.82, P < 0.01), and a lower percentage of day-night change in low-frequency:high frequency ratio (-13.4 +/- 109.9 vs. 28.7 +/- 29.7%, P < 0.05), when compared with control subjects.(ABSTRACT TRUNCATED AT 250 WORDS)
The increased incidence of congestive heart failure and the increased mortality and morbidity in the diabetic patient following myocardial infarction or coronary artery bypass graft can be explained by the presence of diabetic cardiomyopathy. Noninvasive studies in young diabetic patients show no cardiac abnormality, but in older diabetic patients mild cardiac diastolic dysfunction is detectable. This mild cardiomyopathy can become clinically detectable in the presence of hypertension and can be severe in the presence of myocardial ischemia. Microvascular disease is unlikely to cause diabetic cardiomyopathy. Cellular changes, including defects in calcium transport and fatty acid metabolism, may lead to myocellular hypertrophy and myocardial fibrosis, initially causing diastolic dysfunction that may advance to systolic dysfunction. Glycemic control, energetic detection and treatment of hypertension with appropriate antihypertensive agents, and early detection and treatment of ischemic heart disease are essential in preventing and treating diabetic cardiomyopathy.
In diabetic patients, the pathophysiologic mechanisms of exercise-induced left ventricular (LV) dysfunction remain controversial. In this study, the role of myocardial contractility recruitment in determining an abnormal LV response to isometric or dynamic exercise has been investigated in 14 diabetic patients with autonomic dysfunction. Ischemic heat disease was excluded by the absence of LV wall motion abnormalities induced by isotonic and isometric exercise and by coronary angiography. Left ventricular and myocardial function were studied at rest, and during isometric and isotonic exercise, by two-dimensional echocardiography; moreover, recruitment of an inotropic reserve was assessed by postextra-systolic potentiation at rest and at peak handgrip. An abnormal response of LV ejection fraction to isometric (9/14) or to dynamic (8/14) exercise was frequent in study patients. In these patients, baseline myocardial contractility was normal, and the significant increase in ejection fraction by postextrasystolic potentiation indicated a normal contractile reserve (65 ± 7% vs. 74 ± 6%, p=0.001). Nevertheless, the downward displacement of LV ejection fraction-systolic wall stress relationships during exercise suggests an inadequate increase in myocardial contractility. However, the abnormal ejection fraction at peak handgrip was completely reversed by postextrasystolic potentiation (67 ± 6% vs. 58.1 ± 10%, p=0.008), a potent inotropic stimulation independent of the integrity of adrenergic cardiac receptors. A defective inotropic recruitment, despite the presence of a normal LV contractile reserve, plays an important role in deexercise LV dysfunction in diabetic patients with autonomic neuropathy.
Patients with insulin-dependent diabetes mellitus (IDDM) may develop autonomic neuropathy (AN) and cardiac complications. The association between AN and cardiac dysfunction was assessed in 34 IDDM patients (age 40 years, diabetes duration 21 years, 15 women) by echocardiography/Doppler and autonomic nerve function tests. The expiration/inspiration ratio (E/I) was used to assess parasympathetic damage, and the acceleration and brake indices for assessment of sympathetic impairment. AN was present in 21 patients. Patients with abnormal E/I (n = 11) had lower E/A ratios than patients without AN; early to atrial peak filling ratio (E/Amax) was median 1.1 (inter-quartile range 0.2) vs 1.4 (0.7), p = 0.022; early to atrial integral filling ratio (E/Aintegral) was 1.7 (0.3) vs 2.3 (1.2), p = 0.006. Patients with AN and normal E/I (sympathetic neuropathy, n = 10) and patients without AN had similar E/A ratios. E/Aintegral was also lower in patients with abnormal E/I compared with patients with AN and normal E/I; 1.7 (0.3) vs 2.2 (0.7), p = 0.008. Systolic function and cardiac dimensions were generally unaffected and similar in the three groups. In conclusion, diastolic dysfunction and parasympathetic neuropathy are related in IDDM patients.
An echocardiographic study was carried out on 23 young diabetics, 19 of whom had retinopathy. Their diastolic function was analysed by comparing the timing and pattern of mitral valve opening with the pattern of left ventricular wall movement. Only six patients had all their values within the normal range. Fourteen patients had abnormalities similar to those seen in patients with cardiomyopathy; the close time relation between mitral valve movement and wall movement was lost and mitral valve opening delayed in eight patients. Three other patients had considerable outward wall movement before mitral valve opening, which is characteristic of ischaemic heart disease. Although these studies provide no definite evidence of a cause, the abnormalities found may reflect a subclinical diabetic cardiomyopathy due to small-vessel disease.
Four hundred M-mode echocardiographic surveys were distributed to determine interobserver variability in M-mode echocardiographic measurements. This was done with a view toward examining the need and determining the criteria for standardization of measurement. Each survey consisted of five M-mode echocardiograms with a calibration marker, measured by the survey participants anonymously. The echoes were judged of adequate quality for measurement of structures. Seventy-six of the 400 (19%) were returned, allowing comparison of interobserver variability as well as examination of the measurement criteria which were used. Mean measurements and percent uncertainty were derived for each structure for each criterion of measurement. For example, for the aorta, 33% of examiners measured the aorta as an outer/inner or leading edge dimension, and 20% measured it as an outer/outer dimension. The percent uncertainty for the measurement (1.97 SD divided by the mean) showed a mean of 13.8% for the 25 packets of five echoes measured using the former criteria and 24.2% using the latter criteria. For ventricular chamber and cavity measurements, almost one-half of the examiners used the peak of the QRS and one-half of the examiners used the onset of the QRS for determining end-diastole. Estimates of the percent of measurement uncertainty for the septum, posterior wall and left ventricular cavity dimension in this study were 10--25%. They were much higher (40--70%) for the right ventricular cavity and right ventricular anterior wall. The survey shows significant interobserver and interlaboratory variation in measurement when examining the same echoes and indicates a need for ongoing education, quality control and standardization of measurement criteria. Recommendations for new criteria for measurement of M-mode echocardiograms are offered.
Left ventricular pressure and volume during diastole reflect the interaction of ventricular elastic, viscous, and inertial properties, and the completeness of myocardial relazation. Myocardial relaxation may be impaired in the acutely ischemic ventricle, partly accounting for the abnormal diastolic pressure-volume relation in this condition. Altered elasticity of its wall can cause increased stiffness of the ventricular chamber, as in aortic stenosis, coronary heart disease, and infiltrative cardiomyopathies. In aortic stenosis, increased left ventricular stiffness results in an increase in pressure increment associated with left atrial contraction. Generation of such a high filling pressure is critical in maintaining adequate end diastolic sarcomere stretch in the left ventricle and probably accounts for the frequent deterioration of patients with aortic stenosis after development of atrial fibrillation or nodal rhythm. Many signs and symptoms of cardiac failure, previously attributed to impaired systolic performance, may be due to partly to altered diastolic properties of the ventricular chambers.
We compared plasma ANF concentration in 5 diabetic-uremics with combined sympathetic-parasympathetic dysfunction with that in 9 uremic patients without autonomic impairment. Symptomatic dialysis hypotension was a major clinical problem in all diabetic-uremics. In the volume-expanded state, ANF was almost twice as high (p less than 0.025) in diabetic-uremics than in control uremics (152 +/- 29 vs 84 +/- 10 pg/ml) in the face of similar right atrial pressure (14 +/- 3 vs 12 +/- 1 cm H2O). After isolated ultrafiltration, ANF fell significantly in both groups remaining slightly (NS) higher in diabetic-uremics. The slope of the relationship between ANF and right atrial pressure was significantly (p less than 0.01) steeper in diabetic-uremics than in control uremics. The data indicate that autonomic failure amplifies the effect of atrial stretching on plasma ANF in diabetic-uremics on chronic hemodialysis treatment.
Determinants of proliferative diabetic retinopathy (PDR) that occur during the 2nd decade of insulin-dependent diabetes mellitus (IDDM) (early-onset PDR) were investigated in a nested case-control study. From an inception cohort of patients with juvenile-onset IDDM that now has 15-21 yr diabetes duration, the patients with PDR (cases, n = 74) were selected for study along with a random sample of the patients in the cohort without PDR (control subjects, n = 88). The risk of PDR was associated with poor glycemic control during the first 12 yr of diabetes. Relative to patients in the first quartile of the index of hyperglycemia, those in higher quartiles and nonattenders had a four- to fivefold risk of developing PDR. A striking relationship with cardiovascular autonomic neuropathy (CAN) was found. Relative to patients without CAN, patients with significant and mild CAN had odds ratios of 77.5 and 34.6, respectively. Patients with albumin excretion rates greater than 30 micrograms/min had moderately increased risk of PDR (ranging from 4-fold for microalbuminuria to 7-fold for proteinuria). In contrast, patients with impaired renal function had an extremely high risk of PDR. All 20 of these patients were cases, therefore the odds ratio was infinite. All three factors (poor glycemic control, CAN, and various stages of nephropathy) were associated with PDR in multiple logistic regression analysis. However, in models including glycemic control, the association between microalbuminuria or proteinuria and PDR was weakened. In conclusion, our findings are consistent with a hypothesis that the level of glycemia is a primary determinant of early-onset PDR.(ABSTRACT TRUNCATED AT 250 WORDS)
Ambulatory blood pressure (AMBP) measurements were obtained at 20-min intervals for 24 h in 25 subjects with insulin-dependent (type I) diabetes mellitus and 21 control subjects. The diabetic patients had normal kidney function (glomerular filtration rate 112.1 +/- 7.2 ml.min-1.1.73 m-2, renal plasma flow 459.0 +/- 23.4 ml.min-1.1.73 m-2) and were normotensive according to standard sphygmomanometer examinations. Mean +/- SE AMBP (systolic/diastolic in mmHg) measurements in diabetic patients (24 h, 131.7/77.2 +/- 2.9/1.8; 0600-2200, 132.3/78.4 +/- 2.9/3.4; 2200-0600, 125.1/75.7 +/- 3.9/3.4) significantly exceeded control values during all times (24 h, 121.8/70.3 +/- 2.9/1.9; 0600-2200, 120.7/71.8 +/- 2.6/2.0; 2200-0600, 108.2/61.5 +/- 6.6/2.7). Mean 24-h AMBP exceeded 135/85 mmHg in 49% of diabetic patients. The same threshold of 135/85 mmHg was used to determine the prevalence of abnormal measurements per time period (pressure burden). Pressure burden was increased twofold in diabetic patients compared with control subjects. Mean AMBP was significantly reduced at night in control subjects but not in diabetic patients. Changes in blood pressure were not related to kidney function in diabetic patients. AMBP recordings uncovered an increased prevalence of abnormal mean blood pressure, increased pressure burden, and a lack of diurnal variation of blood pressure in subjects with type I diabetes mellitus. These findings have important implications for early intervention strategies in diabetes mellitus because AMBP recordings correlate well with end-organ damage.
The hearts obtained at autopsy of 67 patients with hypertension, diabetes mellitus, or both were examined microscopically and histochemically, and the amount of fibrosis was determined. Significant differences in heart weight, interstitial fibrosis, replacement fibrosis, and perivascular fibrosis were found among the groups. The mean heart weight of the hypertensive-diabetic patients was significantly greater than that of the hypertensive patients and the diabetic patients. The amount of microscopic fibrosis increased between the groups, the lowest in hypertensive hearts, midrange in diabetic hearts, and highest in hypertensive-diabetic hearts. Total fibrosis correlated with heart weight among diabetic and hypertensive-diabetic patients and was significantly greater among patients with congestive heart failure, most of whom had histories of both hypertension and diabetes. The microscopic grade of fibrosis correlated significantly (p less than 0.01) with a quantitative, histochemical determination of the amount of collagen per milligram of total noncollagenous protein in the heart tissue. Myocardial fibrosis may contribute to the diastolic dysfunction typical of hypertensive-diabetic cardiomyopathy, in which congestive heart failure is a common sequela. The importance of hypertension in the pathogenesis of severe diabetic heart disease is discussed.
Indexes of left ventricular diastolic filling were measured by radionuclide ventriculography in 28 patients with insulin-dependent diabetes mellitus without evidence of ischemic heart disease. Six patients (21%) had abnormal diastolic filling and differed from diabetic patients with normal filling in their greater severity of cardiac autonomic neuropathy, assessed by noninvasive means, and their lower plasma norepinephrine levels in the supine (131.1 +/- 24.7 versus 356.2 +/- 58.4 pg/ml, p less than 0.01) and upright (224.9 +/- 47.8 versus 673.3 +/- 122.3 pg/ml, p less than 0.005) positions. The diabetic patients determined as having cardiac autonomic neuropathy (n = 15) had depressed left ventricular diastolic filling compared with subjects free of autonomic neuropathy, whether measured as the time to peak filling rate (154.2 +/- 12.0 versus 119.1 +/- 10.6 ms, p less than 0.05) or the time to peak filling rate normalized to the cardiac cycle length (24.3 +/- 2.2 versus 16.2 +/- 1.5%, p less than 0.01). Of the various tests of autonomic nervous system function, the strongest correlate of impaired diastolic filling was orthostasis, measured as the decrease in systolic blood pressure with standing (r = 0.584, p less than 0.001). Thus, in patients with diabetes mellitus, alterations in sympathetic nervous system activity are associated with abnormalities of left ventricular diastolic filling.
Indexes of left ventricular diastolic filling were measured by pulsed Doppler echocardiography in 21 insulin-dependent diabetic patients and 21 control subjects without clinical evidence of heart disease. No patient had chest pain or electrocardiographic changes during exercise testing. The mean age of patients was 32 years. All patients had a normal ejection fraction. Six (29%) of the 21 diabetic patients had evidence of diastolic dysfunction as assessed by the presence of at least two abnormal variables of mitral inflow velocity. The ratio of peak early to peak late (atrial) filling velocity was significantly decreased in diabetic compared with control subjects (1.24 +/- 0.21 versus 1.66 +/- 0.30, p. less than 0.001). Atrial filling velocity was significantly increased in diabetic patients (74.3 +/- 16.7 versus 60.3 +/- 12.2 cm/s, p less than 0.004), whereas early filling velocity was reduced by a nearly significant degree (88.8 +/- 12.6 versus 98.5 +/- 18.8 cm/s, p less than 0.057). The atrial contribution to stroke volume as assessed by area under the late diastolic filling envelope compared to total diastolic area was also significantly increased in diabetic compared with control subjects (35 versus 27%, p less than 0.001). Left ventricular diastolic filling abnormalities in diabetic patients did not correlate with duration of diabetes, retinopathy, nephropathy or peripheral neuropathy. These data suggest that approximately one-third of such patients have subclinical myocardial dysfunction unrelated to accelerated atherosclerosis. Doppler echocardiography may offer a reliable noninvasive means to assess diastolic function and to follow up diabetic patients serially for any deterioration in cardiac status before the appearance of clinical symptoms.
1. Diurnal patterns of urine output and sodium and potassium excretion were studied in 10 diabetic patients with and 10 without autonomic neuropathy, and in 10 normal subjects.
2. The diurnal patterns of excretion in the diabetic patients with autonomic neuropathy differed significantly from the two other groups, as a smaller proportion of the 24 h output of urine, sodium and potassium was excreted during the day and a larger proportion was excreted at night.
3. Similar changes were noted in the diurnal patterns of urinary kallikrein excretion in diabetic patients with autonomic neuropathy, and urinary kallikrein output correlated significantly with urine volume but not with urinary sodium excretion.
4. The diurnal patterns of excretion of urinary prostaglandin E2 and 6-keto-PGF1α were not significantly different in diabetic patients with autonomic neuropathy.
5. Nocturia was a common complaint in this group, and the number of nocturnal voidings correlated with night urine volume. There was no evidence of premature bladder emptying.
6. The changes observed in the day/night urine output and sodium excretion could not be explained by glycosuria, insulin regimens, impaired renal function or abnormal diurnal prostaglandin excretion; their possible relevance to the diurnal changes of urinary kallikrein excretion is discussed.
The incidence of congestive heart failure was determined in relation to prior diabetic status in 5,209 men and women aged 30 to 62 years followed up for 18 years in the Framingham study. Men aged 45 to 74 years had more than twice the frequency of congestive failure as their nondiabetic cohorts, and diabetic women had a fivefold increased risk. This excessive risk appears to be caused by factors other than accelerated atherogenesis and coronary heart disease. Even when patients with prior coronary or rheumatic heart disease were excluded, the diabetic subjects had a four- to fivefold increased risk of congestive heart failure. In women (but not men) with prior coronary disease, diabetes also imposed a threefold increased risk of congestive failure. Furthermore, the increased risk of heart failure in the diabetic patients persisted after taking into account age, blood pressure, weight and cholesterol values as well as coronary heart disease. Women with diabetes appeared to be especially vulnerable and, irrespective of coronary disease status, had twice the frequency of congestive heart failure as men. The excessive risk of heart failure among diabetic subjects was confined to those treated with insulin. The data suggest that diabetes is another discrete cause of congestive heart failure and that some form of cardiomyopathy is associated with diabetes, as a result of either small vessel disease or metabolic disorders.
1. The effect of catecholamines on the time course and amplitude of contraction and on KCl‐induced contractures has been studied in mammalian hearts.
2. Marked and reproducible contractures could be obtained in mammalian ventricular trabeculae and papillary muscles after β‐adrenergic block with propanolol or if the hearts were depleted of their catecholamine stores by reserpine or by chemical denervation with 6‐hydroxydopamine.
3. In neonatal hearts with lower endogenous catecholamine stores and poorly developed sarcoplasmic reticulum KCl contractures are easily produced.
4. Catecholamines potentiate twitch tension and relax the contracture tension under all of the above circumstances.
5. The relaxant effect of catecholamines is present during the time course of a twitch. This increased relaxation rate as well as the shortening of the time‐to‐peak of tension is independent of the variation in the duration of the action potential.
6. The shortened relaxation time is present when the action potential is shortened with anodal repolarization or prolonged with cathodal depolarization (voltage‐clamp).
7. The relaxant effect of catecholamines on the twitch is temperature and rate dependent. The effect is observed in the presence of high or low concentrations of calcium.
8. The presence of catecholamines is necessary for full relaxation of mammalian heart muscle under high performance conditions or states of calcium overload.
9. It is proposed that catecholamines exert their relaxant effect independent of their positive inotropic effect by stimulating the sequestering system (sarcoplasmic reticulum, mitochondria or sarcolemma) for calcium.
The existence of a specific cardiomyopathy secondary to diabetes mellitus is controversial. During a 2-year period, we had the opportunity to examine nine diabetic patients at autopsy who had clinically severe congestive heart failure and minimal extramural coronary artery atherosclerosis. Unexpectedly, all nine patients were found to be hypertensive. Accordingly, we initiated a detailed study of the clinical and morphological features of this group, and compared the findings to age-matched autopsied subjects with either isolated hypertension, isolated diabetes mellitus, or no heart disease.The study of the hypertensive-diabetic hearts revealed severe interstitial fibrosis, focal or confluent scars, and extensive myocytolytic activity. Comparison with the diabetic, hypertensive, and normal groups showed statistically significant differences in regard to the degree of interstitial and focal scarring, and the presence of myocytolysis. Only the hypertensive group had minimal interstitial scarring. There were no statistical differences in the small vessel changes between the four groups, although subjectively the hypertensive and hypertensive-diabetic patients had more severe disease.It is concluded that the association of diabetes mellitus and hypertension in the absence of significant coronary artery atherosclerosis may lead to a severe cardiomyopathy. Although the etiology of myocardial failure in this syndrome is uncertain, the degree of myocardial fibrosis and the frequency of myocytolytic lesions possibly related to catecholamine hypersensitivity, are potential explanations. Several studies suggesting that hypertension has adverse consequences in diabetes, as well as an animal model of hypertensive-diabetic cardiomyopathy, support our conclusion that cardiomyopathy associated with diabetes mellitus is a specific entity which may be secondary to the combined effects of diabetes and hypertension on the myocardium.
Subclinical autonomic nerve damage occurs more widely in diabetics than was hitherto suspected and is assuming greater importance because of the implications for morbidity and mortality. Symptomatic autonomic neuropathy carries a worse prognosis than any other complication of diabetes. The simple bedside tests described above can provide an objective guide to whether or not autonomic damage is present, and to what degree. Some of the troublesome symptoms in the later stages can now be more successfully treated than before. The longer-term aim of management should, however, be the prevention or reversal of autonomic damage, particularly in its early stages.
To determine whether diastolic dysfunction preceded systolic dysfunction in the evolution of diabetic cardiopathy.
A total of 157 young (mean age 26.6 years) cardiac asymptomatic type I diabetic patients and 54 age- and sex-matched healthy (nondiabetic) subjects were studied. The severity of diabetic complications (retinopathy, nephropathy, and cardiac autonomic neuropathy) was evaluated by the diabetic complication index (DCI), a sum of individual scores for each complication. Left ventricular (LV) function was studied by M-mode echocardiography. Impaired systolic and diastolic functions were presumed if at least two echocardiographic variables for systolic function (fractional shortening [FS], mean velocity of circumference fiber shortening, and stroke index) and for diastolic function (slope of anterior mitral leaflet in early diastole, isovolumic relaxation time [IRT], and left atrium emptying index) were out of the control range (mean +/- 2 SD).
Diastolic dysfunction was twice as common as systolic dysfunction (27% and 12%, respectively, P < 0.001). Of diabetic patients with systolic dysfunction, 83% had impaired diastolic function, whereas only 30% of diabetic patients with diastolic dysfunction had systolic damage (P < 0.001). On the other hand, only 3 of 157 diabetic patients (1.9%) had systolic dysfunction with preserved diastolic function (P > 0.05). Diastolic dysfunction, represented by the interval from minimal LV dimension to mitral valve opening, was seen in diabetic patients approximately 8 years after onset of diabetes and systolic dysfunction represented by FS after approximately 18 years. Diastolic dysfunction, represented by IRT, was found in the presence of mild complications (DCI = 2), and systolic dysfunction, represented by FS, was found in the presence of more severe complications (DCI = 4).
Our findings indicate that myocardial damage in patients with diabetes affects diastolic function before systolic function. The intentional assessment of diastolic function is advisable for early detection of LV dysfunction before clinical symptoms appear, with follow-up to detect further deterioration of cardiac status.
Based on our recent reports that increased myocardial contractility has been found in newly diagnosed diabetic patients, and that diastolic (D) dysfunction precedes systolic (S) dysfunction, we suggested that the development of diabetic cardiopathy passes through the following stages: (I) increased myocardial contractility, (II) intact S and D function, (III) intact S function and D dysfunction, and (IV) S and D dysfunction. The aim of this pilot study was to test this hypothesis. One hundred fifty-seven young (26.2 +/- 7.4 years) cardiac-asymptomatic patients with type I diabetes and 54 healthy subjects were studied using M-mode echocardiography. The presence of at least one of the variables for systolic function (ejection fraction, mean velocity of circumference, fiber shortening, and stroke index) or diastolic function [left atrium emptying index (LAEI), EFo slope of anterior mitral leaflet, and isovolumetric relaxation time (IRT)] outside the control mean +/- 2 SD was interpreted as an increased or depressed myocardial contractility, and diastolic dysfunction, respectively. The severity of diabetic complications (retinopathy, nephropathy, and cardiac autonomic neuropathy) was evaluated by the diabetic complication index (DCI = 0 divided by 6 scores). Our hypothesis was confirmed significantly (p < 0.001) in 148 (94%) patients with diabetes. Duration of diabetes and DCI progressed significantly (ANOVA: F = 36.6, p < 0.001; F = 70.8, p < 0.001) with hypothetical stages. Diastolic dysfunction was more pronounced in stage IV than in stage III: IRT (80.5 +/- 18.6 ms vs. 62.5 +/- 16.4, p < 0.001), EFo (63 +/- 15 mm/s vs. 72 +/- 21, p < 0.05), LAEI (0.58 +/- 0.13 vs. 0.8 +/- 0.15, p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
Doppler assessment of diastolic function has become a standard part of routine echocardiographic examination and imparts information relevant to a patient's functional class, management and prognosis. This review describes the Doppler patterns of diastolic function relative to physical signs and physiology. A continuum of doppler patterns of diastolic function exists, including normal diastolic function, impaired relaxation, pseudonormal filling, restriction, constriction and tamponade. These patterns evolve from one to another in a single individual, with changes in disease evolution, treatment and loading conditions. New applications of continuous wave Doppler, color Doppler M-mode and Doppler tissue imaging are refining our understanding of diastolic function.
Two echo-Doppler cardiographic investigations were performed 7 years apart in 17 insulin-dependent diabetic children without hypertension or nephropathy in order to detect early signs of cardiac abnormalities in this group without ischaemic heart disease. Relative to two matched control groups, the patients had reduced increase in left ventricular size (p < 0.01) and stroke volume (p < 0.05). An initially reduced end systolic wall stress and increased fractional shortening (p < 0.003) was normalized during the 7 years. Concomitant with early signs of autonomic neuropathy and aortic stiffening, left ventricular filling changed with increased velocity during atrial contraction (p < 0.01) correlating to the decreased stroke volumes (r = -0.57, p = 0.016). These early changes could suggest left ventricular restriction but could also reflect a changed sympathetic/parasympathetic balance in diabetic children. A reduced left ventricular cavity size and increased atrial ejection has thus been described in these insulin-dependent children without hypertension, nephropathy or evidence for ischaemic heart disease, suggesting the existence of a metabolically-induced cardiomyopathy.
Monteagudo PT, Nóbrega JC, Cezarini PR, Ferreira SRG, Kohlmann Jr O, Ribeiro AB, Zanella M-T. Altered blood pressure profile, autonomie neuropathy and nephropathy in insulin-dependent diabetic patients. Eur J Endocrinol 1996;135:683–8. ISSN 0809–4643
To evaluate the relationship between autonomie neuropathy (AN) and nephropathy we measured 24-h blood pressure (BP) and overnight urinary albumin excretion (UAE) in 38 patients with insulin dependent diabetes mellitus (IDDM). Autonomie function was evaluated by the heart rate response to deep breathing. Valsalva maneuver, heart rate at rest and BP variation with posture. Sympathetic cutaneous reflex was also tested in both inferior and superior limbs. Patients with mean day diastolic BP (DDBP) ⩽ 90 mmHg without AN (N = 15) compared to 12 normal controls had similar BP values, but compared to those with DDBP ⩽90 mmHg and AN (N = 12) they had lower night diastolic BP (NDBP) (66 ± 4.8 vs 72 ± 8.8 mmHg; p < 0.05) and UAE (9.8 ± 2.3 vs 107.2 ± 3.5 μg/min; p < 0.001). No difference in DDBP was observed between these two diabetic groups (80 ± 3.9 vs 83 ± 6.1 mmHg). Of the 11 patients with DDBP > 90 mmHg, only three were free of AN and only two of the eight with AN where free of diabetic nephropathy. The percentage day/night changes in systolic BP were lower in patients with AN (13 vs 7.9%; p < 0.05) and were inversely related to autonomie score, used as an index of the degree of autonomie dysfunction (r = −0.48; p < 0.01) and to UAE (r = −0.39; p < 0.05). Furthermore, UAE correlated with autonomie score (r = 0.69; p < 0.0001) and with NDBP (r = 0.44; p < 0.01). Our results show that AN in IDDM patients is associated with a reduced nocturnal fall in BP and suggest a pathogenic role of autonomie dysfunction in the development of diabetic nephropathy, possibly favoring both BP elevation during the night and increases in intraglomerular pressure.
Maria Teresa Zanella, Disciplina de Endocrinologia, Escola Paulista de Medicina, Rua Botucatu 720, Vila dementino, São Paulo, Brazil
Cardiac autonomic neuropathy (CAN) is a very frequent complication of insulin-dependent mellitus type 1, affecting the sympathetic or parasympathetic sections or both. The different impairment in the two sections might modify left ventricular function early. To evaluate this relationship, we studied 61 patients (mean age 39.6 +/- 7 years) with type 1 diabetes for more than 10 years, without coronary artery disease (CAD); negative ergometric stress test) and without other pathologies that could interfere with ventricular function. All patients underwent MONO-, 2-dimensional and Doppler echocardiographic examination and radionuclide angiography with 99Tc (RNA). According to the outcome of the Ewing tests, patients were divided into two groups: group A with two or more tests altered (26 patients with CAN) and group B with one or no tests altered (35 patients without CAN). No significant differences between the two groups were found in the systolic function parameters with either technique. In contrast, a pattern of abnormal relaxation was found for the diastolic function parameters: in group A a decrease in E-wave velocity and its time-velocity integral and an increase in A-wave and its time-velocity integral were detected with echocardiography. Moreover, RNA showed a reduced peak filling rate and an increased isovolumic relaxation time. When compared with normal values, an abnormal diastolic filling, defined as two independent echocardiography plus one RNA variable impairment, was found in 15 patients (57.6%) in group A and in only 4 patients (11.4%) in group B (P < 0.001). Our findings suggest an early involvement of diastolic function in patients with CAN.
Left ventricular diastolic filling can be determined reliably by Doppler-derived mitral and pulmonary venous flow velocities. Diastolic filling abnormalities are broadly classified at their extremes to impaired relaxation and restrictive physiology with many patterns in between. An impaired relaxation pattern identifies patients with early stages of heart disease, and appropriate therapy may avert progression and functional disability. Pseudonormalization is a transitional phase between abnormal relaxation and restrictive physiology and signifies increased filling pressure and decreased compliance. In this phase, reducing preload, optimizing afterload, and treating the underlying disease are clinically helpful. A restrictive physiology pattern identifies advanced, usually symptomatic disease with a poor prognosis. Therapeutic intervention is directed toward normalizing loading conditions and improving the restrictive filling pattern, although this may not be feasible in certain heart diseases. Finally, many patients have left ventricular filling patterns that appear indeterminate or mixed. In these cases, clinical information, left atrial and left ventricular size, pulmonary venous flow velocity, and alteration of preload help assess diastolic function and estimate diastolic filling pressures.
During the continuous and simultaneous recording of left ventricular diastolic pressures and changes in the length of a segment of left ventricular myocardium it was demonstrated that neither cardiac sympathetic nor vagal efferent nerve stimulation produces a change in ventricular myocardial extensibility. It was further shown that, at the heart rates studied, autonomic nerve stimulation does not modify the end-diastolic pressurelength curve. These data indicate that, during cardiac sympathetic stimulation, the augmented ventricular stroke work from any given end-diastolic Pressure is accomplished without a change in end-diastolic fiber length.
Evidence was obtained, however, which suggests that the abbreviation of diastole at high imposed heart rates or large stroke volumes may leave an inadequate time for ventricular relaxation to take place and for inertial and viscous factors to be dissipated. Under these circumstances, sympathetic stimulation, by shortening systole and thereby lengthening diastole, permits the ventricle to remain on its "normal" pressure-length curve. This component of cardiac sympathetic efferent activity is peculiarly appropriate to the tachycardia that occurs with increased sympathetic outflow to the heart.
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