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(A) Example of isometric (black) and isotonic (grey) contractions at different muscle length. (B) Example of the length-dependent activation under isotonic (light grey) and isometric (dark grey) conditions (diastolic tension F dia = black).
Source publication
Aims
The Frank–Starling mechanism (rapid response (RR)) and the secondary slow response (SR) are known to contribute to increases contractile performance. The contractility of the heart muscle is influenced by pre‐load and after‐load. Because of the effect of pre‐load vs. after‐load on these mechanisms in not completely understood, we studied the e...
Contexts in source publication
Context 1
... first investigated the length-dependent activation in isolated muscle strips under isometric and isotonic conditions. The muscle length with maximal contractile performance (L max ) was reached earlier under isotonic conditions (L max-isotonic ) compared with isometric conditions (L max-isometric ; Figure 2A and B). In muscle strips from human failing myocardium, the muscle shortening under isotonic conditions increased to 6.9 ± 0.9% at L max-isotonic and with a further increase in pre-load decreased again by À42 ± 4% to 4.0 ± 0.6% at L max-isometric (P < 0.01; Figure 3A). ...
Citations
... It is also important to note that the much greater increase in BP and HR response during the seizure in Patient 2 may have contributed to the decline in this patient's cardiac function secondary to increased cardiac afterload and demand, independent of the patient's age, sex, and cardiovascular risk factors [18,19]. ...
Background:
Electroconvulsive therapy (ECT) is a procedure commonly used to treat a number of severe psychiatric disorders, including pharmacologic refractory depression, mania, and catatonia by purposefully inducing a generalized seizure that results in significant hemodynamic changes as a result of an initial transient parasympathetic response that is followed by a marked sympathetic response from a surge in catecholamine release. While the physiologic response of ECT on classic hemodynamic parameters such as heart rate and blood pressure has been described in the literature, real-time visualization of cardiac function using point-of-care ultrasound (POCUS) during ECT has never been reported. This study utilizes POCUS to examine cardiac function in two patients with different ages and cardiovascular risk profiles undergoing ECT.
Methods:
Two patients, a 74-year-old male with significant cardiovascular risks and a 23-year-old female with no significant cardiovascular risks presenting for ECT treatment, were included in this study. A portable ultrasound device was used to obtain apical four-chamber images of the heart before ECT stimulation, after seizure induction, and 2 min after seizure resolution to assess qualitative cardiac function. Two physicians with expertise in echocardiography reviewed the studies. Hemodynamic parameters, ECT settings, and seizure duration were recorded.
Results:
Cardiac standstill was observed in both patients during ECT stimulation. The 74-year-old patient with a significant cardiovascular risk profile exhibited a transient decline in cardiac function during ECT, while the 23-year-old patient showed no substantial worsening of cardiac function. These findings suggest that age and pre-existing cardiovascular conditions may influence the cardiac response to ECT. Other potential contributing factors to the cardiac effects of ECT include the parasympathetic and sympathetic responses, medication regimen, and seizure duration with ECT. This study also demonstrates the feasibility of using portable POCUS for real-time cardiac monitoring during ECT.
Conclusion:
This study reports for the first time cardiac standstill during ECT stimulation visualized using POCUS imaging. In addition, it reports on the potential differential impact of ECT on cardiac function based on patient-specific factors such as age and cardiovascular risks that may have implications for ECT and perioperative anesthetic management and optimization.
... Extensive research has focused on the elasticity of large veins, including the IVC and internal jugular vein, to determine standardized parameters for fluid responsiveness, such as the collapsibility index. (33) These parameters are linked to traditional predictors of fluid responsiveness, such as central venous pressure. (34). ...
Keywords: renal replacement therapy. Point-of-Care Ultrasound; intensive care; acute kidney injury; nephrologist.Point of care ultrasonography (POCUS) is gaining heightened significance in critical care settings as it allows for quick decision making at the bedside. While computerized to-mography is still considered the standard imaging modality for many diseases, the risks and delays associated with transferring a critically ill patient out of the Intensive Care Unit (ICU) have prompted physicians to explore alternative tools. Ultrasound guidance has increased safety of invasive procedures in the ICU, such as the placement of vascular catheters and drainage of collections. Ultrasonography is now seen as an extension of the clinical examination, providing quick answers for rapidly deteriorating patients in the ICU. The field of nephrology is increasingly acknowledging the value of diagnostic Point-of-Care Ultrasound (POCUS). By employing multi-organ POCUS, nephrologists can address specific queries arising during the diagnosis and treatment of patients with acute kidney injury. This approach aids in ruling out hydronephrosis and offering immediate information on hemodynamics, thereby consolidating patient data and facilitating the development of personalized treatment strategies.
... The negative inotropic effect of S. nutans could explain by a lower peripheral vascular resistance. This hypothesis is supported because the extract caused coronary vasodilation, leading to a reduction in afterload (peripheral vascular resistance (Khatib and Wilson, 2018); and an increase of the heart to preload as a function of afterload (Schotola et al., 2017). ...
Ethnopharmacology relevance
The plant Senecio nutans SCh. Bip. is used by Andean communities to treat altitude sickness. Recent evidence suggests it may produce vasodilation and negative cardiac inotropy, though the cellular mechanisms have not been elucidated.
Purpose
To determinate the mechanisms action of S. nutans on cardiovascular function in normotensive animals.
Methods
The effect of the extract on rat blood pressure was measured with a transducer in the carotid artery and intraventricular pressure by a Langendorff system. The effects on sheep ventricular intracellular calcium handling and contractility were evaluated using photometry. Ultra-high-performance liquid-chromatography with diode array detection coupled with heated electrospray-ionization quadrupole-orbitrap mass spectrometric detection (UHPLC-DAD-ESI-Q-OT-MSn) was used for extract chemical characterization.
Results
In normotensive rats, S. nutans (10 mg/kg) reduced mean arterial pressure (MAP) by 40% (p < 0.05), causing a dose-dependent coronary artery dilation and decreased left ventricular pressure. In isolated cells, S. nutans extract (1 μg/ml) rapidly reduced the [Ca²⁺]i transient amplitude and sarcomere shorting by 40 and 49% (p < 0.001), respectively. The amplitude of the caffeine evoked [Ca²⁺]i transient was reduced by 24% (p < 0.001), indicating reduced sarcoplasmic reticulum (SR) Ca²⁺ content. Sodium-calcium exchanger (NCX) activity increased by 17% (p < 0.05), while sarcoendoplasmic reticulum Ca²⁺-ATPase (SERCA) activity was decreased by 21% (p < 0.05). LC-MS results showed the presence of vitamin C, malic acid, and several antioxidant phenolic acids reported for the first time. Dihydroeuparin and 4-hydroxy-3-(3-methylbut-2-enyl) acetophenone were abundant in the extract.
Conclusion
In normotensive animals, S. nutans partially reduces MAP by decreasing heart rate and cardiac contractility. This negative inotropy is accounted for by decreased SERCA activity and increased NCX activity which reduces SR Ca²⁺ content. These results highlight the plant's potential as a source of novel cardio-active phytopharmaceuticals or nutraceuticals.
... However, such a result is not ubiquitous (13,42,43). The measurement of length-dependent Ca 2 þ transients may be confounded by the slow-force response of cardiac muscle to sudden length changes, which can induce a transitory modification of the Ca 2 þ transient (44,45). ...
Preload and afterload dictate the dynamics of the cyclical work-loop contraction that the heart undergoes in vivo. Cellular Ca ²⁺ dynamics drive contraction, but the effects of afterload alone on the Ca ²⁺ transient are inconclusive. No study has investigated whether the putative afterload dependence of the Ca ²⁺ transient is preload dependent. This study is designed to provide the first insight into the Ca ²⁺ handling of cardiac trabeculae undergoing work-loop contractions, with the aim to examine whether the conflicting afterload dependency of the Ca ²⁺ transient can be accounted for by considering preload under isometric and physiological work‑loop contractions. Thus, we subjected ex vivo rat right-ventricular trabeculae, loaded with the fluorescent dye Fura‑2, to work‑loop contractions over a wide range of afterloads at two preloads while measuring stress, length changes, and Ca ²⁺ transients. Work‑loop control was implemented with a real-time Windkessel model to mimic the contraction patterns of the heart in vivo. We extracted a range of metrics from the measured steady‑state twitch stress and Ca ²⁺ transients, including the amplitudes, time courses, rates of rise, and integrals. Results show that parameters of stress were afterload and preload dependent. In contrast, the parameters associated with Ca ²⁺ transients displayed a mixed dependence on afterload and preload. Most notably, its time course was afterload-dependent - an effect augmented at the greater preload. This study reveals that the afterload dependence of cardiac Ca ²⁺ transients is modulated by preload, which brings the study of Ca ²⁺ transients during isometric contractions into question when aiming to understand physiological Ca ²⁺ handling.
... Isotonic shortening is associated with larger fatigue development since it involves greater actin-myosin cycling and energy needs, compared with isometric contraction [55]. Hence, modern studies on cardiac and SkM now conduct both isometric and isotonic contractions for a more realistic examination of muscle performance [1,33,55,63]. ...
... Although it is now possible to translate this 3-element Windkessel arterial model to an in vitro work-loop contractility assay using mathematical modelling [75], for the purpose of evaluating MF at the cellular level, afterload can be simplified as the force opposing shortening, i.e., wall stress experienced by the sarcomeres during contraction. This can be adjusted by ramping up afterload as a percentage of the maximal isometric force at a pre-determined sarcomere length (SL): a method that has been validated in experiments on myocytes or muscle strips [33,34,44,63,94]. SL can be stretched from an unloaded (< 1.9 µm) to overloaded state (> 2.3 µm) to recreate physiological and pathological conditions, while work output, contractile and relaxation kinetics can be monitored in realtime [28]. ...
... Studies that subject ventricular tissue to only a transient increase in preload (some as short as a few seconds) only observe the immediate Frank-Starling mechanism-mediated force [33,34,100,101] and overlooks the delayed increase in contractile force, known as the slowforce response or Anrep effect, which normally develops over 5-15 min [104]. It constitutes a powerful mechanism by which the heart compensates for a reduced SV in the face of high afterload by enhancing inotropy, possibly via mechanostimulated signalling pathways that increase intracellular Ca 2+ [63]. This can be elicited by reducing the Lmax (i.e., length for maximal force production) to 88% before immediately stretching it to 98% Lmax [63]. ...
Purpose of Review
This review combines existing mechano-energetic principles to provide a refreshing perspective in heart failure (HF) and examine if the phenomenon of myocardial fatigue can be rigorously tested in vitro with current technological advances as a bridge between pre-clinical science and clinical practice.
Recent Findings
As a testament to the changing paradigm of HF pathophysiology, there has been a shift of focus from structural to functional causes, as reflected in its modern universal definition and redefined classification. Bolstered by recent landmark trials of sodium-glucose cotransport-2 inhibitors across the HF spectrum, there is a rekindled interest to revisit the basic physiological tenets of energetic efficiency, metabolic flexibility, and mechanical load on myocardial performance. Indeed, these principles are well established in the study of skeletal muscle fatigue. Since both striated muscles share similar sarcomeric building blocks, is it possible that myocardial fatigue can occur in the face of sustained adverse supra-physiological load as a functional cause of HF?
Summary
Myocardial fatigue is a mechano-energetic concept that offers a novel functional mechanism in HF. It is supported by current studies on exercise-induced cardiac fatigue and reverse translational science such as from recent landmark trials on sodium glucose co-transporter 2 inhibitors in HF. We propose a novel framework of myocardial fatigue, injury, and damage that aligns with the contemporary notion of HF as a continuous spectrum, helps determine the chance and trajectory of myocardial recovery, and aims to unify the plethora of cellular and molecular mechanisms in HF.
... To date, it is known that SFR is manifested at all structural levels of myocardial tissue: 276 from a single cardiomyocyte to a whole chamber [17,18,[21][22][23][24][25] and it provides ~20-30% 277 additional contractility relative to the state immediately after stretch. The exact mecha-278 nism(s) of extra calcium that provides the development of SFR remains unknown [17,26]. 279 The physiological role of SFR is a medium-term adaptation (i.e., during minutes) of myo-280 ...
... To date, it is known that SFR is manifested at all structural levels of myocardial tissue: from a single cardiomyocyte to a whole chamber [17,18,[21][22][23][24][25] and it provides~20-30% additional contractility relative to the state immediately after stretch. The exact mechanism(s) of extra calcium that provides the development of SFR remains unknown [17,26]. The physiological role of SFR is a medium-term adaptation (i.e., during minutes) of myocardial contractility to changes in the pre-and/or afterload. ...
There is a lack of data about the contractile behavior of the right atrial myocardium in chronic pulmonary heart disease. We thoroughly characterized the contractility and Ca transient of isolated right atrial strips of healthy rats (CONT) and rats with the experimental model of monocrotaline-induced pulmonary hypertension (MCT) in steady state at different preloads (isometric force-length), during slow force response to stretch (SFR), and during post-rest potentiation after a period of absence of electrical stimulation (PRP). The preload-dependent changes in the isometric twitch and Ca transient did not differ between CONT and MCT rats while the kinetics of the twitch and Ca transient were noticeably slowed down in the MCT rats. The magnitude of SFR was significantly elevated in the MCT right atrial strips and this was accompanied by the significantly higher elevation of the Ca transient relative amplitude at the end of SFR. The slow changes in the contractility and Ca transient in the PRP protocol did not differ between CONT and MCT. In conclusion, the alterations in the contractility and Ca transient of the right atrial myocardium of monocrotaline-treated rats with pulmonary hypertension mostly concern the elevation in SFR. We hypothesize that this positive inotropic effect in the atrial myocardium may (partly) compensate the systolic deficiency of the right ventricular failing myocardium.
... A micromanipulator was used to shorten the muscle length by 5% of the pin-to-pin distance, resulting in a trabecula shortening of 5-12%. The muscle was then allowed to equilibrate for 20 min at the reduced preload before data acquisition in order to avoid slow force response effects [16,21,22]. Feedback-controlled afterload clamps were then performed following the same protocol that was used at Lo. ...
Rapid myocardial relaxation is essential in maintaining cardiac output, and impaired relaxation is an early indicator of diastolic dysfunction. While the biochemical modifiers of relaxation are well known to include calcium handling, thin filament activation, and myosin kinetics, biophysical and biomechanical modifiers can also alter relaxation. We have previously shown that the relaxation rate is increased by an increasing strain rate, not a reduction in afterload. The slope of the relaxation rate to strain rate relationship defines Mechanical Control of Relaxation (MCR). To investigate MCR further, we performed in vitro experiments and computational modeling of preload-adjustment using intact rat cardiac trabeculae. Trabeculae studies are often performed using isometric (fixed-end) muscles at optimal length (Lo, length producing maximal developed force). We determined that reducing muscle length from Lo increased MCR by 20%, meaning that reducing preload could substantially increase the sensitivity of the relaxation rate to the strain rate. We subsequently used computational modeling to predict mechanisms that might underlie this preload-dependence. Computational modeling was not able to fully replicate experimental data, but suggested that thin-filament properties are not sufficient to explain preload-dependence of MCR because the model required the thin-filament to become more activated at reduced preloads. The models suggested that myosin kinetics may underlie the increase in MCR at reduced preload, an effect that can be enhanced by force-dependence. Relaxation can be modified and enhanced by reduced preload. Computational modeling implicates myosin-based targets for treatment of diastolic dysfunction, but further model refinements are needed to fully replicate experimental data.
... Thus, the manipulation of the loading condition during ejection, which affects the ejection velocity, also affects the pressure generation and the end-systolic pressure volume relation 39 . These findings are supported by the work of Schotola et al. 40 , who investigated the effects of afterload and preload on force generation in isolated heart muscle preparations of rabbits. Accordingly, the response to preload alterations is modulated by the afterload level. ...
The linearity and load insensitivity of the end-systolic pressure–volume-relationship (ESPVR), a parameter that describes the ventricular contractile state, are controversial. We hypothesize that linearity is influenced by a variable overlay of the intrinsic mechanism of autoregulation to afterload (shortening deactivation) and preload (Frank-Starling mechanism). To study the effect of different short-term loading alterations on the shape of the ESPVR, experiments on twenty-four healthy pigs were executed. Preload reductions, afterload increases and preload reductions while the afterload level was increased were performed. The ESPVR was described either by a linear or a bilinear regression through the end-systolic pressure volume (ES-PV) points. Increases in afterload caused a biphasic course of the ES-PV points, which led to a better fit of the bilinear ESPVRs (r ² 0.929 linear ESPVR vs. r ² 0.96 and 0.943 bilinear ESPVR). ES-PV points of a preload reduction on a normal and augmented afterload level could be well described by a linear regression (r ² 0.974 linear ESPVR vs. r ² 0.976 and 0.975 bilinear ESPVR). The intercept of the second ESPVR (V0) but not the slope demonstrated a significant linear correlation with the reached afterload level (effective arterial elastance Ea). Thus, the early response to load could be described by the fixed slope of the ESPVR and variable V0, which was determined by the actual afterload. The ESPVR is only apparently nonlinear, as its course over several heartbeats was affected by an overlay of SDA and FSM. These findings could be easily transferred to cardiovascular simulation models to improve their accuracy.
... Factors that modulate the heart's ability to pump blood (i.e., perform) include heart rate (Bristow et al., 1963;Ceconi et al., 2011), loading conditions (i.e., preload, afterload) (Milnor, 1975;Norton, 2001;Skrzypiec-Spring et al., 2007;Milan et al., 2011;Westerhof and Westerhof, 2013;O'Rourke et al., 2016), the myosin molecules contractile state (Spudich, 2011), ventricular geometry (Lieb et al., 2014), elastance (i.e., stiffness) (Fry et al., 1964;Gaasch et al., 1976;Suga et al., 1980;Sagawa, 1981;Suga, 1990;Palladino et al., 1998;Zhong et al., 2005;Campbell et al., 2008;Walley, 2016;Kerkhof et al., 2018), ventricular-vascular coupling (Kass and Kelly, 1992;Antonini-Canterin et al., 2013;Walley, 2016) and prevailing neurohumoral activity, especially sympathetic-parasympathetic tone (Thomas, 2011;Gordan et al., 2015). Changes in preload and afterload have been described as "preload reserve" and "afterload matching, " respectively (Brutsaert and Sonnenblick, 1973;Ross et al., 1976;Ross, 1983;Walley, 2016;Schotola et al., 2017;Boudoulas et al., 2018). Key determinants of pump performance include heart rate, preload (volume of blood within a chamber), afterload (hindrance to ejection), and contractility. ...
... Inotropy is muscle fiber length dependent and is modified by heterometric autoregulation [Cyon-Frank-Starling mechanism (Zimmer, 1998(Zimmer, , 2002Katz, 2002;Amiad and Landesberg, 2016;Sequeira and van der Velden, 2017)], homeometric autoregulation [von Anrep effect in vivo; slow force response in vitro (Sarnoff et al., 1960;Cingolani et al., 2013;Clancy et al., 1968;Furst, 2015;Schotola et al., 2017)], the force-frequency relationship [Bowditch, treppe, staircase effect, chronotropicinotropy (Bowditch, 1871;Noble et al., 1966;Anderson et al., 1973;Higgins et al., 1973;Gwathmey et al., 1990;Ross et al., 1995;Endoh, 2004;Janssen and Periasamy, 2007;Janssen, 2010;Puglisi et al., 2013)], and autonomic activity (Glick and Braunwald, 1965;Thames and Kontos, 1970;Ross et al., 1995). Inotropy decreases almost instantly, within one heartbeat, when parasympathetic activity increases, and more slowly, over 6-8 s, when sympathetic efferent activity changes (Olshansky et al., 2008). ...
... It represents a unique and intrinsic ability of cardiac muscle (contracting at a fixed heart rate) to generate a force that is independent of any load or stretch applied" (Wijayasiri et al., 2012). Integral to all current definitions of the term contractility is the tacit requirement that it is independent of loading conditions (Braunwald, 1971;Davidson et al., 1974;Katz, 1983;Kass et al., 1987;Penefsky, 1994;Bombardini, 2005;Schotola et al., 2017) ...
The term myocardial contractility is thought to have originated more than 125 years ago and has remained and enigma ever since. Although the term is frequently used in textbooks, editorials and contemporary manuscripts its definition remains illusive often being conflated with cardiac performance or inotropy. The absence of a universally accepted definition has led to confusion, disagreement and misconceptions among physiologists, cardiologists and safety pharmacologists regarding its definition particularly in light of new discoveries regarding the load dependent kinetics of cardiac contraction and their translation to cardiac force-velocity and ventricular pressure-volume measurements. Importantly, the Starling interpretation of force development is length-dependent while contractility is length independent. Most historical definitions employ an operational approach and define cardiac contractility in terms of the hearts mechanical properties independent of loading conditions. Literally defined the term contract infers that something has become smaller, shrunk or shortened. The addition of the suffix “ility” implies the quality of this process. The discovery and clinical investigation of small molecules that bind to sarcomeric proteins independently altering force or velocity requires that a modern definition of the term myocardial contractility be developed if the term is to persist. This review reconsiders the historical and contemporary interpretations of the terms cardiac performance and inotropy and recommends a modern definition of myocardial contractility as the preload, afterload and length-independent intrinsic kinetically controlled, chemo-mechanical processes responsible for the development of force and velocity.
... All preeclamptic women showed dipstick positive proteinuria [2þ: 12 (40%) patients; 3þ: 7 (23%) patients; 4þ: 11 (37%) patients]. In preeclampsia group, 17 (57%) patients had serum albumin below lower limit of normal (median value 31.5 [29][30][31][32][33][34][35] g/L ); whereas the median value of serum total protein was 56 [53-59] g/L. ...
... We speculate that in healthy women increased preload after delivery was coupled with increased cardiac size that augmented SV. This is also in line with the Frank-Starling mechanism, by which increased preload would augment myocardial contraction, as long as contractility is normal and there are no changes in afterload [31,32]. ...
Objectives:
In women with severe preeclampsia the period immediately before and early postdelivery carries the greatest risk for cardiac decompensation due to acute changes in loading conditions. The authors aimed to evaluate dynamic changes in hemodynamic and echocardiographic-derived systolic and diastolic function parameters in preeclamptic women compared with healthy controls.
Methods:
Thirty women with severe preeclampsia and 30 healthy controls underwent transthoracic echocardiography 1 day before, 1 and 4 days postdelivery. Fluid responsiveness was assessed by passive leg raising.
Results:
Peak systolic myocardial velocities (s') and global longitudinal strain (GLS) were significantly lower in preeclamptic group compared with controls only postdelivery (s': 7.3 ± 0.8 vs. 8.3 ± 0.9 cm/s, P < 0.001; GLS: -21.4 ± 2.0 vs. -23.0 ± 1.4%, P = 0.027). In addition, significant decrease in s' after delivery was observed only in preeclamptic group (P = 0.004). For diastolic parameters there were differences both before and postdelivery in E/e' ratio (before: 8.4 ± 2.16 vs. 6.7 ± 1.89, P = 0.002; postdelivery: 8.3 ± 1.64 vs. 6.8 ± 1.27, P = 0.003) and mitral e' velocity (before: 11.0 ± 2.39 vs. 12.6 ± 1.86, P = 0.004; postdelivery: 11.1 ± 2.28 vs. 14.0 ± 2.40 cm/s, P < 0.001). Significant increase in left ventricular stroke volume (P = 0.005) and transmitral E velocity (P = 0.003) was observed only in control group, reflecting response to volume load after delivery. Accordingly, only the minority of preeclamptic women were fluid responsive (11 vs. 43%, P = 0.014 between groups).
Conclusion:
Variations in cardiac parameters in healthy women seem to follow changes in loading conditions before and early after delivery. Different pattern in preeclamptic women, however, may be related to subtle myocardial dysfunction, that becomes uncovered with augmented volume load in early postpartum period.
