Starling Mechanism Research Articles

Abstract 18495: Right and Left Ventricular Starling Function in Heart Failure With Preserved Ejection Fraction

Background: Efficient conversion of cardiac filling pressure to stroke volume (SV) is described by the Frank-Starling mechanism. Our group has previously characterized dynamic Starling mechanisms (DSM) in the frequency domain using respiratory mediated changes in beat-by-beat SV as a function of changes in pulmonary artery diastolic pressures (PAD) and shown this to be impaired in heart failure with preserved ejection fraction (HFpEF). Right ventricular (RV) dysfunction is common in HFpEF but efficiency of the RV Starling mechanism is unknown. The goal of this study was to characterize RV and LV DSM in patients with HFpEF. Methods: We studied 16 HFpEF patients (10 females; age: 68 ± 6 years) at seated rest following the placement of a radial arterial and right heart catheter. DSM was quantified by transfer function (input/output frequency) analyses of beat-by-beat changes in PAD (for LV) and A wave right atrial pressures (for RV) as input variables. Output variable was SV (Modelflow from radial arterial line waveform) and normalized for LV DSM using direct-Fick derived SV and for RV DSM using acetylene rebreathing derived SV as a measure of pulmonary blood flow. Results: The power spectral density (PSD) was higher for LV compared to RV filling pressure (521 ± 446 vs 125 ± 111 mmHg 2 , P = 0.001); there was no difference for adjusted SV PSD (819 ± 764 vs 808 ± 765 ml 2 , P = 0.232). DSM gain was higher for LV compared to RV for all but 1 subject (0.58 ± 0.29 vs 0.30 ± 0.16 ml/mmHg, P = 0.002; Figure). Conclusions: RV DSM gain was significantly worse than LV DSM gain suggesting decreased RV contractile and/or compliance reserve in patients with HFpEF. These results highlight the utility of RV DSM gain to characterize RV dysfunction in patients with HFpEF.

Differences in Mechanical, Electrical and Calcium Transient Performance of the Isolated Right Atrial and Ventricular Myocardium of Guinea Pigs at Different Preloads (Lengths)

There are only a few studies devoted to the comparative and simultaneous study of the mechanisms of the length-dependent regulation of atrial and ventricular contractility. Therefore, an isometric force-length protocol was applied to isolated guinea pig right atrial (RA) strips and ventricular (RV) trabeculae, with a simultaneous measurement of force (Frank–Starling mechanism) and Ca2+ transients (CaT) or transmembrane action potentials (AP). Over the entire length-range studied, the duration of isometric contraction, CaT and AP, were shorter in the RA myocardium than in the RV myocardium. The RA myocardium was stiffer than the RV myocardium. With the increasing length of the RA and RV myocardium, the amplitude and duration of isometric contraction and CaT increased, as well as the amplitude and area of the “CaT difference curves” (shown for the first time). However, the rates of the tension development and relaxation decreased. No contribution of AP duration to the heterometric regulation of isometric tension was found in either the RA or RV myocardium of the guinea pig. Changes in the degree of overlap of the contractile proteins of the guinea pig RA and RV myocardium mainly affect CaT kinetics but not AP duration.

Abstract 14195: The Effects of Pulmonary Capillary Wedge Pressure (PCWP) Reduction on Starling Mechanisms in Heart Failure With Preserved Ejection Fraction (HFpEF): Potential for Harm?

Introduction: Elevated left ventricular (LV) filling pressure during exercise is a pathognomonic characteristic of HFpEF. Multiple therapies aiming to reduce filling pressures in HFpEF patients have failed to improve exercise capacity and in some studies, decreased activity levels. The Dynamic Starling Mechanism (DSM) quantifies beat-by-beat modulation of stroke volume (SV) by respiratory-mediated changes in LV filling and provides insight into the efficiency with which changes in LV filling pressure are converted to SV. Low DSM gain reflects inefficient conversion of LV pressures (input) into stroke volume (output). In this study, we examined the effect of sublingual nitroglycerin (NTG; 400μg given q15 minutes) to lower PCWP compared to placebo on DSM. Methods: HFpEF patients (n=11, 7 women; age 73 ± 7 years) were studied seated upright at rest following sublingual administration of placebo or NTG. DSM was quantified by transfer function analyses of beat-by-beat changes in pulmonary artery diastolic pressure (PAD, right heart catheterization as index for PCWP) and SV (Modelflow from radial arterial line waveform, normalized to direct Fick-derived SV) at the prevailing respiratory frequency. Direct Fick SV was calculated as VO2/a-vO2 difference divided by heart rate. Results: Compared to placebo, NTG decreased both SV (Placebo: 53 ml vs NTG: 43 ml, p=0.004) and PAD (Placebo: 15.0 mmHg vs NTG: 13.9 mmHg, p=0.026). The DSM gain was decreased with NTG compared to placebo (0.57 vs 0.82 ml/mmHg, p<0.0001) suggesting a smaller change in SV for a change in filling pressure. Conclusions: Lowering cardiac filling pressures in the seated upright position decreased efficiency of the beat-by-beat Starling mechanism. The results may provide insight into how reducing LV filling pressures impacts stroke volume regulation, potentially leading to decreased exercise tolerance in HFpEF patients.

A Feasible Method to Control Left Ventricular Assist Devices for Heart Failure Patients: A Numerical Study

Installing and developing a sophisticated control system to optimize left ventricular assist device (LVAD) pump speed to meet changes in metabolic demand is essential for advancing LVAD technology. This paper aims to design and implement a physiological control method for LVAD pumps to provide optimal cardiac output. The method is designed to adjust the pump speed by regulating the pump flow based on a predefined set point (operating point). The Frank–Starling mechanism technique was adopted to control the set point within a safe operating zone (green square), and it mimics the physiological demand of the patient. This zone is predefined by preload control lines, which are known as preload lines. A proportional–integral (PI) controller was utilized to control the operating point within safe limits to prevent suction or overperfusion. In addition, a PI type 1 fuzzy logic controller was designed and implemented to drive the LVAD pump. To evaluate the design method, rest, moderate, and exercise scenarios of heart failure (HF) were simulated by varying the hemodynamic parameters in one cardiac cycle. This evaluation was conducted using a lumped parameter model of the cardiovascular system (CVS). The results demonstrated that the proposed control method efficiently drives an LVAD pump under accepted clinical conditions. In both scenarios, the left ventricle pressure recorded 112 mmHg for rest and 55 mmHg for exercise, and the systematic flow recorded 5.5 L/min for rest and 1.75 L/min for exercise.

An Optimal H-Infinity Controller for Left Ventricular Assist Devices Based on a Starling-like Controller: A Simulation Study

Left ventricular assist devices (LVADs) are emerging innovations that provide a feasible alternative treatment for heart failure (HF) patients to enhance their quality of life. In this work, a novel physiological control system to optimize LVAD pump speed using an H-infinity controller was developed. The controller regulates the calculated target pump flow vs. measured pump flow to meet the changes in metabolic demand. The method proposes the implementation of the Frank–Starling mechanism (FSM) approach to control the speed of an LVAD using the left ventricle end-diastolic volume (Vlved) parameter (preload). An operating point was proposed to move between different control lines within the safe area to achieve the FSM. A proportional–integral (PI) controller was used to control the gradient angle between control lines to obtain the flow target. A lumped parameter model of the cardiovascular system was used to evaluate the proposed method. Exercise and rest scenarios were assessed under multi-physiological conditions of HF patients. Simulation results demonstrated that the control system was stable and feasible under different physiological states of the cardiovascular system (CVS). In addition, the proposed controller was able to keep hemodynamic variables within an acceptable range of the mean pump flow (Qp) (max = 5.2 L/min and min = 3.2 L/min) during test conditions.

Critical Evaluation of Current Hypotheses for the Pathogenesis of Hypertrophic Cardiomyopathy.

Hereditary hypertrophic cardiomyopathy (HCM), due to mutations in sarcomere proteins, occurs in more than 1/500 individuals and is the leading cause of sudden cardiac death in young people. The clinical course exhibits appreciable variability. However, typically, heart morphology and function are normal at birth, with pathological remodeling developing over years to decades, leading to a phenotype characterized by asymmetric ventricular hypertrophy, scattered fibrosis and myofibrillar/cellular disarray with ultimate mechanical heart failure and/or severe arrhythmias. The identity of the primary mutation-induced changes in sarcomere function and how they trigger debilitating remodeling are poorly understood. Support for the importance of mutation-induced hypercontractility, e.g., increased calcium sensitivity and/or increased power output, has been strengthened in recent years. However, other ideas that mutation-induced hypocontractility or non-uniformities with contractile instabilities, instead, constitute primary triggers cannot yet be discarded. Here, we review evidence for and criticism against the mentioned hypotheses. In this process, we find support for previous ideas that inefficient energy usage and a blunted Frank–Starling mechanism have central roles in pathogenesis, although presumably representing effects secondary to the primary mutation-induced changes. While first trying to reconcile apparently diverging evidence for the different hypotheses in one unified model, we also identify key remaining questions and suggest how experimental systems that are built around isolated primarily expressed proteins could be useful.

Серцева недостатність зі збереженою фракцією викиду лівого шлуночка

Серцева недостатність зі збереженою фракцією викиду лівого шлуночка є частим явищем, що спостерігається в осіб похилого віку. Вона супроводжується артеріальною гіпертензією та гіпертрофією лівого шлуночка. До симптомів відносять ригідність стінок лівого шлуночка з компенсаторним збільшенням тиску наповнення і знижену здатність збільшувати ударний об’єм за законом Франка Старлінга. Прогнози практично такі ж невтішні, як і при серцевій недостатності зі зниженою фракцією викиду, що певною мірою відображає наявність супутніх захворювань. До встановлення діагнозу серцевої недостатності зі збереженою фракцією викиду важливо виключити кардіологічну природу захворювання. Через неспецифічність симптомів серцевої недостатності необхідно знайти об’єктивне підтвердження діастолічної дисфункції, що за відсутності даних, отриманих інвазивно, має бути підтверджена з використанням ехокардіографії, при якій будуть виявлені ознаки підвищеного тиску наповнення лівого шлуночка, порушення його розслаблення чи збільшення його діастолічної ригідності. Лікування серцевої недостатності зі збереженою фракцією викиду симптоматичне, із застосуванням тих же препаратів, що і при серцевій недостатності зі зниженою фракцією викиду.

Abstract 13543: Impaired Stroke Volume Response During Exercise in Patients With Heart Failure With Preserved Ejection Fraction (HFpEF): The Role of Dynamic Starling Mechanisms

Introduction: Impaired stroke volume (SV) response during exercise is common in HFpEF. The regulation of SV during low intensity exercise is dependent on end-diastolic volume (EDV) reserve from a compliant left ventricle (LV). The Dynamic Starling Mechanism (DSM) quantifies beat-by-beat modulation of SV by respiratory-mediated changes in LV filling pressure and provides insight into the relationship between changes in LV compliance and SV response during exercise. We hypothesized low SV reserve during exercise would track with greater impairments in DSM gain in HFpEF patients. Methods: 11 HFpEF patients (68 ± 6 years; 7 females) were studied at rest and during 20 Watts of upright cycling and separated into higher or lower SV reserve (direct Fick) groups based on median SV response (> vs ≤ 20% increase). DSM was quantified by transfer function (input/output frequency) analyses of beat-by-beat changes in pulmonary artery diastolic pressure (PAD, right heart catheterization) and SV (modelflow from radial arterial line waveform). Due to the small group size, magnitude of differences (i.e. effect size) between conditions and groups is assessed via Hedges’ g . Results: HFpEF patients with low SV reserve had blunted increases in SV compared to higher SV group patients (Δ 2 vs 31 ml, g = -2.0; Table). Compared to higher SV reserve, the lower SV reserve group exhibited a moderately greater increase in the power spectral density (PSD) of PAD ( g = 0.4) and decrease in PSD-SV ( g = 0.5) from rest to 20W. While both groups decreased DSM gain from rest to exercise, the lower SV reserve group had a greater decline (Δ -1.37 vs -0.61 ml/mmHg, g = -1.2). Conclusion: Lower SV reserve in patients with HFpEF is associated with impaired DSM gain during exercise. The lower gain was a function of increases in PAD PSD and decreases in SV PSD suggesting lower LV compliance and lower EDV reserve during exercise. Impaired DSM may explain low SV response and contribute to exercise limitations in patients with HFpEF.

Beta-receptor desensitization after a multistage ultralong distance exercise in the desert?

Abstract Background Although cardiac function has been largely investigated during ultra-endurance exercise, few studies addressed to multi-stage endurance race. Methods Serial echocardiographic assessment of cardiac function was performed in male healthy subjects during the 2014 Marathon des Sables before the race (T1), at the second (T2) and fifth (T3) arrival (236 km) then after 48h recovery. Analysis were performed by 2 sonographers blind for the results of the other and the time of measure. Results Among the 20 athletes, 18 completed the study (mean age 42.4, median 42). RR intervals and (Left ventricular End Diastolic Volume (Simpson) (LVEDV) changed during the race and were correlated (r2 = 0.539, p<0.001); afterload approched by Left Ventricular Meridional Wall Stress (LVMWS) did not change. LV Global Longitudinal Peak Strain (PS) and subepicardial (Epi) PS did not vary. Subendocardial (Endo) LV.PS was lower at T2 /T1, concomitant to a (non-significant) drop in LVEDV; LV strain rate (SR) was lower at T4. RR and LVEDV were higher at T3 than at T2, and higher at T4 compared to T1 and T2. As preload conditions changed during the race, we studied the response of PS and SR to the change in preload (Starling mechanism). EndoPS/LVEDV, LVPS/LVEDV and SR/LVEDV did not change during the race but were lower after recovery. Conclusions 48h after a multistage ultralong duration exercise, we observed a drop in heart rate and contractility response to preload. The evolution of these parameters could be explained by a beta-receptors desensitization. These data need to be confirmed by other studies. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): CHU Dijon Bourgogne ARS Bourgogne Franche Comté Evolution of parameters

Hierarchical modeling of length-dependent force generation in cardiac muscles and associated thermodynamically-consistent numerical schemes

In the context of cardiac muscle modeling, the availability of the myosin heads in the sarcomeres varies over the heart cycle contributing to the Frank–Starling mechanism at the organ level. In this paper, we propose a new approach that allows to extend the Huxley’57 muscle contraction model equations to incorporate this variation. This extension is built in a thermodynamically consistent manner, and we also propose adapted numerical methods that satisfy thermodynamical balances at the discrete level. Moreover, this whole approach—both for the model and the numerics—is devised within a hierarchical strategy enabling the coupling of the microscopic sarcomere-level equations with the macroscopic tissue-level description. As an important illustration, coupling our model with a previously proposed simplified heart model, we demonstrate the ability of the modeling and numerical framework to capture the essential features of the Frank–Starling mechanism.

Stress-dependent activation of myosin in the heart requires thin filament activation and thick filament mechanosensing

Myosin-based regulation in the heart muscle modulates the number of myosin motors available for interaction with calcium-regulated thin filaments, but the signaling pathways mediating the stronger contraction triggered by stretch between heartbeats or by phosphorylation of the myosin regulatory light chain (RLC) remain unclear. Here, we used RLC probes in demembranated cardiac trabeculae to investigate the molecular structural basis of these regulatory pathways. We show that in relaxed trabeculae at near-physiological temperature and filament lattice spacing, the RLC-lobe orientations are consistent with a subset of myosin motors being folded onto the filament surface in the interacting-heads motif seen in isolated filaments. The folded conformation of myosin is disrupted by cooling relaxed trabeculae, similar to the effect induced by maximal calcium activation. Stretch or increased RLC phosphorylation in the physiological range have almost no effect on RLC conformation at a calcium concentration corresponding to that between beats. These results indicate that in near-physiological conditions, the folded myosin motors are not directly switched on by RLC phosphorylation or by the titin-based passive tension at longer sarcomere lengths in the absence of thin filament activation. However, at the higher calcium concentrations that activate the thin filaments, stretch produces a delayed activation of folded myosin motors and force increase that is potentiated by RLC phosphorylation. We conclude that the increased contractility of the heart induced by RLC phosphorylation and stretch can be explained by a calcium-dependent interfilament signaling pathway involving both thin filament sensitization and thick filament mechanosensing.

Thioredoxin 1 (TRX1) Overexpression Cancels the Slow Force Response (SFR) Development.

The stretch of cardiac muscle increases developed force in two phases. The first phase occurs immediately after stretch and is the expression of the Frank–Starling mechanism, while the second one or slow force response (SFR) occurs gradually and is due to an increase in the calcium transient amplitude. An important step in the chain of events leading to the SFR generation is the increased production of reactive oxygen species (ROS) leading to redox sensitive ERK1/2, p90RSK, and NHE1 phosphorylation/activation. Conversely, suppression of ROS production blunts the SFR. The purpose of this study was to explore whether overexpression of the ubiquitously expressed antioxidant molecule thioredoxin-1 (TRX1) affects the SFR development and NHE1 phosphorylation. We did not detect any change in basal phopho-ERK1/2, phopho-p90RSK, and NHE1 expression in mice with TRX1 overexpression compared to wild type (WT). Isolated papillary muscles from WT or TRX1-overexpressing mice were stretched from 92 to 98% of its maximal length. A prominent SFR was observed in WT mice that was completely canceled in TRX1 animals. Interestingly, myocardial stretch induced a significant increase in NHE1 phosphorylation in WT mice that was not detected in TRX1-overexpressing mice. These novel results suggest that magnification of cardiac antioxidant defense power by overexpression of TRX1 precludes NHE1 phosphorylation/activation after stretch, consequently blunting the SFR development.

Beta-receptor desensitization evoked by a multistage ultralong distance exercise in the desert?

Few studies addressed to the evolution of cardiac function during a multistage ultra-long duration exercise (MULDE). Serial echocardiographic assessment of cardiac function was performed in male healthy subjects during the 2014 Marathon des Sables before the race (T1), at the second (T2) and fifth (T3) arrival (236 km) then after 48 h recovery. Analysis were performed by 2 sonographers blind for the results of the other and the time of measure. Statistical analysis was performed using ANOVA-RM to compare the evolution of the different parameters. Among the 20 athletes, 18 completed the study (mean age 42.4, median 42). RR intervals and (Left ventricular End Diastolic Volume (Simpson) (LVEDV) changed during the race and were correlated (r2 = 0.539, P < 0.001); afterload approached by Left Ventricular Meridional Wall Stress (LVMWS) did not change. LV Global Longitudinal Peak Strain (PS) and subepicardial (Epi) PS did not vary. Subendocardial (Endo) LV.PS was lower at T2/T1, concomitant to a (non-significant) drop in LVEDV; LV strain rate (SR) was lower at T4. RR and LVEDV were higher at T3 than at T2, and higher at T4 compared to T1 and T2. As preload conditions changed during the race, we studied the response of PS and SR to the change in preload (Starling mechanism). EndoPS/LVEDV, LVPS/LVEDV and SR/LVEDV did not change during the race but were lower after recovery ( Table 1 ). 48 h after a MULDE, we observed a drop in heart rate and contractility response to preload. The evolution of these parameters could be explained by a beta-receptors desensitization. These data need to be confirmed by other studies.

A Starling-like total work controller for rotary blood pumps: An in vitro evaluation.

Due to improved durability and survival rates, rotary blood pumps (RBPs) are the preferred left ventricular assist device when compared to volume displacement pumps. However, when operated at constant speed, RBPs lack a volume balancing mechanism which may result in left ventricular suction and suboptimal ventricular unloading. Starling-like controllers have previously been developed to balance circulatory volumes; however, they do not consider ventricular workload as a feedback and may have limited sensitivity to adjust RBP workload when ventricular function deteriorates or improves. To address this, we aimed to develop a Starling-like total work controller (SL-TWC) that matched the energy output of a healthy heart by adjusting RBP hydraulic work based on measured left ventricular stroke work and ventricular preload. In a mock circulatory loop, the SL-TWC was evaluated using a HeartWare HVAD in a range of simulated patient conditions. These conditions included changes in systemic hypertension and hypotension, pulmonary hypertension, blood circulatory volume, exercise, and improvement and deterioration of ventricular function by increasing and decreasing ventricular contractility. The SL-TWC was compared to constant speed control where RBP speed was set to restore cardiac output to 5.0 L/min at rest. Left ventricular suction occurred with constant speed control during pulmonary hypertension but was prevented with the SL-TWC. During simulated exercise, the SL-TWC demonstrated reduced LVSW (0.51 J) and greater RBP flow (9.2 L/min) compared to constant speed control (LVSW: 0.74 J and RBP flow: 6.4 L/min). In instances of increased ventricular contractility, the SL-TWC reduced RBP hydraulic work while maintaining cardiac output similar to the rest condition. In comparison, constant speed overworked and increased cardiac output. The SL-TWC balanced circulatory volumes by mimicking the Starling mechanism, while also considering changes in ventricular workload. Compared to constant speed control, the SL-TWC may reduce complications associated with volume imbalances, adapt to changes in ventricular function and improve patient quality of life.

Delayed Reperfusion-Coronary Artery Reperfusion Close to Complete Myocardial Necrosis Benefits Remote Myocardium and Is Enhanced by Exercise.

The present study aimed to analyze the effects of reperfusion of a distant coronary artery on cardiac function, the ultrastructure, and the molecular environment of the remote myocardium immediately after the completion of myocardial regional necrosis: delayed reperfusion (DR). Additionally, the effects of prior exercise on the outcomes of DR were investigated. Female rats with permanent occlusion or delayed reperfusion were randomly assigned to an exercise (swimming, 1 h/day, 5 days/week for 8 weeks) or sedentary protocol. Thus, the study included the following four groups: sedentary permanent occlusion, exercise permanent occlusion, sedentary delayed reperfusion, and exercise delayed reperfusion. The descending coronary artery was occluded for 1 h. Reperfusion was confirmed by contrast echocardiography, and the rats were observed for 4 weeks. Permanent occlusion and DR caused similar myocardial infarction sizes among the four groups. Interestingly, exercise significantly decreased the mortality rate. Delayed reperfusion resulted in significant benefits, including enhanced hemodynamics and papillary muscle contraction, as well as reduced apoptosis and collagen content. Protein calcium kinetics did not change. Meanwhile, developed tension and the Frank–Starling mechanism were enhanced, suggesting that calcium sensitivity was intensified in myofilaments. Remarkable remote myocardial benefits occurred after distant DR, and prior exercise intensified cardiac recovery. Our findings provide valuable information about DR. Our data might explain the better clinical outcomes in recent studies showing that late reperfusion could improve heart failure in patients with myocardial infarction. In conclusion, DR has remote myocardial benefits, including inotropism enhancement, pulmonary congestion reduction, and collagen and apoptosis attenuation, which are enhanced by prior exercise.

Cardiac Enlargement in the Chick Embryo Induced by Hypothermic Incubation Is Due to a Combination of Hyperplasia and Hypertrophy of Cardiomyocytes

Hypothermic incubation of chicken eggs leads to smaller embryos with enlarged hearts, originally described as hypertrophic. Over the years, however, accumulated evidence suggested that hyperplasia, rather than hypertrophy, is the predominant mechanism of cardiac growth during the prenatal period. We have thus set to re-evaluate the hypothermia model to precise the exact cellular mechanism behind cardiac enlargement. Fertilized chicken eggs were incubated at either 37.5 °C (normothermia) or 33.5 °C from embryonic day (ED) 13 onward (hypothermia). Sampling was performed at ED17, at which point wet embryo and heart weight were recorded, and the hearts were submitted to histological examination. In agreement with previous results, the hypothermic embryos were 29% smaller and had hearts 18% larger, translating into a 67% increase in the heart to body weight ratio (P &lt; 0.05 for all parameters). The cell size was essentially the same between control and hypothermic hearts in all regions analysed. Likewise, there was no significant relationship between the cell size and heart weight; however, in the hypothermic hearts, there was a trend showing positive correlation between cell sizes in different cardiac regions and heart weight. Proliferation rate, determined on the basis of anti-phosphohistone H3 immunofluorescence, showed an overall increase in the hypothermic group, reaching statistical significance (P = 0.02, t-test) in the right ventricle. The proliferation rate was similar among different regions of the same heart. However, the correlation between the proliferation rate and heart weight was only small (r2 = 0.007 and r2 = 0.234 for the normothermic and hypothermic group, respectively). We thus conclude that hyperplasia is the predominant response mechanism in this volume-overload model; mechanistically, decreased heart rate at lower temperature increases the end-diastolic and stroke volume, minimizing the drop in cardiac output through the Frank- Starling mechanism.

Impact of Lifelong Exercise Training Dose on Ventricular-Arterial Coupling.

The dynamic Starling mechanism, as assessed by beat-by-beat changes in stroke volume and left ventricular end-diastolic pressure, reflects ventricular-arterial coupling. It deteriorates with age, and is preserved in highly trained masters athletes. Currently, it remains unclear how much exercise over a lifetime is necessary to preserve efficient ventricular-arterial coupling. The purpose of this study was to assess the dose-dependent relationship between lifelong exercise training and the dynamic Starling mechanism in healthy seniors. One hundred two seniors were recruited and stratified into 4 groups based on 25 years of exercise training history: sedentary subjects (n=27, <2 sessions/week), casual exercisers (n=25, 2-3 sessions/week), committed exercisers (n=25, 4-5 sessions/week), and competitive Masters Athletes (n=25, 6-7 sessions/week). The dynamic Starling mechanism was estimated by transfer function gain between beat-by-beat changes in diastolic pulmonary artery pressure, a surrogate for left ventricular end-diastolic pressure, and stroke volume index. The transfer function gain of pulmonary artery pressure-stroke volume index was markedly enhanced in committed and competitive exercisers compared with more sedentary seniors and correlated with higher peak oxygen uptake (Vo2) and lower left ventricular stiffness. The power spectral density of pulmonary artery pressure was greater in sedentary adults than in committed and competitive exercisers, whereas the power spectral density of stroke volume index was greater in competitive exercisers than in the other groups. There is a graded, dose-dependent improvement in ventricular-arterial coupling with increasing amounts of lifelong regular exercise in healthy older individuals. Our data suggest that the optimal dose of lifelong endurance exercise to preserve ventricular-arterial coupling with age appears to be at least 4 to 5 sessions per week.

The impact of 2years of high-intensity exercise training on a model of integrated cardiovascular regulation.

Heart rate variability, a common and easily measured index of cardiovascular dynamics, is the output variable of complicated cardiovascular and respiratory control systems. Both neural and non-neural control mechanisms may contribute to changes in heart rate variability. We previously developed an innovative method using transfer function analysis to assess the effect of prolonged exercise training on integrated cardiovascular regulation. In the present study, we modified and applied this to investigate the effect of 2years of high-intensity training on circulatory components to tease out the primary effects of training. Our method incorporated the dynamic Starling mechanism, dynamic arterial elastance and arterial-cardiac baroreflex function. The dynamic Starling mechanism gain and arterial-cardiac baroreflex gain were significantly increased in the exercise group. These parameters remained unchanged in the controls. Conversely, neither group experienced a change in dynamic arterial elastance. The integrated cardiovascular regulation gain in the exercise group was 1.34-fold larger than that in the control group after the intervention. In these previously sedentary, otherwise healthy, middle-aged adults, 2 years of high-intensity exercise training improved integrated cardiovascular regulation by enhancing the dynamic Starling mechanism and arterial-cardiac baroreflex sensitivity. Assessing the effects of exercise training on cardiovascular variability is challenging because of the complexity of multiple mechanisms. In a prospective, parallel-group, randomized controlled study, we examined the effect of 2years of high-intensity exercise training on integrated cardiovascular function, which incorporates the dynamic Starling mechanism, dynamic arterial elastance and arterial-cardiac baroreflex function. Sixty-one healthy participants (48% male, aged 53years, range 52-54years) were randomized to either 2years of exercise training (exercise group: n= 34) or control/yoga group (controls: n= 27). Before and after 2years, subjects underwent a 6min recording of beat-by-beat pulmonary artery diastolic pressure (PAD), stroke volume index (SVindex), systolic blood pressure (sBP) and RR interval measurements with controlled respiration at 0.2Hz. The dynamic Starling mechanism, dynamic arterial elastance and arterial-cardiac baroreflex function were calculated by transfer function gain between PAD and SVindex; SVindex and sBP; and sBP and RR interval, respectively. Fifty-three participants (controls: n= 25; exercise group: n= 28) completed the intervention. After 2years, the dynamic Starling mechanism gain (Group× Time interaction: P= 0.008) and the arterial-cardiac baroreflex gain (P= 0.005) were significantly increased in the exercise group but remained unchanged in the controls. There was no change in dynamic arterial elastance in either of the two groups. The integrated cardiovascular function gain in the exercise group increased 1.34-fold, whereas there was no change in the controls (P= 0.02). In these previously sedentary, otherwise healthy middle-aged adults, a 2year programme of high-intensity exercise training improved integrated cardiovascular regulation by enhancing the dynamic Starling mechanism and arterial-cardiac baroreflex sensitivity, without changing dynamic arterial elastance.

Cardiomyopathy mutation (F88L) in troponin T abolishes length dependency of myofilament Ca2+ sensitivity.

Recent clinical studies have revealed a new hypertrophic cardiomyopathy-associated mutation (F87L) in the central region of human cardiac troponin T (TnT). However, despite its implication in several incidences of sudden cardiac death in young and old adults, whether F87L is associated with cardiac contractile dysfunction is unknown. Because the central region of TnT is important for modulating the muscle length-mediated recruitment of new force-bearing cross-bridges (XBs), we hypothesize that the F87L mutation causes molecular changes that are linked to the length-dependent activation of cardiac myofilaments. Length-dependent activation is important because it contributes significantly to the Frank-Starling mechanism, which enables the heart to vary stroke volume as a function of changes in venous return. We measured steady-state and dynamic contractile parameters in detergent-skinned guinea pig cardiac muscle fibers reconstituted with recombinant guinea pig wild-type TnT (TnTWT) or the guinea pig analogue (TnTF88L) of the human mutation at two different sarcomere lengths (SLs): short (1.9 µm) and long (2.3 µm). TnTF88L increases pCa50 (-log [Ca2+]free required for half-maximal activation) to a greater extent at short SL than at long SL; for example, pCa50 increases by 0.25 pCa units at short SL and 0.17 pCa units at long SL. The greater increase in pCa50 at short SL leads to the abolishment of the SL-dependent increase in myofilament Ca2+ sensitivity (ΔpCa50) in TnTF88L fibers, ΔpCa50 being 0.10 units in TnTWT fibers but only 0.02 units in TnTF88L fibers. Furthermore, at short SL, TnTF88L attenuates the negative impact of strained XBs on force-bearing XBs and augments the magnitude of muscle length-mediated recruitment of new force-bearing XBs. Our findings suggest that the TnTF88L-mediated effects on cardiac thin filaments may lead to a negative impact on the Frank-Starling mechanism.

Preload-corrected dynamic Starling mechanism in patients with heart failure with preserved ejection fraction.

10.9 ± 3.8 vs. 11.2 ± 1.3 mmHg, P = 1.00). Transfer function analysis between diastolic pulmonary artery pressure (PAD) representing dynamic changes in LVEDP vs. SV index was applied to obtain gain and coherence of the DSM. The DSM gain was significantly lower in HFpEF patients than in the controls, even at a similar level of LVEDP (0.46 ± 0.19 vs. 0.99 ± 0.39 ml·m-2·mmHg-1, P = 0.0018). Moreover, the power spectral density of PAD, the input variability, was greater in the HFpEF group than the controls (0.75 ± 0.38 vs. 0.28 ± 0.26 mmHg2, P = 0.01). Conversely, the power spectral density of SV index, the output variability, was not different between the groups ( P = 0.97). There was no difference in the coherence, which confirms the reliability of the linear transfer function between the two groups (0.71 ± 0.13 vs. 0.77 ± 0.19, P = 0.87). The DSM gain in HFpEF patients is impaired compared with age-matched controls even at a similar level of LVEDP, which may reflect intrinsic LV diastolic dysfunction and incompetence of ventricular-arterial coupling. NEW & NOTEWORTHY The beat-to-beat dynamic Starling mechanism (DSM), the dynamic modulation of stroke volume because of breath-by-breath changes in left-ventricular end-diastolic pressure (LVEDP), reflects ventricular-arterial coupling. Although the DSM gain is impaired in heart failure with preserved ejection fraction (HFpEF) patients, it is not clear whether this is because of higher LVEDP or left-ventricular diastolic dysfunction. The DSM gain in HFpEF patients is severely impaired, even at a similar level of LVEDP, which may reflect intrinsic left-ventricular diastolic dysfunction.