Exploring the Connection Between Relaxed Myosin States and the Anrep Effect.

The Anrep effect is an adaptive response that increases left ventricular contractility following an acute rise in afterload. Although the mechanistic origin remains undefined, recent findings suggest a two-phase activation of resting myosin for contraction, involving strain-sensitive and posttranslational phases. We propose that this mobilization represents a transition among the relaxed states of myosin-specifically, from the super-relaxed (SRX) to the disordered-relaxed (DRX)-with DRX myosin ready to participate in force generation. This hypothesis offers a unified explanation that connects myosin's SRX-DRX equilibrium and the Anrep effect as parts of a singular phenomenon. We underscore the significance of this equilibrium in modulating contractility, primarily studied in the context of hypertrophic cardiomyopathy, the most common inherited cardiomyopathy associated with diastolic dysfunction, hypercontractility, and left ventricular hypertrophy. As we posit that the cellular basis of the Anrep effect relies on a two-phased transition of myosin from the SRX to the contraction-ready DRX configuration, any dysregulation in this equilibrium may result in the pathological manifestation of the Anrep phenomenon. For instance, in hypertrophic cardiomyopathy, hypercontractility is linked to a considerable shift of myosin to the DRX state, implying a persistent activation of the Anrep effect. These valuable insights call for additional research to uncover a clinical Anrep fingerprint in pathological states. Here, we demonstrate through noninvasive echocardiographic pressure-volume measurements that this fingerprint is evident in 12 patients with hypertrophic obstructive cardiomyopathy before septal myocardial ablation. This unique signature is characterized by enhanced contractility, indicated by a leftward shift and steepening of the end-systolic pressure-volume relationship, and a prolonged systolic ejection time adjusted for heart rate, which reverses post-procedure. The clinical application of this concept has potential implications beyond hypertrophic cardiomyopathy, extending to other genetic cardiomyopathies and even noncongenital heart diseases with complex etiologies across a broad spectrum of left ventricular ejection fractions.

Functional interaction of aortic valve and ascending aorta in patients after valve-sparing procedures.

Pressure recovery (PR) is essential part of the post stenotic fluid mechanics and depends on the ratio of EOA/AA, the effective aortic valve orifice area (EOA) and aortic cross-sectional area (AA). In patients with advanced ascending aortic aneurysm and mildly diseased aortic valves, the effect of AA on pressure recovery and corresponding functional aortic valve opening area (ELCO) was evaluated before and after valve-sparing surgery (Dacron graft implantation). 66 Patients with ascending aortic aneurysm (mean aortic diameter 57 +/- 10 mm) and aortic valve-sparing surgery (32 reimplantation technique (David), 34 remodeling technique (Yacoub)) were routinely investigated by Doppler echocardiography. Dacron graft with a diameter between 26 and 34 mm were implanted. EOA was significantly declined after surgery (3.4 +/- 0.8 vs. 2.6 +/- 0.9cm2; p < 0.001). Insertion of Dacron prosthesis resulted in a significant reduction of AA (26.7 +/- 10.2 vs. 6.8 +/- 1.1cm2; p < 0.001) with increased ratio of EOA/AA (0.14 +/- 0.05 vs. 0.40 +/- 0.1; p < 0.001) and pressure recovery index (PRI; 0.24 +/- 0.08 vs. 0.44 +/- 0.06; p < 0.0001). Despite reduction of EOA, ELCO (= EOA corrected for PR) increased from 4.0 +/- 1.1 to 5.0 +/- 3.1cm2 (p < 0.01) with reduction in transvalvular LV stroke work (1005 +/- 814 to 351 +/- 407 mmHg × ml, p < 0.001) after surgery. These effects were significantly better in patients with Yacoub technique than with the David operation. The hemodynamic findings demonstrate a valve-vessel interaction almost entirely caused by a marked reduction in the ascending AA with significant PR gain. The greater hemodynamic benefit of the Yacoub technique due to higher EOA values compared to the David technique was evident and may be of clinical relevance.

Impact of heart rate, aortic compliance and stroke volume on the aortic regurgitation fraction studied in an ex vivo pig model.

INTRODUCTION: Drug therapy to reduce the regurgitation fraction (RF) of high-grade aortic regurgitation (AR) by increasing heart rate (HR) is generally recommended. However, chronic HR reduction in HFREF patients can significantly improve aortic compliance and thereby potentially decrease RF. To clarify these contrasts, we examined the influence of HR, aortic compliance and stroke volume (SV) on RF in an ex vivo porcine model of severe AR. METHODS: Experiments were performed on porcine ascending aorta with aortic valves (n=12). Compliance was varied by inserting a Dacron graft close to the aortic valve. Both tube systems were connected to a left heart simulator varying HR and SV. AR was accomplished by punching a 0.3 cm2 hole in one aortic cusp. Flow, RF, SV and aortic pressure were measured, aortic compliance with transoesophageal ultrasound probes. RESULTS: Compliance of the aorta was significantly reduced after Dacron graft insertion (0.55%±0.21%/mm Hg vs 0.01%±0.007%/mm Hg, p<0.001, respectively). With increasing HR, RF was significantly reduced in each steady state of the native aorta (HR 40 bpm: 88%±7% vs HR 120 bpm: 42%±10%; p<0.001), but Dacron tube did not affect RF (HR 40 bpm: 87%±8%; p=0.79; HR 120 bpm: 42%±3%; p=0.86). Increasing SV also reduced RF independent of the stiff Dacron graft. CONCLUSION: Aortic compliance did not affect AR in the ex vivo porcine model of AR. RF was significantly reduced with increasing HR and SV. These results affirm that HR lowering and negative inotropic drugs should be avoided to treat severe AR.

New insights into the hemodynamics of pulmonary homograft patients under stress echocardiography: The contribution of pressure recovery.

BACKGROUND: The importance of pulmonary artery pressure recovery (PR) in patients with Ross procedures in whom a homograft substitutes the resected pulmonary valve, is unknown. The aim of the study was to evaluate the occurrence and extent of PR in the pulmonary artery in 65 asymptomatic patients with pulmonary homograft after Ross surgery during rest and exercise. METHODS: Stress echocardiography was performed in 65 pulmonary homograft patients and 31 controls with native pulmonary valves up to 75 W. Right ventricular systolic pressure (RVSP), transvalvular flow, mean pressure gradient (Pmean ), valve resistance, and RV stroke work were determined in the exercise (max. 75 W) and recovery phases in increments of 25 W each. RESULTS: Pulmonary homografts demonstrated significantly elevated Pmean compared to controls at all stages. When considering pressure recovery (absolute and relative PR at rest 3.8 ± 1.8 mm Hg, 42.6 ± 7.2%, respectively) and transvalvular energy loss (EL; at rest 4.5 ± 4.3 mm Hg) the homograft hemodynamics reached the level of controls. In a subgroup of patients with tricuspid regurgitation, resting RVSP was the same in homograft patients and controls (21.3 ± 6.1 vs. 20.4 ± 6.3, p = .62), despite significant different Pmax values. CONCLUSIONS: Ross patients with pulmonary homograft showed systematically increased hemodynamic parameters compared to normal pulmonary valves. These differences were abolished when PR was considered for homograft patients. The equality of RVSP values at rest in both groups shows non-invasive evidence for PR in the pulmonary system after homograft implantation. Therefore, PR appears to be an important measure in calculating the actual hemodynamics in pulmonary homografts.

Hemodynamic Assessment in Takotsubo Syndrome.

BACKGROUND: Takotsubo syndrome (TTS) is a reversible form of heart failure with incompletely understood pathophysiology. OBJECTIVES: This study analyzed altered cardiac hemodynamics during TTS to elucidate underlying disease mechanisms. METHODS: Left ventricular (LV) pressure-volume loops were recorded in 24 consecutive patients with TTS and a control population of 20 participants without cardiovascular diseases. RESULTS: TTS was associated with impaired LV contractility (end-systolic elastance 1.74 mm Hg/mL vs 2.35 mm Hg/mL [P = 0.024]; maximal rate of change in systolic pressure over time 1,533 mm Hg/s vs 1,763 mm Hg/s [P = 0.031]; end-systolic volume at a pressure of 150 mm Hg, 77.3 mL vs 46.4 mL [P = 0.002]); and a shortened systolic period (286 ms vs 343 ms [P < 0.001]). In response, the pressure-volume diagram was shifted rightward with significantly increased LV end-diastolic (P = 0.031) and end-systolic (P < 0.001) volumes, which preserved LV stroke volume (P = 0.370) despite a lower LV ejection fraction (P < 0.001). Diastolic function was characterized by prolonged active relaxation (relaxation constant 69.5 ms vs 45.9 ms [P < 0.001]; minimal rate of change in diastolic pressure -1,457 mm Hg/s vs -2,192 mm Hg/s [P < 0.001]), whereas diastolic stiffness (1/compliance) was not affected during TTS (end-diastolic volume at a pressure of 15 mm Hg, 96.7 mL vs 109.0 mL [P = 0.942]). Mechanical efficiency was significantly reduced in TTS (P < 0.001) considering reduced stroke work (P = 0.001), increased potential energy (P = 0.036), and a similar total pressure-volume area compared with that of control subjects (P = 0.357). CONCLUSIONS: TTS is characterized by reduced cardiac contractility, a shortened systolic period, inefficient energetics, and prolonged active relaxation but unaltered diastolic passive stiffness. These findings may suggest decreased phosphorylation of myofilament proteins, which represents a potential therapeutic target in TTS. (Optimized Characterization of Takotsubo Syndrome by Obtaining Pressure Volume Loops [OCTOPUS]; NCT03726528).

Impact of pressure recovery on the assessment of pulmonary homograft function using Doppler ultrasound.

Relevant pressure recovery (PR) has been shown to increase functional stenotic aortic valve orifice area and reduce left ventricular load. However, little is known about the relevance of PR in the pulmonary artery. The study examined the impact of PR using 2D-echocardiography in the pulmonary artery distal to the degenerated homograft in patients after Ross surgery. Ninety-two patients with pulmonary homograft were investigated by Doppler echocardiography (mean time interval after surgery 31 ± 26 months). PR was measured as a function of pulmonary artery diameter determined by computed tomography angiography. Homograft orifice area, valve resistance, and transvalvular stroke work were calculated with and without considering PR. PR decreased as the pulmonary artery diameter increased (r = -0.69, p < 0.001). Mean PR was 41.5 ± 7.1% of the Doppler-derived pressure gradient (Pmax ), which resulted in a markedly increased homograft orifice area (energy loss coefficient index [ELCOI] vs. effective orifice area index [EOAI], 1.3 ± 0.4 cm2 /m2 vs. 0.9 ± 0.4 cm2 /m2 , p < 0.001). PR significantly reduced homograft resistance and transvalvular stroke work (822 ± 433 vs. 349 ± 220 mmHg × ml, p < 0.0001). When PR was considered, the correlations of the parameters used were significantly better, and 11 of 18 patients (61%) in the group with severe homograft stenosis (EOAI <0.6 cm2 /m2 ) could be reclassified as moderate stenosis. Our results showed that the Doppler measurements overestimated the degree of homograft stenosis and thus the right ventricular load, when PR was neglected in the pulmonary artery. Therefore, Doppler measurements that ignore PR can misclassify homograft stenosis and may lead to premature surgery.

Reduced left ventricular contractility, increased diastolic operant stiffness and high energetic expenditure in patients with severe aortic regurgitation without indication for surgery.

OBJECTIVES: Recent mortality studies showed worse prognosis in patients (ARNS) with severe aortic regurgitation and preserved ejection fraction (EF) not fulfilling the criteria of current guidelines for surgery. The aim of our study was to analyse left ventricular (LV) systolic and diastolic function and mechanical energetics to find haemodynamic explanations for the reduced prognosis of these patients and to seek a new concept for surgery. METHODS: Global longitudinal strain (GLS) and echo-based single-beat pressure-volume analyses were performed in patients with ARNS (LV end-diastolic diameter <70 mm, EF >50%, GLS > -19% n = 41), with indication for surgery (ARS; n = 19) and in mild hypertensive controls (C; n = 20). Additionally, end-systolic elastance (LV contractility), stroke work and total energy (pressure-volume area) were calculated. RESULTS: ARNS demonstrated significantly depressed LV contractility versus C: end-systolic elastance (1.58 ± 0.7 vs 2.54 ± 0.8 mmHg/ml; P < 0.001), despite identical EF (EF: 59 ± 6% vs 59 ± 7%). Accordingly, GLS was decreased [-15.7 ± 2.7% (n = 31) vs -21.2 ± 2.4%; P < 0.001], end-diastolic volume (236 ± 90 vs 136 ± 30 ml; P < 0.001) and diastolic operant stiffness were markedly enlarged, as were pressure-volume area and stroke work, indicating waste of energy. The correlation of GLS versus end-systolic elastance was good (r = -0.66; P < 0.001). ARNS and ARS patients demonstrated similar haemodynamic disorders, whereas only GLS was worse in ARS. CONCLUSIONS: ARNS patients almost matched the ARS patients in their haemodynamic and energetic deterioration, thereby explaining poor prognosis reported in literature. GLS has been shown to be a reliable surrogate for LV contractility, possibly overestimating contractility due to exhausted preload reserve in aortic regurgitation patients. GLS may outperform conventional echo parameters to predict more precisely the timing of surgery.

CaMKII activity contributes to homeometric autoregulation of the heart: A novel mechanism for the Anrep effect.

KEY POINTS: The Anrep effect represents the alteration of left ventricular (LV) contractility to acutely enhanced afterload in a few seconds, thereby preserving stroke volume (SV) at constant preload. As a result of the missing preload stretch in our model, the Anrep effect differs from the slow force response and has a different mechanism. The Anrep effect demonstrated two different phases. First, the sudden increased afterload was momentary equilibrated by the enhanced LV contractility as a result of higher power strokes of strongly-bound myosin cross-bridges. Second, the slightly delayed recovery of SV is perhaps dependent on Ca2+ /calmodulin-dependent protein kinase II activation caused by oxidation and myofilament phosphorylation (cardiac myosin-binding protein-C, myosin light chain 2), maximizing the recruitment of available strongly-bound myosin cross-bridges. Short-lived oxidative stress might present a new facet of subcellular signalling with respect to cardiovascular regulation. Relevance for human physiology was demonstrated by echocardiography disclosing the Anrep effect in humans during handgrip exercise. ABSTRACT: The present study investigated whether oxidative stress and Ca2+ /calmodulin-dependent protein kinase II (CaMKII) activity are involved in triggering the Anrep effect. LV pressure-volume (PV) analyses of isolated, preload controlled working hearts were performed at two afterload levels (60 and 100 mmHg) in C57BL/6N wild-type (WT) and CaMKII-double knockout mice (DKOCaMKII ). In snap-frozen WT hearts, force-pCa relationship, H2 O2 generation, CaMKII oxidation and phosphorylation of myofilament and Ca2+ handling proteins were assessed. Acutely raised afterload showed significantly increased wall stress, H2 O2 generation and LV contractility in the PV diagram with an initial decrease and recovery of stroke volume, whereas end-diastolic pressure and volume, as well as heart rate, remained constant. Afterload induced increase in LV contractility was blunted in DKOCaMKII -hearts. Force development of single WT cardiomyocytes was greater with elevated afterload at submaximal Ca2+ concentration and associated with increases in CaMKII oxidation and phosphorylation of cardiac-myosin binding protein-C, myosin light chain and Ca2+ handling proteins. CaMKII activity is involved in the regulation of the Anrep effect and associates with stimulation of oxidative stress, presumably starting a cascade of CaMKII oxidation with downstream phosphorylation of myofilament and Ca2+ handling proteins. These mechanisms improve LV inotropy and preserve stroke volume within few seconds.

Hyperaldosteronism induces left atrial systolic and diastolic dysfunction.

Patients with hypertension and hyperaldosteronism show an increased risk of stroke compared with patients with essential hypertension. Aim of the study was to assess the effects of aldosterone on left atrial function in rats as a potential contributor to thromboembolism. Osmotic mini-pumps delivering 1.5 µg aldosterone/h were implanted in rats subcutaneously (Aldo, n = 39; controls, n = 38). After 8 wk, left ventricular pressure-volume analysis of isolated working hearts was performed, and left atrial systolic and diastolic function was also assessed by atrial pressure-diameter loops. Moreover, left atrial myocytes were isolated to investigate their global and local Ca2+ handling and contractility. At similar heart rates, pressure-volume analysis of isolated hearts and in vivo hemodynamic measurements revealed neither systolic nor diastolic left ventricular dysfunction in Aldo. In particular, atrial filling pressures and atrial size were not increased in Aldo. Aldo rats showed a significant reduction of atrial late diastolic A wave, atrial active work index, and increased V waves. Consistently, in Aldo rats, sarcomere shortening and the amplitude of electrically evoked global Ca2+ transients were substantially reduced. Sarcoplasmic reticulum-Ca2+ content and fractional Ca2+ release were decreased, substantiated by a reduced sarcoplasmic reticulum calcium ATPase activity, resulting from a reduced CAMKII-evoked phosphorylation of phospholamban. Hyperaldosteronism induced atrial systolic and diastolic dysfunction, while atrial size and left ventricular hemodynamics, including filling pressures, were unaffected in rats. The described model suggests a direct causal link between hyperaldosteronism and decreased atrial contractility and diastolic compliance.

Heart rate reduction by If-inhibition improves vascular stiffness and left ventricular systolic and diastolic function in a mouse model of heart failure with preserved ejection fraction.

AIMS: In diabetes mellitus, heart failure with preserved ejection fraction (HFPEF) is a significant comorbidity. No therapy is available that improves cardiovascular outcomes. The aim of this study was to characterize myocardial function and ventricular-arterial coupling in a mouse model of diabetes and to analyse the effect of selective heart rate (HR) reduction by If-inhibition in this HFPEF-model. METHODS AND RESULTS: Control mice, diabetic mice (db/db), and db/db mice treated for 4 weeks with the If-inhibitor ivabradine (db/db-Iva) were compared. Aortic distensibility was measured by magnetic resonance imaging. Left ventricular (LV) pressure-volume analysis was performed in isolated working hearts, with biochemical and histological characterization of the cardiac and aortic phenotype. In db/db aortic stiffness and fibrosis were significantly enhanced compared with controls and were prevented by HR reduction in db/db-Iva. Left ventricular end-systolic elastance (Ees) was increased in db/db compared with controls (6.0 ± 1.3 vs. 3.4 ± 1.2 mmHg/µL, P < 0.01), whereas other contractility markers were reduced. Heart rate reduction in db/db-Iva lowered Ees (4.0 ± 1.1 mmHg/µL, P < 0.01), and improved the other contractility parameters. In db/db active relaxation was prolonged and end-diastolic capacitance was lower compared with controls (28 ± 3 vs. 48 ± 8 µL, P < 0.01). These parameters were ameliorated by HR reduction. Neither myocardial fibrosis nor hypertrophy were detected in db/db, whereas titin N2B expression was increased and phosphorylation of phospholamban was reduced both being prevented by HR reduction in db/db-Iva. CONCLUSION: In db/db, a model of HFPEF, selective HR reduction by If-inhibition improved vascular stiffness, LV contractility, and diastolic function. Therefore, If-inhibition might be a therapeutic concept for HFPEF, if confirmed in humans.

Aldosterone promotes atrial fibrillation.

AIMS: Hyperaldosteronism is associated with an increased prevalence of atrial fibrillation (AF). However, it is unclear whether this is the consequence of altered haemodynamics or a direct aldosterone effect. It was the aim of the study to demonstrate load-independent effects of aldosterone on atrial structure and electrophysiology. METHODS: Osmotic mini-pumps delivering 1.5 µg/h aldosterone were implanted subcutaneously in rats (Aldo). Rats without aldosterone treatment served as controls. After 8 weeks, surface electrocardiogram, the inducibility of AF, and atrial pressures were recorded in vivo. In isolated working hearts, left ventricular function was measured, and conduction in the right atrium (RA) and the left atrium (LA) was mapped epicardially. The atrial effective refractory period (AERP) was determined. Atrial tissue was analysed histologically. RESULTS: Neither systolic nor diastolic ventricular function nor atrial pressures were altered in Aldo rats. All Aldo (11/11) showed inducible atrial arrhythmias vs. two of nine controls (P = 0.03). In Aldo, the P-wave duration and the total RA activation time were longer. Prolongation of local conduction times occurred more often in Aldo, whereas the AERP did not differ between both groups. In Aldo, atrial fibroblasts and interstitial collagen were increased, active matrix metalloproteinase 13 was reduced, and atrial myocytes were hypertrophied. The connexin 43 content was unaltered. CONCLUSIONS: Aldosterone causes a substrate for atrial arrhythmias characterized by atrial fibrosis, myocyte hypertrophy, and conduction disturbances. The described model imputes atrial proarrhythmia directly to aldosterone, since ventricular haemodynamics appeared unaltered in this model. This mechanism may have therapeutical impact for primary and secondary prevention of AF.

Heart rate reduction by I(f)-channel inhibition and its potential role in heart failure with reduced and preserved ejection fraction.

Selective heart rate (HR) reduction by I(f)-channel inhibition is a recently developed pharmacological principle in cardiovascular therapy. Among these newly identified HR-lowering drugs, only ivabradine has now become approved for clinical use. I(f)-channel inhibition mainly reduces HR, thereby improving myocardial oxygen supply, energy balance, and cardiac function. Ivabradine was well tolerated and revealed a good safety profile in the investigated study populations. The guiding experimental and clinical results of I(f)-channel inhibition were compared to those of beta-blockade as a HR reducing principle as well as cornerstone of heart failure standard therapy. Beside its use in therapy of coronary artery disease, I(f)-channel inhibition potentially exhibits beneficial effects in systolic and diastolic heart failure as well. Therefore, hemodynamic effects of ivabradine and its limitations in heart failure together with the biological impact of HR reduction will be considered in this context. Because no clinical data with specific heart-rate-reducing agents are available in heart failure patients until now, the prospective significance of I(f)-channel inhibition can only be speculated on. However, the presented results and considerations are encouraging: ivabradine may play a therapeutic role in the future protecting left ventricular function and structure from early deterioration in heart failure with reduced and preserved ventricular ejection fraction.