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.

Left atrial appendage closure in end-stage renal disease and hemodialysis: Data from a German multicenter registry.

BACKGROUND: Left atrial appendage closure (LAAC) has emerged as an alternative to oral anticoagulation (OAC) for stroke prevention in patients with atrial fibrillation (AF). OAC treatment has been proven feasible in mild-to-moderate chronic kidney disease (CKD). In contrast, the optimal antithrombotic management of AF patients with end-stage renal disease (ESRD) is unknown and LAAC has not been proven in these patients in prospective randomized clinical trials. OBJECTIVES: The objective of this study is to evaluate safety and efficacy of LAAC in patients with ESRD. METHODS: Patients undergoing LAAC were collected in a German multicenter real-world observational registry. A composite endpoint consisting of the occurrence of ischemic stroke/transient ischemic attack, systemic embolism, and/or major clinical bleeding was assessed. Patients with ESRD were compared with propensity score-matched patients without severe CKD. ESRD was defined as a glomerular filtration rate < 15 ml/min/1.73 m2 or chronic hemodialysis treatment. RESULTS: A total of 604 patients were analyzed, including 57 with ESRD and 57 propensity-matched patients. Overall, 596 endocardial and 8 epicardial LAAC procedures were performed. Frequency of major complications was 7.0% (42/604 patients) in the overall cohort, 8.8% (5/57 patients) in patients with ESRD, and 10.5% (6/57 patients) in matched controls (p = 0.75). The estimated event-free survival of the combined endpoint after 500 days was 90.7 ± 4.5% in patients with ESRD and 90.2 ± 5.5% in matched controls (p = 0.33). CONCLUSIONS: LAAC had comparable procedural safety and clinical efficacy in patients with ESRD and patients without severe CKD.

The individual relationship between atrial fibrillation sources from CARTOFINDER mapping and atrial cardiomyopathy: The catch me if you can trial.

BACKGROUND: Targeting individual sources identified during atrial fibrillation (AF) has been used as an ablation strategy with varying results. OBJECTIVE: Aim of this study was to evaluate the relationship between regions of interest (ROIs) from CARTOFINDER (CF) mapping and atrial cardiomyopathy from late gadolinium enhancement (LGE) cardiovascular magnetic resonance imaging (CMR). METHODS: Twenty consecutive patients underwent index catheter ablation for persistent AF (PERS AF). Pre-processed LGE CMR images were merged with the results from CF mapping to visualize harboring regions for focal and rotational activities. Atrial cardiomyopathy was classified based on the four Utah stages. RESULTS: Procedural success was achieved in all patients (n = 20, 100%). LGE CMR revealed an intermediate amount of 21.41% ± 6.32% for LA fibrosis. ROIs were identified in all patients (mean no ROIs per patient n = 416.45 ± 204.57). A tendency towards a positive correlation between the total amount of atrial cardiomyopathy and the total number of ROIs per patient (regression coefficient, ß = 10.86, p = .15) was observed. The degree of fibrosis and the presence of ROIs per segment showed no consistent spatial correlation (posterior: ß = 0.36, p-value (p) = .24; anterior: ß = -0.08, p = .54; lateral: ß = 0.31, p = 39; septal: ß = -0.12; p = .66; right PVs: ß = 0.34, p = .27; left PVs: ß = 0.07, p = .79; LAA: ß = -0.91, p = .12). 12 months AF-free survival was 70% (n = 14) after ablation. CONCLUSION: The presence of ROIs from CF mapping was not directly associated with the extent and location of fibrosis. Further studies evaluating the relationship between focal and rotational activity and atrial cardiomyopathy are mandatory.

Zyxin protects from hypertension-induced cardiac dysfunction.

Arterial hypertension causes left ventricular hypertrophy leading to dilated cardiomyopathy. Following compensatory cardiomyocyte hypertrophy, cardiac dysfunction develops due to loss of cardiomyocytes preceded or paralleled by cardiac fibrosis. Zyxin acts as a mechanotransducer in vascular cells that may promote cardiomyocyte survival. Here, we analyzed cardiac function during experimental hypertension in zyxin knockout (KO) mice. In zyxin KO mice, made hypertensive by way of deoxycorticosterone acetate (DOCA)-salt treatment telemetry recording showed an attenuated rise in systolic blood pressure. Echocardiography indicated a systolic dysfunction, and isolated working heart measurements showed a decrease in systolic elastance. Hearts from hypertensive zyxin KO mice revealed increased apoptosis, fibrosis and an upregulation of active focal adhesion kinase as well as of integrins α5 and ß1. Both interstitial and perivascular fibrosis were even more pronounced in zyxin KO mice exposed to angiotensin II instead of DOCA-salt. Stretched microvascular endothelial cells may release collagen 1α2 and TGF-ß, which is characteristic for the transition to an intermediate mesenchymal phenotype, and thus spur the transformation of cardiac fibroblasts to myofibroblasts resulting in excessive scar tissue formation in the heart of hypertensive zyxin KO mice. While zyxin KO mice per se do not reveal a cardiac phenotype, this is unmasked upon induction of hypertension and owing to enhanced cardiomyocyte apoptosis and excessive fibrosis causes cardiac dysfunction. Zyxin may thus be important for the maintenance of cardiac function in spite of hypertension.

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.

Repeat catheter ablation in patients with atrial arrhythmia recurrence despite durable pulmonary vein isolation.

INTRODUCTION: Arrhythmia recurrence after pulmonary vein isolation (PVI) in patients with atrial fibrillation (AF) is common and often linked to pulmonary vein reconnection. In patients with arrhythmia recurrences despite durable PVI the optimal ablation approach is unclear. The purpose of the present study was to analyze efficacy of extended ablation maneuvers in these patients and predictors of procedural success. METHODS: Consecutive patients with durable PVI undergoing repeat ablation procedures were prospectively enrolled. Patients underwent substrate modification with creation of linear lesions and/or mechanism-specific atrial tachycardia (AT) ablation. Three dimensional-mapping images were analyzed for the presence of left atrial (LA) low-voltage areas according to published scoring systems. RESULTS: Seventy-four patients were analyzed. Mode of recurrence after durable PVI was AF in 27 patients (36.5%) and AT in 47 patients (63.5%). Linear lesion ablation was performed in 60 patients (81.1%). Twenty-four patients (32.4%) were treated for focal AT mechanisms. Mean follow-up was 565 ± 342 days. Estimated arrhythmia-free survival after 24 months was significantly higher in patients with AT than in patients with AF as mode of recurrence after durable PVI (42.9 ± 8.2% vs. 24.7 ± 8.5%, p = .023) and in patients without compared to patients with marked LA low-voltage areas (40.5 ± 9.2% vs. 22.8 ± 8.5%, p = .041). The mode of recurrence after durable PVI was the only independent predictor of further arrhythmia recurrence after repeat ablation. CONCLUSION: Arrhythmia-free survival following repeat ablation procedures in patients with durable PVI highly depends on mode of arrhythmia recurrence and the presence of LA low-voltage areas.

Cathepsin A contributes to left ventricular remodeling by degrading extracellular superoxide dismutase in mice.

In the heart, the serine carboxypeptidase cathepsin A (CatA) is distributed between lysosomes and the extracellular matrix (ECM). CatA-mediated degradation of extracellular peptides may contribute to ECM remodeling and left ventricular (LV) dysfunction. Here, we aimed to evaluate the effects of CatA overexpression on LV remodeling. A proteomic analysis of the secretome of adult mouse cardiac fibroblasts upon digestion by CatA identified the extracellular antioxidant enzyme superoxide dismutase (EC-SOD) as a novel substrate of CatA, which decreased EC-SOD abundance 5-fold. In vitro, both cardiomyocytes and cardiac fibroblasts expressed and secreted CatA protein, and only cardiac fibroblasts expressed and secreted EC-SOD protein. Cardiomyocyte-specific CatA overexpression and increased CatA activity in the LV of transgenic mice (CatA-TG) reduced EC-SOD protein levels by 43%. Loss of EC-SOD-mediated antioxidative activity resulted in significant accumulation of superoxide radicals (WT, 4.54 µmol/mg tissue/min; CatA-TG, 8.62 µmol/mg tissue/min), increased inflammation, myocyte hypertrophy (WT, 19.8 µm; CatA-TG, 21.9 µm), cellular apoptosis, and elevated mRNA expression of hypertrophy-related and profibrotic marker genes, without affecting intracellular detoxifying proteins. In CatA-TG mice, LV interstitial fibrosis formation was enhanced by 19%, and the type I/type III collagen ratio was shifted toward higher abundance of collagen I fibers. Cardiac remodeling in CatA-TG was accompanied by an increased LV weight/body weight ratio and LV end diastolic volume (WT, 50.8 µl; CatA-TG, 61.9 µl). In conclusion, CatA-mediated EC-SOD reduction in the heart contributes to increased oxidative stress, myocyte hypertrophy, ECM remodeling, and inflammation, implicating CatA as a potential therapeutic target to prevent ventricular remodeling.

[Atrial fibrillation-Syndromic phenotype in HFpEF or primary disease?] / Vorhofflimmern ­ syndromaler Phänotyp bei HFpEF oder primäre Erkrankung?

Atrial fibrillation and heart failure with preserved left ventricular (LV) ejection fraction (HFpEF) are of high importance in cardiology due to the increasing number of cases. Both diseases can mutually affect each other and important cardiovascular risk factors, e.g. arterial hypertension, diabetes mellitus, obesity and chronic renal insufficiency can be observed with increasing frequency. Currently proven treatment concepts for patients with heart failure and reduced ejection fraction (HFrEF) do not appear to have a comparable prognostic or symptomatic benefit for patients with HFpEF. In addition, there are indications that de novo manifestation of atrial fibrillation in HFpEF patients has been linked to reduced survival. Also, heart and kidney function are negatively affected by atrial fibrillation. Retrospective analyses of patients with HFpEF and atrial fibrillation who had been treated by pulmonary vein isolation could show that interventional treatment of the atrial fibrillation led to an improvement in the New York Heart Association (NYHA) stage and diastolic function. Currently running prospective randomized clinical trials, such as the AMPERE study including patients with HFpEF and atrial fibrillation undergoing pulmonary vein isolation, will hopefully provide reliable prospective randomized data and possibly show an improved symptom control and perhaps also prognostically relevant treatment for HFpEF patients with atrial fibrillation.

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.

Defibrillator-Heart Pump: An Implantable Ventricular Assist Device With Integrated Defibrillator Component-The First In Vitro Testing.

Left ventricular assist devices (LVADs) are an important therapeutic option for patients with end-stage heart failure waiting for heart transplantation or in older patients as definite therapy for heart failure. Interestingly, about 62% of patients receiving LVADs do not have an automatic implantable cardioverter-defibrillator (AICD) at the time of implantation, although these patients have increased risk of being confronted with dangerous arrhythmia. Therefore, an LVAD system including AICD function is a reasonable alternative for such heart failure patients thereby avoiding a second surgical intervention for AICD implantation. In this article, a newly developed system including LVAD and AICD function is introduced, and we also report its first in vitro testing.

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.

Inhibition of NHE3-mediated Sodium Absorption in the Gut Reduced Cardiac End-organ Damage Without Deteriorating Renal Function in Obese Spontaneously Hypertensive Rats.

Increased sodium absorption in the gut is one mechanism contributing to hypertensive blood pressure values. The sodium-proton-exchanger subtype 3 (NHE3) is an important mediator of intestinal sodium absorption. The compound SAR is a new specific NHE3 inhibitor with extremely low oral absorbability leading to decreased sodium absorption in the gut and substantial systolic blood pressure reduction. The effects of intestinal NHE3 inhibition on cardiac and renal hypertensive end-organ damage are unknown. The effects of SAR (1 mg·kg⁻¹·d⁻¹ in chow) on left ventricular (LV) and renal remodeling processes were studied by magnetic resonance imaging and biochemical and histological analysis in obese spontaneously hypertensive rats (SHR-ob SAR) compared with placebo-treated SHR-ob (SHR-ob PLAC). Inhibition of intestinal NHE3 by SAR lowered blood pressure and reduced LV end-diastolic pressure from 21 ± 3.0 to 15 ± 2.0 mm Hg (P = 0.0016), whereas heart rate kept unchanged. LV mass indices, LV myocyte diameters, and LV fibrosis formation were lower in SHR-ob SAR compared with SHR-ob PLAC. SAR did not influence urinary albumin to creatinine ratio or glomerular filtration rate. Renal interstitial fibrosis formation, as well as podocyte damage and glomerulosclerosis remained unchanged. Reduction of intestinal sodium absorption by selective NHE3 inhibition in the gut lowered high blood pressure and reduced LV remodeling without deteriorating renal functional and structural parameters in SHR-ob.

Cardiac CaM Kinase II genes δ and γ contribute to adverse remodeling but redundantly inhibit calcineurin-induced myocardial hypertrophy.

BACKGROUND: Ca(2+)-dependent signaling through CaM Kinase II (CaMKII) and calcineurin was suggested to contribute to adverse cardiac remodeling. However, the relative importance of CaMKII versus calcineurin for adverse cardiac remodeling remained unclear. METHODS AND RESULTS: We generated double-knockout mice (DKO) lacking the 2 cardiac CaMKII genes δ and γ specifically in cardiomyocytes. We show that both CaMKII isoforms contribute redundantly to phosphorylation not only of phospholamban, ryanodine receptor 2, and histone deacetylase 4, but also calcineurin. Under baseline conditions, DKO mice are viable and display neither abnormal Ca(2+) handling nor functional and structural changes. On pathological pressure overload and ß-adrenergic stimulation, DKO mice are protected against cardiac dysfunction and interstitial fibrosis. But surprisingly and paradoxically, DKO mice develop cardiac hypertrophy driven by excessive activation of endogenous calcineurin, which is associated with a lack of phosphorylation at the auto-inhibitory calcineurin A site Ser411. Likewise, calcineurin inhibition prevents cardiac hypertrophy in DKO. On exercise performance, DKO mice show an exaggeration of cardiac hypertrophy with increased expression of the calcineurin target gene RCAN1-4 but no signs of adverse cardiac remodeling. CONCLUSIONS: We established a mouse model in which CaMKII's activity is specifically and completely abolished. By the use of this model we show that CaMKII induces maladaptive cardiac remodeling while it inhibits calcineurin-dependent hypertrophy. These data suggest inhibition of CaMKII but not calcineurin as a promising approach to attenuate the progression of heart failure.

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.

Retrofitting the Heart: Explaining the Enigmatic Septal Thickening in Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy is the most common genetic cardiac disease and is characterized by left ventricular hypertrophy. Although this hypertrophy often associates with sarcomeric gene mutations, nongenetic factors also contribute to the disease, leading to diastolic dysfunction. Notably, this dysfunction manifests before hypertrophy and is linked to hypercontractility, as well as nonuniform contraction and relaxation (myofibril asynchrony) of the myocardium. Although the distribution of hypertrophy in hypertrophic cardiomyopathy can vary both between and within individuals, in most cases, it is primarily confined to the interventricular septum. The reasons for septal thickening remain largely unknown. In this article, we propose that alterations in muscle fiber geometry, present from birth, dictate the septal shape. When combined with hypercontractility and exacerbated by left ventricular outflow tract obstruction, these factors predispose the septum to an isometric type of contraction during systole, consequently constraining its mobility. This contraction, or more accurately, this focal increase in biomechanical stress, prompts the septum to adapt and undergo remodeling. Drawing a parallel, this is reminiscent of how earthquake-resistant buildings are retrofitted with vibration dampers to absorb the majority of the shock motion and load. Similarly, the heart adapts by synthesizing viscoelastic elements such as microtubules, titin, desmin, collagen, and intercalated disc components. This pronounced remodeling in the cytoskeletal structure leads to noticeable septal hypertrophy. This structural adaptation acts as a protective measure against damage by attenuating myofibril shortening while reducing cavity tension according to Laplace Law. By examining these events, we provide a coherent explanation for the septum's predisposition toward hypertrophy.

Mortality after cardiac resynchronization therapy or right ventricular pacing in transcatheter aortic valve replacement recipients.

BACKGROUND: Permanent pacemaker implantation (PMI) is associated with increased morbidity after transcatheter aortic valve replacement (TAVR). Cardiac resynchronization-therapy (CRT) is recommended for patients if left ventricular ejection fraction (LVEF) is ≤ 40% and ventricular pacing is expected in favor to sole right ventricular (RV) pacing. Meanwhile, LVEF may recover after TAVR in patients with aortic valve disease and the benefit of CRT is unknown. OBJECTIVE: To analyze the impact of CRT implantation as compared to RV pacing after TAVR. METHODS AND RESULTS: Between 2012 and 2022, 4385 patients (53.1% female, mean age 81 ± 6 years) without prior PMI undergoing TAVR were retrospectively identified in our institutional registry. After stratification of patients in LVEF ≤ 40%, 41-49% and ≥ 50%, Kaplan-Meier analysis revealed significantly different survival rates in each subgroup at 5 years (37.0% vs. 43.5% vs. 55.1%; P ≤ 0.021). At multivariate regression, LVEF and new PMI after TAVR were not relevant for survival. A total of 105 patients with LVEF ≤ 40% received PMI after TAVR (86 patients with RV pacing and 19 with CRT). At 5 years, all-cause mortality was significantly lower in patients with CRT-device as compared to patients without CRT-device (Kaplan Meier estimate of 21.1% vs. 48.8%; HR 0.48, CI 0.204 - 1.128; log rank p = 0.045). In multivariate analysis CRT remained a significant factor for 5-year survival in these patients (HR 0.3, CI 0.095-0.951, p = 0.041). CONCLUSION: In patients undergoing TAVR, PMI did not influence 5-year survival. In patients with LVEF ≤ 40%, CRT-device implantation was associated with improved survival compared to non-CRT-device implantation.

Heart rate and heart failure: the role of ivabradine therapy.

PURPOSE OF REVIEW: The clinical data about the impact of heart rate reduction in heart failure therapy will be reviewed. RECENT FINDINGS: Clinical and experimental studies showed an association between elevated resting heart rate and mortality risk in heart failure patients. This review summarizes that heart rate level at rest and its extent of reduction is a sensitive indicator for outcome in heart failure. In addition to the nonspecific heart rate reducing drugs like ß-blockers, cardiac glycosides and Ca(2+) antagonists, ivabradine is a highly selective heart rate reducing agent without modifying ventricular contractility and atrioventricular conduction in humans and animals, and has recently been shown to improve cardiovascular outcomes in patients with systolic heart failure by lowering the heart rate only. The present and future role of heart rate reduction in the spectrum of heart failure disease and therapy will be outlined and evaluated. SUMMARY: Elevated heart rate at rest represents a key indicator of adverse outcome in heart failure and implies a major treatment target in these patients.

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.

Alcohol Septal Ablation or Mavacamten for Obstructive Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is a genetic disease characterized by an increased left ventricular wall thickness in the absence of increased afterload conditions. In addition to diastolic dysfunction, obstruction of the left ventricular outflow tract is common in HCM and has an important influence on symptoms and outcome. Over the last five decades or two decades, respectively, surgical myectomy and alcohol septal ablation were the only therapeutic options if standard medical care was not sufficient. Recently, a new option has become available that has the potential to revolutionize the therapeutic strategies for patients with HCM. Mavacamten is a myosin inhibitor that belongs to a completely new drug class and targets the excessive actin-myosin cross-bridging that is the underlying pathology of HCM. By reducing the actin-myosin interactions, mavacamten not only reduces the left ventricular outflow tract (LVOT) obstruction but also seems to have positive effects on the diastolic function, microcirculation, and cardiac structure. This article summarizes the current evidence on alcohol septal ablation and reviews the preclinical and clinical data on mavacamten for the treatment of patients with obstructive HCM.

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.