Left ventricular clefts - incidental finding or pathologic sign of Wilson's disease?

Background: Wilson’s disease is an inherited autosomal recessive multi-systemic disorder characterized by reduced excretion and consequently excessive accumulation of copper in different organs, such as the heart. Results: In a prospective controlled trial, which is the largest to date, we evaluated 61 patients with Wilson’s disease, age- and sex-matched to 61 healthy patients, for cardiac manifestation using cardiac magnetic resonance imaging. Patients were under stable disease and had no signs of heart failure at the time of examination. We detected a left ventricular cleft, an invagination penetrating more than 50% wall thickness of the adjoining compact myocardium in diastole, in 20% of the patients (12 out of 61) compared to 5% among control patients (3 out of 61, p = 0.013). No correlation between the incidence of cleft and a certain genotype of Wilson’s disease was found. All described cases were incidental findings and none of the patients showed other signs of cardiac involvement. Conclusions: To conclude, the results of this study suggests that the increased occurrence of left ventricular clefts is due to Wilson’s disease. Large studies with a long observation period are needed for further evaluation

Variations in local calcium signaling in adjacent cardiac myocytes of the intact mouse heart detected with two-dimensional confocal microscopy

Dyssynchronous local Ca release within individual cardiac myocytes has been linked to cellular contractile dysfunction. Differences in Ca kinetics in adjacent cells may also provide a substrate for inefficient contraction and arrhythmias. In a new approach we quantify variation in local Ca transients between adjacent myocytes in the whole heart. Langendorff-perfused mouse hearts were loaded with Fluo-8 AM to detect Ca and Di-4-ANEPPS to visualize cell membranes. A spinning disc confocal microscope with a fast camera allowed us to record Ca signals within an area of 465 μm by 315 μm with an acquisition speed of 55 fps. Images from multiple transients recorded at steady state were registered to their time point in the cardiac cycle to restore averaged local Ca transients with a higher temporal resolution. Local Ca transients within and between adjacent myocytes were compared with regard to amplitude, time to peak and decay at steady state stimulation (250 ms cycle length). Image registration from multiple sequential Ca transients allowed reconstruction of high temporal resolution (2.4 ± 1.3 ms) local CaT in 2D image sets (N = 4 hearts, n = 8 regions). During steady state stimulation, spatial Ca gradients were homogeneous within cells in both directions and independent of distance between measured points. Variation in CaT amplitudes was similar across the short and the long side of neighboring cells. Variations in TAU and TTP were similar in both directions. Isoproterenol enhanced the CaT but not the overall pattern of spatial heterogeneities. Here we detected and analyzed local Ca signals in intact mouse hearts with high temporal and spatial resolution, taking into account 2D arrangement of the cells. We observed significant differences in the variation of CaT amplitude along the long and short axis of cardiac myocytes. Variations of Ca signals between neighboring cells may contribute to the substrate of cardiac remodeling

Long‐term effects of Na+/Ca2+ exchanger inhibition with ORM‐11035 improves cardiac function and remodelling without lowering blood pressure in a model of heart failure with preserved ejection fraction

Aims: Heart failure with preserved ejection fraction (HFpEF) is increasingly common but there is currently no established pharmacological therapy. We hypothesized that ORM-11035, a novel specific Na+/Ca2+ exchanger (NCX) inhibitor, improves cardiac function and remodelling independent of effects on arterial blood pressure in a model of cardiorenal HFpEF. Methods and results: Rats were subjected to subtotal nephrectomy (NXT) or sham operation. Eight weeks after intervention, treatment for 16 weeks with ORM-11035 (1 mg/kg body weight) or vehicle was initiated. At 24 weeks, blood pressure measurements, echocardiography and pressure–volume loops were performed. Contractile function, Ca2+ transients and NCX-mediated Ca2+ extrusion were measured in isolated ventricular cardiomyocytes. NXT rats (untreated) showed a HFpEF phenotype with left ventricular (LV) hypertrophy, LV end-diastolic pressure (LVEDP) elevation, increased brain natriuretic peptide (BNP) levels, preserved ejection fraction and pulmonary congestion. In cardiomyocytes from untreated NXT rats, early relaxation was prolonged and NCX-mediated Ca2+ extrusion was decreased. Chronic treatment with ORM-11035 significantly reduced LV hypertrophy and cardiac remodelling without lowering systolic blood pressure. LVEDP [14 ± 3 vs. 9 ± 2 mmHg; NXT (n = 12) vs. NXT + ORM (n = 12); P = 0.0002] and BNP levels [71 ± 12 vs. 49 ± 11 pg/mL; NXT (n = 12) vs. NXT + ORM (n = 12); P < 0.0001] were reduced after ORM treatment. LV cardiomyocytes from ORM-treated rats showed improved active relaxation and diastolic cytosolic Ca2+ decay as well as restored NCX-mediated Ca2+ removal, indicating NCX modulation with ORM-11035 as a promising target in the treatment of HFpEF. Conclusion: Chronic inhibition of NCX with ORM-11035 significantly attenuated cardiac remodelling and diastolic dysfunction without lowering systemic blood pressure in this model of HFpEF. Therefore, long-term treatment with selective NCX inhibitors such as ORM-11035 should be evaluated further in the treatment of heart failure

Remote Ischemic Preconditioning Neither Improves Survival nor Reduces Myocardial or Kidney Injury in Patients Undergoing Transcatheter Aortic Valve Implantation (TAVI)

BACKGROUND: Peri-interventional myocardial injury occurs frequently during transcatheter aortic valve implantation (TAVI). We assessed the effect of remote ischemic preconditioning (RIPC) on myocardial injury, acute kidney injury (AKIN) and 6-month mortality in patients undergoing TAVI. METHODS: We performed a prospective single-center controlled trial. Sixty-six patients treated with RIPC prior to TAVI were enrolled in the study and were matched to a control group by propensity-score. RIPC was applied to the upper extremity using a conventional tourniquet. Myocardial injury was assessed using high-sensitive troponin-T (hsTnT), and kidney injury was assessed using serum creatinine levels. Data were compared with the Wilcoxon-Rank and McNemar tests. Mortality was analysed with the log-rank test. RESULTS: TAVI led to a significant rise of hsTnT across all patients (p < 0.001). No significant inter-group difference in maximum troponin release or areas-under-the-curve was detected. Medtronic CoreValve and Edwards Sapien valves showed similar peri-interventional troponin kinetics and patients receiving neither valve did benefit from RIPC. AKIN occurred in one RIPC patient and four non-RIPC patients (p = 0.250). No significant difference in 6-month mortality was observed. No adverse events related to RIPC were recorded. CONCLUSION: Our data do not show a beneficial role of RIPC in TAVI patients for cardio- or renoprotection, or improved survival

Oxidative Stress and Inflammatory Modulation of Ca2+ Handling in Metabolic HFpEF-Related Left Atrial Cardiomyopathy

Metabolic syndrome-mediated heart failure with preserved ejection fraction (HFpEF) is commonly accompanied by left atrial (LA) cardiomyopathy, significantly affecting morbidity and mortality. We evaluate the role of reactive oxygen species (ROS) and intrinsic inflammation (TNF-α, IL-10) related to dysfunctional Ca2+ homeostasis of LA cardiomyocytes in a rat model of metabolic HFpEF. ZFS-1 obese rats showed features of HFpEF and atrial cardiomyopathy in vivo: increased left ventricular (LV) mass, E/e' and LA size and preserved LV ejection fraction. In vitro, LA cardiomyocytes exhibited more mitochondrial-fission (MitoTracker) and ROS-production (H2DCF). In wildtype (WT), pro-inflammatory TNF-α impaired cellular Ca2+ homeostasis, while anti-inflammatory IL-10 had no notable effect (confocal microscopy; Fluo-4). In HFpEF, TNF-α had no effect on Ca2+ homeostasis associated with decreased TNF-α receptor expression (western blot). In addition, IL-10 substantially improved Ca2+ release and reuptake, while IL-10 receptor-1 expression was unaltered. Oxidative stress in metabolic syndrome mediated LA cardiomyopathy was increased and anti-inflammatory treatment positively affected dysfunctional Ca2+ homeostasis. Our data indicates, that patients with HFpEF-related LA dysfunction might profit from IL-10 targeted therapy, which should be further explored in preclinical trials

Left ventricular dysfunction in heart failure with preserved ejection fraction-molecular mechanisms and impact on right ventricular function

The current classification of heart failure (HF) based on left ventricular (LV) ejection fraction (EF) identifies a large group of patients with preserved ejection fraction (HFpEF) with significant morbidity and mortality but without prognostic benefit from current HF therapy. Co-morbidities and conditions such as arterial hypertension, diabetes mellitus, chronic kidney disease, adiposity and aging shape the clinical phenotype and contribute to mortality. LV diastolic dysfunction and LV structural remodeling are hallmarks of HFpEF, and are linked to remodeling of the cardiomyocyte and extracellular matrix. Pulmonary hypertension (PH) and right ventricular dysfunction (RVD) are particularly common in HFpEF, and mortality is up to 10-fold higher in HFpEF patients with vs. without RV dysfunction. Here, we review alterations in cardiomyocyte function (i.e., ion homeostasis, sarcomere function and cellular metabolism) associated with diastolic dysfunction and summarize the main underlying cellular pathways. The contribution and interaction of systemic and regional upstream signaling such as chronic inflammation, neurohumoral activation, and NO-cGMP-related pathways are outlined in detail, and their diagnostic and therapeutic potential is discussed in the context of preclinical and clinical studies. In addition, we summarize prevalence and pathomechanisms of RV dysfunction in the context of HFpEF and discuss mechanisms connecting LV and RV dysfunction in HFpEF. Dissecting the molecular mechanisms of LV and RV dysfunction in HFpEF may provide a basis for an improved classification of HFpEF and for therapeutic approaches tailored to the molecular phenotype

Subcellular heterogeneity of ryanodine receptor properties in ventricular myocytes with low T-tubule density

Rationale: In ventricular myocytes of large mammals, not all ryanodine receptor (RyR) clusters are associated with T-tubules (TTs); this fraction increases with cellular remodeling after myocardial infarction (MI). Objective: To characterize RyR functional properties in relation to TT proximity, at baseline and after MI. Methods: Myocytes were isolated from left ventricle of healthy pigs (CTRL) or from the area adjacent to a myocardial infarction (MI). Ca2+ transients were measured under whole-cell voltage clamp during confocal linescan imaging (fluo-3) and segmented according to proximity of TTs (sites of early Ca2+ release, F&gt;F50 within 20 ms) or their absence (delayed areas). Spontaneous Ca2+ release events during diastole, Ca2+ sparks, reflecting RyR activity and properties, were subsequently assigned to either category. Results: In CTRL, spark frequency was higher in proximity of TTs, but spark duration was significantly shorter. Block of Na+/Ca2+ exchanger (NCX) prolonged spark duration selectively near TTs, while block of Ca2+ influx via Ca2+ channels did not affect sparks properties. In MI, total spark mass was increased in line with higher SR Ca2+ content. Extremely long sparks (&gt;47.6 ms) occurred more frequently. The fraction of near-TT sparks was reduced; frequency increased mainly in delayed sites. Increased duration was seen in near-TT sparks only; Ca2+ removal by NCX at the membrane was significantly lower in MI. Conclusion: TT proximity modulates RyR cluster properties resulting in intracellular heterogeneity of diastolic spark activity. Remodeling in the area adjacent to MI differentially affects these RyR subpopulations. Reduction of the number of sparks near TTs and reduced local NCX removal limit cellular Ca2+ loss and raise SR Ca2+ content, but may promote Ca2+ waves

Right‐ventricular dysfunction in HFpEF is linked to altered cardiomyocyte Ca2+ homeostasis and myofilament sensitivity

Aim Heart failure with preserved ejection fraction (HFpEF) is frequently (30%) associated with right ventricular (RV) dysfunction, which increases morbidity and mortality in these patients. Yet cellular mechanisms of RV remodelling and RV dysfunction in HFpEF are not well understood. Here, we evaluated RV cardiomyocyte function in a rat model of metabolically induced HFpEF. Methods: and results Heart failure with preserved ejection fraction-prone animals (ZSF-1 obese) and control rats (Wistar Kyoto) were fed a high-caloric diet for 13 weeks. Haemodynamic characterization by echocardiography and invasive catheterization was performed at 22 and 23 weeks of age, respectively. After sacrifice, organ morphometry, RV histology, isolated RV cardiomyocyte function, and calcium (Ca2+) transients were assessed. ZSF-1 obese rats showed a HFpEF phenotype with left ventricular (LV) hypertrophy, LV diastolic dysfunction (including increased LV end-diastolic pressures and E/e ' ratio), and preserved LV ejection fraction. ZSF-1 obese animals developed RV dilatation (50% increased end-diastolic area) and mildly impaired RV ejection fraction (42%) with evidence of RV hypertrophy. In isolated RV cardiomyocytes from ZSF-1 obese rats, cell shortening amplitude was preserved, but cytosolic Ca2+ transient amplitude was reduced. In addition, augmentation of cytosolic Ca2+ release with increased stimulation frequency was lost in ZSF-1 obese rats. Myofilament sensitivity was increased, while contractile kinetics were largely unaffected in intact isolated RV cardiomyocytes from ZSF-1 obese rats. Western blot analysis revealed significantly increased phosphorylation of cardiac myosin-binding protein C (Ser282 cMyBP-C) but no change in phosphorylation of troponin I (Ser23, 24 TnI) in RV myocardium from ZSF-1 obese rats. Conclusions: Right ventricular dysfunction in obese ZSF-1 rats with HFpEF is associated with intrinsic RV cardiomyocyte remodelling including reduced cytosolic Ca2+ amplitudes, loss of frequency-dependent augmentation of Ca2+ release, and increased myofilament Ca2+ sensitivity

Impaired Relaxation and Reduced Lusitropic Reserve in Atrial Myocardium in the Obese Patients

Background: Obesity can influence the structure and function of the atrium, but most studies focused on the relationship of body mass index (BMI) and overt left atrium (LA) dysfunction as assessed by clinical imaging. We combined the assessment of right atrium (RA) function in vivo and in vitro in obese and non-obese patients scheduled for elective cardiac surgery. Methods: Atrial structure and function were quantified pre-operatively by echocardiography. RA tissue removed for the establishment of extracorporeal support was collected and RA trabeculae function was quantified in vitro at baseline and with adrenergic stimulation (isoproterenol). Fatty acid-binding protein 3 (FABP3) was quantified in RA tissue. Results were stratified according to the BMI of the patients. Results: About 76 patients were included pre-operatively for the echocardiographic analysis. RA trabeculae function at baseline was finally quantified from 46 patients and RA function in 28 patients was also assessed with isoproterenol. There was no significant correlation between BMI and the parameters of atrial function measured by the clinical echocardiography. However, in vitro measurements revealed a significant correlation between BMI and a prolonged relaxation of the atrial myocardium at baseline, which persisted after controlling for the atrial fibrillation and diabetes by the partial correlation analysis. Acceleration of relaxation with isoproterenol was significantly lower in the obese group (BMI ≥ 30 kg/m(2)). As a result, relaxation with adrenergic stimulation in the obese group remained significantly higher compared to the overweight group (25 kg/m(2) ≤ BMI < 30 kg/m(2), p = 0.027) and normal group (18.5 kg/m(2) ≤ BMI < 25 kg/m(2), p = 0.036). There were no differences on impacts of the isoproterenol on (systolic) developed force between groups. The expression of FABP3 in the obese group was significantly higher compared to the normal group (p = 0.049) and the correlation analysis showed the significant correlations between the level of FABP3 in the RA trabeculae function. Conclusion: A higher BMI is associated with the early subclinical changes of RA myocardial function with the slowed relaxation and reduced adrenergic lusitropy

Wearable cardioverter‐defibrillator: friend or foe in suspected myocarditis?

Aim: Wearable cardioverter defibrillator (WCD, LifeVest, and Zoll) therapy has become a useful tool to bridge a temporarily increased risk for sudden cardiac death. However, despite extensive use, there is a lack of evidence whether patients with myocarditis and impaired LVEF may benefit from treatment with a WCD. Methods and results: We conducted a single-centre retrospective observational study analysing patients with a WCD prescribed between September 2015 and April 2020 at our institution. In total, 135 patients were provided with a WCD, amongst these 76 patients (mean age 48.9 +/- 13.7 years; 84.2% male) for clinically suspected myocarditis. Based on the results of the endomyocardial biopsy and, where available cardiac magnetic resonance imaging, 39 patients (51.3%) were diagnosed with myocarditis and impaired LVEF and 37 patients (48.7%) with dilated cardiomyopathy (DCM) without evidence of cardiac inflammation. The main immunohistopathological myocarditis subtype was lymphocytic myocarditis in 36 (92.3%) patients, and four patients (10.3%) of this group had an acute myocarditis. Three patients had cardiac sarcoidosis (7.7%). Ventricular tachycardia occurred in seven myocarditis (in total 41 VTs; 85.4% non-sustained) and one DCM patients (in total one non-sustained ventricular tachycardia). Calculated necessary WCD wearing time until ventricular tachycardia occurrence is 86.41 days in myocarditis compared with 6.46 years in DCM patients. Conclusions: Our data suggest that myocarditis patients may benefit from WCD therapy. However, as our study is not powered for outcome, further randomized studies powered for the outcome morbidity and mortality are necessary