Work and oxygen consumption of isolated right ventricular papillary muscle in experimental pulmonary hypertension

Right-sided myocardial mechanical efficiency (work output/metabolic energy input) in pulmonary hypertension can be severely reduced. We determined the contribution of intrinsic myocardial determinants of efficiency using papillary muscle preparations from monocrotaline-induced pulmonary hypertensive (MCT-PH) rats. The hypothesis was tested that efficiency is reduced by mitochondrial dysfunction in addition to increased activation heat reported previously. Right ventricular (RV) muscle preparations were subjected to 5 Hz sinusoidal length changes at 37°C. Work and suprabasal oxygen consumption (VO2) were measured before and after cross-bridge inhibition by blebbistatin. Cytosolic cytochrome c concentration, myocyte cross-sectional area, proton permeability of the inner mitochondrial membrane (PP IMM), and monoamine oxidase (MAO)-A and glucose 6-phosphate dehydrogenase (G-6-PDH) activities and phosphatidylglycerol (PG) and cardiolipin (CL) contents were determined. Mechanical efficiency ranged from 23 to 11% in control (n = 6) and from 22 to 1% in MCT-PH (n = 15) and correlated with work (r2 = 0.68, P < 0.0001) but not with VO2 (r2 = 0.004, P = 0.7919). VO2 for cross-bridge cycling was proportional to work (r2 = 0.56, P = 0.0005). Blebbistatin-resistant VO2 (r2 = 0.32, P = 0.0167) and IMM PP (r2 = 0.36, P = 0.0110) correlated inversely with efficiency. Together, these variables explained the variance of efficiency (coefficient of multiple determination R2 = 0.79, P = 0.0001). Cytosolic cytochrome c correlated inversely with work (r2 = 0.28, P = 0.0391), but not with efficiency (r2 = 0.20, P = 0.0867). G-6-PDH, MAO-A and PG/CL increased in the RV wall of MCT-PH but did not correlate with efficiency. Reduced myocardial efficiency in MCT-PH is due to activation processes and mitochondrial dysfunction. The variance of work and the ratio of activation heat reported previously and blebbistatin-resistant VO2 are discussed.

Diagnostic Pitfalls in Papillary Muscle Rupture-Associated Acute Mitral Regurgitation after Acute Myocardial Infarction

Papillary muscle rupture (PMR) is a rare and fatal complication of acute myocardial infarction (AMI). We report a case of acute mitral regurgitation (MR) due to PMR with pulmonary edema and cardiogenic shock following AMI with small myocardial necrosis. An 88-year-old woman was brought to our emergency department in acute respiratory distress, shock, and coma. She had no systolic murmur, and transthoracic echocardiography was inconclusive. Coronary angiography showed obstruction of the posterior descending branch of the right coronary artery. Although the infarction was small, the hemodynamics did not improve. Transesophageal echocardiography established papillary muscle rupture with severe mitral regurgitation 5 days after admission. Thereafter, the patient and her family did not consent to heart surgery, and she eventually died of progressive heart failure. Physicians should be aware of papillary muscle rupture with acute mitral regurgitation following AMI in patients with unstable hemodynamics, no systolic murmur, and no abnormalities revealed on transthoracic echocardiography.

787 Ablation of the ventricular ectopic foci: a therapeutic option for dilated cardiomyopathy due to arrhythmic MVP

Aims A subset of patients with mitral valve prolapse (MVP) are affected by a still not well understood condition characterized by frequent ventricular arrhythmias (mostly originating from papillary muscles) and sudden cardiac death (SCD). It is called MVP malignant syndrome (MVP MS). In these patients, the high arrhythmic burden may lead to left ventricular (LV) dyssynchrony and dysfunction, determining a tachycardia-induced cardiomyopathy (TIC). Reduction in arrhythmic burden determines LV recovery and ejection fraction improvement and interrupts LV progressive dilatation. Methods and reports We report the case of a 52-year-old woman with MVP and family history of both MVP and SCD who was referred to our department for symptomatic extrasystoles and dyspnoea during exercise. Palpitations begun 11 years before: in that occasion she performed a 3-lead-ECG-Holter monitoring which documented 3457 ventricular extrasystoles. Transthoracic echocardiography (TTE) showed normal LV dimension and function and a myxomatous mitral valve with prolapse of both leaflets. At that time beta-blocker therapy was introduced, but soon suspended because of patient’s clinical intolerance (bradycardia and hypotension). Since then she was lost at follow-up for years, until symptoms worsened. When she came to our attention, TTE showed dilated and hypokinetic LV (ejection fraction was 38%, S2 wave at TDI was 6.4 cm/s and global longitudinal strain value was −13%). CMR was performed and confirmed TTE findings. Mitral-annulus disjunction was described in anterior, lateral, and posterior wall and late gadolinium enhancement analyses showed subendocardial fibrosis in correspondence of the posterior papillary muscle (PM) and in the mid-inferior wall. Holter monitoring enlightened a high arrhythmic burden with 24 065 premature ventricular complexes (PVCs) of two morphologies (right bundle branch block-like and −120° axis and right bundle branch block-like and −75° axis). During stress test, PVCs increased as the heart rate increased, resulting in bigeminism at peak exercise. Considering all these features, we hypothesized a case of MVP MS in which the high ventricular arrhythmic burden resulted in TIC. Any available pharmacological attempt to reduce arrhythmias failed. Transcatheter (TC) ablation of PVCs was then proposed. Electrophysiological study identified the inner part of the posterior papillary muscle implantation region and the antero-lateral basal wall as PVCs sites of origin. Radiofrequency ablation was performed in both sites. After the procedure, despite an incomplete suppression of the posterior PM focus, 12-lead 24-h Holter monitoring and TTE performed during the hospitalization showed a consistent arrhythmic burden reduction and LV function improvement. At 6 months from the procedure, symptoms improved and Holter monitoring showed 7515 PVCs with a 54% arrhythmic burden reduction compared with the presentation. TE showed lower LV end-diastolic volume and an increase in ejection fraction up to 47%; global longitudinal strain was −17% and TDI showed a S2 wave on lateral wall of 11 cm/s, confirming left ventricle improvement after the arrhythmic burden reduction. Conclusions Complete suppression of PMs PVCs with TC ablation is difficult to obtain, especially when the focus is in the inner part of the PM and TC ablation of ventricular arrhythmias in MVP patients has not yet demonstrated his efficacy in reducing SCD. Nevertheless, it should be taken into consideration to obtain at least PVCs reduction in patients with high arrhythmic burden leading to TIC.

Extended myectomy for apical hypertrophic cardiomyopathy: a case report

Background Apical hypertrophic cardiomyopathy is a variant of hypertrophic cardiomyopathy that predominantly affects the apex of the left ventricle and rarely involves the right ventricular apex or both apexes. Heart transplantation is the traditional treatment for apical hypertrophic cardiomyopathy. Although surgical myectomy approaching the apex has been available for decades, its safety and accuracy greatly depend on the surgeon’s skills and experience. Case presentation The first case involved a 63-year-old man with apical hypertrophic cardiomyopathy, wherein preoperative contrast computed tomography findings revealed apical hypertrophy and complete apical cavity obliteration. The patient underwent extended myectomy, which revealed the apex cavity filled with abnormal muscles. Using the transaortic approach, the location of the bilateral papillary muscle was confirmed, thereby providing the required orientation. The abnormal muscle mass was successfully resected, and the postoperative end-diastolic volume was extremely increased. The second case involved a 43-year-old man with an apical left ventricular aneurysm and mid-hypertrophic cardiomyopathy obstruction. The thin-walled apical aneurysm contained a large apical-basal band. Upon detecting the bilateral papillary muscle, mid-ventricular myectomy was performed from the apex. During postoperative catheterization, there was no pressure gradient between the left ventricle and aorta. Conclusions We reviewed two cases of apical hypertrophic cardiomyopathy, efficiently treated using extended apical myectomy. Although it is an uncommon procedure, the cases presented show how it can be used to successfully manage cases of apical hypertrophic cardiomyopathy. However, it is important to secure the postoperative left ventricular end-diastolic volume.

Selective Interventricular Septal Radiofrequency Ablation in Patients With Hypertrophic Obstructive Cardiomyopathy: Who Can Benefit?

Introduction: Septal mass reduction is beneficial for hypertrophic obstructive cardiomyopathy (HOCM) patients with severe left ventricular outflow (LVOT) gradient and symptoms, with surgical myectomy or alcohol septal ablation (ASA) currently recommended in selected patients. Radiofrequency (RF) ablation of hypertrophied septum has been published as a novel method to alleviate LVOT obstruction in small populations. This study aims to investigate factors influencing clinical outcomes of radiofrequency septum ablation.Methods and Results: In this study, 20 patients with HOCM who underwent endocardial ablation were included. Echocardiography and cardiac MRI (CMR) data was collected and analyzed pre- and (or) post- procedure. Nineteen patients underwent ablation successfully, while ablation was aborted in one patient with prior RBBB due to transient complete atrioventricular block (AVB). After 6 months of follow-up, NYHA heart functional class improved from III (2 - 3) to II (1 - 2) (p &lt; 0.001), and resting LVOT gradient was significantly reduced (87.6 ± 29.5 mmHg vs. 48.1 ± 29.7, p &lt; 0.001). LVOT gradient reduction was significantly higher in patients with limited basal septal hypertrophy (60.9 ± 8.3 vs. 27.9 ± 7.1, p = 0.01), shorter anterior mitral leaflet (56.1 ± 6.4 vs. 20.4 ± 5.0, p &lt; 0.01), and normally positioned papillary muscle (36.9 ± 7.1 vs. 75.0 ± 6.3, p &lt; 0.05).Conclusions: Endocardial septal ablation appears to be a safe and effective procedure for alleviating LVOT gradient in patients with HOCM, especially in those with limited basal septal hypertrophy, shorter anterior mitral leaflet, and normal positioned papillary muscle.

Modulation of Myosin by Cardiac Myosin Binding Protein-C Peptides Improves Cardiac Contractility in Ex-Vivo Experimental Heart Failure Models

Cardiac myosin binding protein-C (cMyBP-C) is an important regulator of sarcomeric function. Although reduced phosphorylation of cMyBP-C has been linked to compromised contractility in heart failure patients, direct modulation of cMyBP-C to myosin using small molecules or peptides has not been reported to improve cardiac performance. Here we used previously published cMyBP-C peptides 302A and 302S (surrogates to the regulatory phosphorylation site serine 302) as tool molecules to investigate the role of cMyBP-C in modulating cardiac contraction and relaxation in experimental heart failure (HF) models in vitro. cMyBP-C peptides 302A and 302S were able to increase contractility of papillary muscle fibers isolated from a cMyBP-C phospho-ablation (cMyBP-CAAA) mouse model. In addition, 302A was able to improve the force redevelopment rate (ktr) in papillary muscle fibers from cMyBP-CAAA mice. Consistent with above findings, cMyBP-C peptides 302A and 302S were able to increase the ATPase rates in myofibrils isolated from MI rats but not from sham rats. Furthermore, in cMyBP-CAAA mouse and myocardial infarction (MI) HF models, both cMyBP-C peptides 302A and 302S were able to improve ATPase hydrolysis rates. These changes were not observed in non-transgenic (NTG) mice or sham rats, indicating the specific effects of these peptides in regulating the reduced or unphosphorylated state of cMyBP-C only under pathological conditions of heart failure. Taken together, these studies demonstrate that modulation of cMyBP-C in a reduced phosphorylation or unphosphorylated state can be a therapeutic approach to improve myosin function, sarcomere contractility and relaxation. Therefore, targeting cMyBP-C can be a differentiated approach to improve overall cardiac performance on top of standard care drugs in HF patients.

Acute exposure to the chemotherapy cisplatin has a biphasic effect in cardiac contractility

Cancer and cardiovascular diseases are the main causes of death in Uruguay and developed countries. In clinical practice, there is often the need to administrate chemotherapy with cisplatin (CTP) to patients with cardiovascular comorbidities. The aim of this work is to characterize the possible detrimental effects in cardiac function by the acute exposition to CPT using isolated heart and cardiomyocytes from guinea pigs (Cavia porcellus). All the procedures regarding animal experimentation were performed following approved protocols by the university ethics committee. Isolated hearts were placed in a Langendorff system and perfused with Tyrode 1.8 mM Ca2+ as control medium, or with extracellularly added CPT (0–100 µM). Tension was recorded with a gauge force transducer attached to the papillary muscle and electrical responses were measured with Ag-AgCl electrodes placed in surface extremes near the papillary muscle. Cardiomyocytes were isolated by enzymatic methods. Data were obtained by patch clamp and confocal microscopy with Rhodamine and Fluo dyes sensitive to Ca2+ binding. Non-parametric t tests were used for data comparison. The best fit of Hill’s equation to dose–response curves was done using nonlinear regression methods. In isolated hearts, CPT showed a biphasic effect over the development of tension, increasing up to 5–10 µM to decrease at higher concentrations. In isolated cardiomyocytes, Ca2+ currents were stimulated and inhibited by CPT in a similar dose. Confocal microscopy showed an increment and a reduction of relative fluorescence of the calcium-sensitive dyes with CPT as well. Our results suggest that CPT may affect cardiac contraction and automatism upon acute exposure of the heart, presumably by blocking L-type (Cav1.2) calcium channels and interference with molecules involved in maintaining the homeostasis of intracellular Ca2+.