Hypochlorite-Modified LDL Induces Arrhythmia and Contractile Dysfunction in Cardiomyocytes

Neutrophil-derived myeloperoxidase (MPO) and its potent oxidant, hypochlorous acid (HOCl), gained attention as important oxidative mediators in cardiac damage and dysfunction. As cardiomyocytes generate low-density lipoprotein (LDL)-like particles, we aimed to identify the footprints of proatherogenic HOCl-LDL, which adversely affects cellular signalling cascades in various cell types, in the human infarcted myocardium. We performed immunohistochemistry for MPO and HOCl-LDL in human myocardial tissue, investigated the impact of HOCl-LDL on electrophysiology and contractility in primary cardiomyocytes, and explored underlying mechanisms in HL-1 cardiomyocytes and human atrial appendages using immunoblot analysis, qPCR, and silencing experiments. HOCl-LDL reduced ICa,L and IK1, and increased INaL, leading to altered action potential characteristics and arrhythmic events including early- and delayed-afterdepolarizations. HOCl-LDL altered the expression and function of CaV1.2, RyR2, NCX1, and SERCA2a, resulting in impaired contractility and Ca2+ homeostasis. Elevated superoxide anion levels and oxidation of CaMKII were mediated via LOX-1 signaling in HL-1 cardiomyocytes. Furthermore, HOCl-LDL-mediated alterations of cardiac contractility and electrophysiology, including arrhythmic events, were ameliorated by the CaMKII inhibitor KN93 and the INaL blocker, ranolazine. This study provides an explanatory framework for the detrimental effects of HOCl-LDL compared to native LDL and cardiac remodeling in patients with high MPO levels during the progression of cardiovascular disease.

164 Effect of cardiac contractility modulation therapy on myocardial work in patients with heart failure with reduced ejection fraction

Aims Cardiac contractility modulation therapy (CCMT) has been shown to reduce hospitalizations and to improve quality of life in heart failure patients with reduced ejection fraction (HFrEF) who remain symptomatic despite disease-modifying therapies. Strain imaging derived myocardial work (MW) is an emerging tool for evaluating left ventricular mechanics by incorporating systolic deformation and afterload burden in the analysis. To evaluate prospectively the impact of CCMT in HFrEF patients on MW derived parameters in relation to standard echocardiographic indices. Methods and results We recruited 12 HFrEF patients with indications to CCMT according to current clinical practice. A comprehensive echo-Doppler evaluation, including speckle tracking derived assessment of global longitudinal strain (GLS), was performed before and after three months from the CCM device implantation. Parameters of MW such as global work index (GWI), global constructive work (GCW) global wasted work (GWW), and global work efficiency (GWE) were calculated according to standardized procedures. Median values (interquartile range) were compared for all those parameters from baseline and 3-month follow-up with Wilcoxon Rank Sum test for continuous variables. At three months from CCM implant an improvement of LVEF [from 32% (27–34) to 36% (29–39), P < 0.05], GLS [from 7.4% (6.2–11.2) to 9.9% (7.5–9.4), P < 0.05], GWI [from 461 mmHg (372–613) to 589 mmHg (413–696), P < 0.05], GCW [from 800 mmHg (620–930) to 970 mmHg (644–1009), P = 0.236], and GWE [from 73% (65–78) to 85% (78–87), P < 0.05] was observed, with a consistent reduction of GWW [from 161 mmHg (148–227) to 125 mmHg (101–188), P < 0.05]. We also found a positive correlation between the magnitude of LVEF improvement and the baseline values of GCW (r = 0.727, P = 0.011). Conclusions At 3 months, CCMT significantly improves standard and advanced left ventricular systolic function indices. This improvement is due to the increase of constructive work and a reduction of wasted work. In addition, the increase of left ventricular ejection fraction can be predicted by the global constructive work levels at baseline.

49 A case report of cardiac contractility modulation therapy for heart failure treatment in patient with amyloidosis: is to be considered a valid therapeutic option?

Aims Cardiac amyloidosis (CA) is primarily associated with fibril deposits in many cardiac structures, causing biventricular wall thickness and stiffness. CA may result in arrhythmias and particularly in an aggressive form of heart failure (HF). Cardiac contractility modulation (CCM) showed to be a concrete therapeutic option in patients with symptomatic HF despite optimal medical therapy (OMT), with Left Ventricular Ejection Fraction (LVEF) between 25% and 45%, with narrow QRS complex (<130 ms). This case aims to further explore the effectiveness of CCM therapy in a patient affected by concomitant ischaemic cardiomyopathy and CA. Methods and results A 42-year-old man with Chronic HF secondary to both post-ischaemic due to spontaneous coronary artery dissection (SCAD) and post alcoholic dilated cardiomyopathy was hospitalized at our department in February 2020 due to worsening HF (3rd HF hospitalization in the same year). The patient was a NYHA class III, with chronic kidney failure, a narrow QRS complex (100 ms) and a LVEF of 27% with familiar history of sudden death, already implanted with ICD. The patient resulted untreatable with sacubitril/valsartan, as it elicited strong hypotension. During current hospitalization the BNP value was 942.60 pg/ml, and the Quality of Life (QoL) evaluated from Minnesota Living with Heart Failure Questionnaire (MLHFQ) score was 72 points. Moreover, the patient underwent umbilical biopsy that confirmed the presence of amyloidosis. Thus, the CCM therapy device (Optimizer® Smart, Impulse Dynamics) was implanted to try to reduce HF symptoms and hospitalizations. The therapy was programmed for 10 h per day, with delivery of CCM from both septal leads with amplitude of 6.5 V at 20.56 ms pulses duration. Figure 1A and B shows the septal position of leads and a surface ECG with the CCM therapy spike after QRS. The patient significantly improved as early as the first period after implantation. The 10-month in-office FU performed on December 2020 revealed in addition to the absence of new HF hospitalizations, a significant improvement in QoL and HF-symptoms, with a MLWHFQ score of 42, an enhancement to NHYA class II, and even a slight decrease of BNP of 767 pg/ml. The echo exam revealed no significant changes in the EF, with an improvement of global longitudinal strain and no worsening of other haemodynamic parameters. A further FU performed in June 2021 showed continuous improvement of QoL with a MLWHFQ score of 25 e no HF hospitalizations. Conclusions In this patient affected by multiple cardiomyopathies, including CA, CCM therapy proved to improve its QoL with no HF hospital admissions since the implantation. The absence of significant echocardiographic worsening is a positive aspect, considering the patient’s status, the concomitant aetiologies, and the presence of amyloidosis, given its progressive and infiltrative nature.

Serum NT-Pro-BNP versus Noninvasive Bedside Inotropic Index in Paediatric Shock: A Contest of Myocardial Performance in Response to Fluid Loading

Background. Mild elevation of serum amino-terminal pro-B-type natriuretic peptide (NT-pro-BNP) is associated with myocardial dysfunction. A significantly lower Smith–Madigan inotropic index (SMII) has been shown to accurately represent cardiac contractility among heart failure subjects. We aim to monitor the effect of fluid resuscitation on cardiac function among paediatric patients by measuring serum NT-pro-BNP and SMII. Methods. This is an observational study on 70 paediatric shock patients. NT-pro-BNP and noninvasive bedside haemodynamic monitoring were done by using an ultrasonic cardiac output monitor (USCOM, USCOM, Sydney, Australia). The presence of cardiac diseases was excluded. SMII was obtained from the USCOM. An increase in the stroke volume index (SVI) of ≥15% indicates fluid responders. Measurements were taken before and after fluid loading. Results. Preloading NT-pro-BNP and SMII category were significantly different between the fluid responsiveness group, p = 0.001 and p = 0.004 , respectively. Higher median NT-pro-BNP (preloading NT-pro-BNP of 1175.00 (254.50–9965.00) ng/mL vs. 196.00 (65.00–509.00) ng/mL, p = 0.002 ) was associated with fluid nonresponders (subjects >12 months old). Preloading NT-pro-BNP <242.5 ng/mL was associated with fluid responders (AUC: 0.768 (0.615–0.921), p = 0.003 ), 82.1% sensitivity, and 68.7% specificity for subjects >12 years old. Delta NT-pro-BNP in fluid responders (15.00 (−16.00–950.00) ng/mL) did not differ from fluid nonresponders (505.00 (−797.00–1600.00) ng/mL), p = 0.456 . Postloading SMII >1.25 W·m−2 was associated with fluid responders (AUC: 0.683 (0.553–0.813), p = 0.011), 61.9% sensitivity, and 66.7% specificity, but not preloading SMII. Fluid responders had a higher mean postloading SMII compared to nonresponders (1.36 ± 0.38 vs. 1.10 ± 0.34, p = 0.006 ). Conclusion. Higher NT-pro-BNP and lower SMII in the absence of cardiac diseases were associated with poor response to fluid loading. The SMII is affected by low preload conditions.

MiR 208a Regulates Mitochondrial Biogenesis in Metabolically Challenged Cardiomyocytes

Metabolic syndrome increases the risk for cardiovascular disease including metabolic cardiomyopathy that may progress to heart failure. The decline in mitochondrial metabolism is considered a critical pathogenic mechanism that drives this progression. Considering its cardiac specificity, we hypothesized that miR 208a regulates the bioenergetic metabolism in human cardiomyocytes exposed to metabolic challenges. We screened in silico for potential miR 208a targets focusing on mitochondrial outcomes, and we found that mRNA species for mediator complex subunit 7, mitochondrial ribosomal protein 28, stanniocalcin 1, and Sortin nexin 10 are rescued by the CRISPR deletion of miR 208a in human SV40 cardiomyocytes exposed to metabolic challenges (high glucose and high albumin-bound palmitate). These mRNAs translate into proteins that are involved in nuclear transcription, mitochondrial translation, mitochondrial integrity, and protein trafficking. MiR 208a suppression prevented the decrease in myosin heavy chain α isoform induced by the metabolic stress suggesting protection against a decrease in cardiac contractility. MiR 208a deficiency opposed the decrease in the mitochondrial biogenesis signaling pathway, mtDNA, mitochondrial markers, and respiratory properties induced by metabolic challenges. The benefit of miR 208a suppression on mitochondrial function was canceled by the reinsertion of miR 208a. In summary, miR 208a regulates mitochondrial biogenesis and function in cardiomyocytes exposed to diabetic conditions. MiR 208a may be a therapeutic target to promote mitochondrial biogenesis in chronic diseases associated with mitochondrial defects.

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+.

Cardiomyocytes Cellular Phenotypes After Myocardial Infarction

Despite the increasing success of interventional coronary reperfusion strategies, mortality related to acute myocardial infarction (MI) is still substantial. MI is defined as sudden death of myocardial tissue caused by an ischemic episode. Ischaemia leads to adverse remodelling in the affected myocardium, inducing metabolic and ionic perturbations at a single cell level, ultimately leading to cell death. The adult mammalian heart has limited regenerative capacity to replace lost cells. Identifying and enhancing physiological cardioprotective processes may be a promising therapy for patients with MI. Studies report an increasing amount of evidence stating the intricacy of the pathophysiology of the infarcted heart. Besides apoptosis, other cellular phenotypes have emerged as key players in the ischemic myocardium, in particular senescence, inflammation, and dedifferentiation. Furthermore, some cardiomyocytes in the infarct border zone uncouple from the surviving myocardium and dedifferentiate, while other cells become senescent in response to injury and start to produce a pro-inflammatory secretome. Enhancing electric coupling between cardiomyocytes in the border zone, eliminating senescent cells with senolytic compounds, and upregulating cardioprotective cellular processes like autophagy, may increase the number of functional cardiomyocytes and therefore enhance cardiac contractility. This review describes the different cellular phenotypes and pathways implicated in injury, remodelling, and regeneration of the myocardium after MI. Moreover, we discuss implications of the complex pathophysiological attributes of the infarcted heart in designing new therapeutic strategies.

Long-term Results of Drug and Interventional Treatment in Patients with Morphologically Verified Idiopathic Arrhythmias

Aim. To study the late results of medical and interventional treatment in patients with morphologically verified nature of idiopathic arrhythmias.Methods. The prospective study included 20 patients (mean age 43.1±11.3 years, 10 female) with atrial fibrillation (AF), supraventricular and ventricular extrasystole, supraventricular and ventricular tachycardia, conduction disturbance without structural heart changes. In addition to the standard examination, the level of anti-heart antibodies was initially determined; endomyocardial biopsy (EMB) of the right ventricle with PCR study for the viral genome; DNA diagnostics (n=4), coronary angioraphy (n=6), skin biopsy (n=1) were performed. The median follow-up was 134 [128; 138] months.Results. By EMB in the initial examination were diagnosed: active (n=8)/borderline (n=3) infectious immune myocarditis; parvovirus-positive endomyocarditis (n=1); undifferentiated vasculitis (n=2); myocardial vasculitis (n=1); Fabry disease (n=1); arrhythmogenic right ventricular dysplasia (n=1); unspecified cardiomyopathy (n=2). Anti-heart antibodies were the most important in myocarditis diagnosis and monitoring. All patients with myocarditis/vasculitis (n=15) received its basic therapy: acyclovir (n=10); immunoglobulin G 10-12.5 g (n=2); hydroxychloroquine 200 mg/day (n=15); glucocorticoids (n=14); azathioprine 150 mg/day (n=2). The late results were evaluated in all patients with myocarditis. Initially, in 62.5% of patients a resistance of AF to all antiarrhythmic drugs was noted. After treatment the average frequency of AF paroxysms decreased (from 8 [5; 8] to 3 [1,25; 7,75] points). By the end of the follow-up, six patients underwent radiofrequency ablation (RFA) for AF, the full effect was achieved once. All patients without RFA have AF partially or completely resistant to drugs. Two patients (without RFA) died from ischemic stroke/ pulmonary embolism.Conclusion. Using EMB the causes of idiopathic arrhythmias (mainly AF) were diagnosed: immune inflammatory diseases in 75% and genetic in 25% of patients. As a result of complex treatment, the general burden of arrhythmias has decreased. But the presence of myocarditis and primary cardiomyopathy, without reducing the cardiac contractility and dilatation, does not allow achieving a stable antiarrhythmic effect. Lethality for 11 years was 10%. The causes of death were thromboembolic complications.

Use of Cardiac Contractility Modulation in an Older Patient with Non-Ischemic Dilated Cardiomyopathy: A Case Report

Cardiac contractility modulation (CCM) is a novel device-based therapy used in patients with HFrEF. CCM therapy is associated with an improvement in exercise tolerance, increased quality of life, reduced HF hospitalizations, and reverse remodelling of the left ventricle in patients with HFrEF. In this case, we report the clinical benefit of CCM in an older patient with advanced HFrEF due to ischemic dilated cardiomyopathy with frequent heart failure-related hospitalizations and poor quality of life despite optimal medical therapy.