Objective
Despite growing evidence about myocardial injury in hospitalized COronaVIrus Disease 2019 (COVID-19) patients, the mechanism behind this injury is only poorly understood and little is known ...about its association with SARS-CoV-2-mediated myocarditis. Furthermore, definite evidence of the presence and role of SARS-CoV-2 in cardiomyocytes in the clinical scenario is still lacking.
Methods
We histologically characterized myocardial tissue of 40 patients deceased with severe SARS-CoV-2 infection during the first wave of the pandemic. Clinical data were also recorded and analyzed. In case of findings supportive of myocardial inflammation, histological analysis was complemented by RT-PCR and immunohistochemistry for SARS-CoV-2 viral antigens and in situ RNA hybridization for the detection of viral genomes.
Results
Both chronic and acute myocardial damage was invariably present, correlating with the age and comorbidities of our population. Myocarditis of overt entity was found in one case (2.5%). SARS-CoV-2 genome was not found in the cardiomyocytes of the patient with myocarditis, while it was focally and negligibly present in cardiomyocytes of patients with known viral persistence in the lungs and no signs of myocardial inflammation. The presence of myocardial injury was not associated with myocardial inflammatory infiltrates.
Conclusions
In this autopsy cohort of COVID-19 patients, myocarditis is rarely found and not associated with SARS-CoV-2 presence in cardiomyocytes. Chronic and acute forms of myocardial damage are constantly found and correlate with the severity of COVID-19 disease and pre-existing comorbidities.
Graphic abstract
Abstract
While chronic heart failure (CHF) treatment has considerably improved patient prognosis and survival, the therapeutic management of acute heart failure (AHF) has remained virtually unchanged ...in the last decades. This is partly due to the scarcity of pre-clinical models for the pathophysiological assessment and, consequently, the limited knowledge of molecular mechanisms involved in the different AHF phenotypes. This scientific statement outlines the different trajectories from acute to CHF originating from the interaction between aetiology, genetic and environmental factors, and comorbidities. Furthermore, we discuss the potential molecular targets capable of unveiling new therapeutic perspectives to improve the outcome of the acute phase and counteracting the evolution towards CHF.
Graphical Abstract
Graphical Abstract
Assembling the acute heart failure (AHF) in a translational view. Different causes of AHF can be reproduced in pre-clinical models to unveil novel pathophysiological and molecular mechanisms. Identifying novel molecular targets amongst organelles and cellular compartments can be tested again in the pre-clinical models. Effective strategies can be exploited in human scenarios. Image was partially created with BioRender.com.
Diverse genetic backgrounds often lead to phenotypic heterogeneity in cardiomyopathies (CMPs). Previous genotype-phenotype studies have primarily focused on the analysis of a single phenotype, and ...the diagnostic and prognostic features of the CMP genotype across different phenotypic expressions remain poorly understood.
We sought to define differences in outcome prediction when stratifying patients based on phenotype at presentation compared with genotype in a large cohort of patients with CMPs and positive genetic testing.
Dilated cardiomyopathy (DCM), arrhythmogenic right ventricular cardiomyopathy, left-dominant arrhythmogenic cardiomyopathy, and biventricular arrhythmogenic cardiomyopathy were examined in this study. A total of 281 patients (80% DCM) with pathogenic or likely pathogenic variants were included. The primary and secondary outcomes were: 1) all-cause mortality (D)/heart transplant (HT); 2) sudden cardiac death/major ventricular arrhythmias (SCD/MVA); and 3) heart failure-related death (DHF)/HT/left ventricular assist device implantation (LVAD).
Survival analysis revealed that SCD/MVA events occurred more frequently in patients without a DCM phenotype and in carriers of DSP, PKP2, LMNA, and FLNC variants. However, after adjustment for age and sex, genotype-based classification, but not phenotype-based classification, was predictive of SCD/MVA. LMNA showed the worst trends in terms of D/HT and DHF/HT/LVAD.
Genotypes were associated with significant phenotypic heterogeneity in genetic cardiomyopathies. Nevertheless, in our study, genotypic-based classification showed higher precision in predicting the outcome of patients with CMP than phenotype-based classification. These findings add to our current understanding of inherited CMPs and contribute to the risk stratification of patients with positive genetic testing.
: Skeletal muscle (SM) mitochondrial dysfunction, oxidative stress, inflammation and muscle mass loss may worsen prognosis in chronic heart failure (CHF). Diet-induced obesity may also cause SM ...mitochondrial dysfunction as well as oxidative stress and inflammation, but obesity per se may be paradoxically associated with high SM mass and mitochondrial adenosine triphosphate (ATP) production, as well as with enhanced survival in CHF.
: We investigated interactions between myocardial infarction(MI)-induced CHF and diet-induced obesity (12-wk 60% vs. standard 10% fat) in modulating gastrocnemius muscle (GM) mitochondrial ATP and tissue superoxide generation, oxidized glutathione (GSSG), cytokines and insulin signalling activation in 10-wk-old mice in the following groups: lean sham-operated, lean CHF (LCHF), obese CHF (ObCHF; all
= 8). The metabolic impact of obesity per se was investigated by pair-feeding ObCHF to standard diet with stabilized excess body weight until sacrifice at wk 8 post-MI.
: Compared to sham, LCHF had low GM mass, paralleled by low mitochondrial ATP production and high mitochondrial reative oxygen species (ROS) production, pro-oxidative redox state, pro-inflammatory cytokine changes and low insulin signaling (
< 0.05). In contrast, excess body weight in pair-fed ObCHF was associated with high GM mass, preserved mitochondrial ATP and mitochondrial ROS production, unaltered redox state, tissue cytokines and insulin signaling (
= non significant vs. Sham,
< 0.05 vs. LCHF) despite higher superoxide generation from non-mitochondrial sources.
: CHF disrupts skeletal muscle mitochondrial function in lean rodents with low ATP and high mitochondrial ROS production, associated with tissue pro-inflammatory cytokine profile, low insulin signaling and muscle mass loss. Following CHF onset, obesity per se is associated with high skeletal muscle mass and preserved tissue ATP production, mitochondrial ROS production, redox state, cytokines and insulin signaling. These paradoxical and potentially favorable obesity-associated metabolic patterns could contribute to reported obesity-induced survival advantage in CHF.
Abstract
The reduced availability of human donor hearts compared with the needs of patients with advanced heart failure refractory to medical therapy has promoted the search for therapeutic ...alternatives to cardiac allografts. Porcine heart xenotransplantation represents one of the most promising frontiers in this field today. From the first researches in the 1960s to today, the numerous advances achieved in the field of surgical techniques, genetic engineering and immunosuppression have made it possible at the beginning of 2022 to carry out the first swine-to-human heart transplant, attaining a survival of 2 months after surgery. The main intellectual and experimental stages that have marked the history of xenotransplantation, the latest acquisitions in terms of genetic editing, as well as the improvement of immunosuppressive therapy are discussed analytically in this article in order to illustrate the underlying complexity of this therapeutic model.
Abstract
Arrhythmogenic right ventricular cardiomyopathy is a myocardial disease generally caused by desmosomal mutations and characterized by progressive replacement of cardiomyocites with ...fibro-adipose tissue. In the classic form of the disease right ventricle is predominantly affected. However, biventricular and left-dominant variants have been recently recognized, leading to the new nosological definition of arrhythmogenic cardiomyopathy. The condition affects mostly young adults and athletes and is clinically characterized by ventricular arrhythmias, heart failure and sudden cardiac death. The diagnosis is based on clinical-instrumental criteria, including family history, morpho-functional and electrocardiographic abnormalities, ventricular arrhythmias and genetic defects (Task Force Criteria, 2010). The main goal in the management of patients is the prevention of sudden cardiac death, where implantable cardioverter-defibrillator is the only effective therapeutic strategy. Many arrhythmic risk factors have been described. Recently, an on-line calculator has been proposed, but it needs further validation.
In the wide phenotypic spectrum of cardiomyopathies, sudden cardiac death (SCD) has always been the most visible and devastating disease complication. The introduction of implantable ...cardioverter-defibrillators for SCD prevention by the late 1980s has moved the question from how to whom we should protect from SCD, leaving clinicians with a measure of uncertainty regarding the most reliable option to guide identification of the highest-risk patients. In this review, we will go through all the available evidence in the field of arrhythmic expression and arrhythmic risk stratification in the different phenotypes of cardiomyopathies to provide practical suggestions in daily clinical management.
Functional screening of expression libraries in vivo would offer the possibility of identifying novel biotherapeutics without a priori knowledge of their biochemical function. Here we describe a ...procedure for the functional selection of tissue-protective factors based on the in vivo delivery of arrayed cDNA libraries from the mouse secretome using adeno-associated virus (AAV) vectors. Application of this technique, which we call FunSel, in the context of acute ischaemia, revealed that the peptide ghrelin protects skeletal muscle and heart from ischaemic damage. When delivered to the heart using an AAV9 vector, ghrelin markedly reduces infarct size and preserves cardiac function over time. This protective activity associates with the capacity of ghrelin to sustain autophagy and remove dysfunctional mitochondria after myocardial infarction. Our findings describe an innovative tool to identify biological therapeutics and reveal a novel role of ghrelin as an inducer of myoprotective autophagy.
Skeletal muscle derangements, potentially including mitochondrial dysfunction with altered mitochondrial dynamics and high reactive oxygen species (ROS) generation, may lead to protein catabolism and ...muscle wasting, resulting in low exercise capacity and reduced survival in chronic heart failure (CHF). We hypothesized that 8-week
-3-PUFA isocaloric partial dietary replacement (Fat = 5.5% total cal; EPA + DHA = 27% total fat) normalizes gastrocnemius muscle (GM) mitochondrial dynamics regulators, mitochondrial and tissue pro-oxidative changes, and catabolic derangements, resulting in preserved GM mass in rodent CHF Myocardial infarction (MI)-induced CHF by coronary artery ligation, left-ventricular ejection fraction <50%.
Compared to control animals (Sham), CHF had a higher GM mitochondrial fission-fusion protein ratio, with low ATP and high ROS production, pro-inflammatory changes, and low insulin signalling.
-3-PUFA normalized all mitochondrial derangements and the pro-oxidative state (oxidized to total glutathione ratio), associated with normalized GM cytokine profile, and enhanced muscle-anabolic insulin signalling and prevention of CHF-induced GM weight loss (all
< 0.05 vs. CHF and
= NS vs. S).
-3-PUFA isocaloric partial dietary replacement for 8 weeks normalizes CHF-induced derangements of muscle mitochondrial dynamics regulators, ROS production and function.
-3-PUFA mitochondrial effects result in preserved skeletal muscle mass, with potential to improve major patient outcomes in clinical settings.
Diagnosis of Arrhythmogenic CardioMyopathy (ACM) is challenging and often late after disease onset. No circulating biomarkers are available to date. Given their involvement in several cardiovascular ...diseases, plasma microRNAs warranted investigation as potential non-invasive diagnostic tools in ACM. We sought to identify circulating microRNAs differentially expressed in ACM with respect to Healthy Controls (HC) and Idiopathic Ventricular Tachycardia patients (IVT), often in differential diagnosis. ACM and HC subjects were screened for plasmatic expression of 377 microRNAs and validation was performed in 36 ACM, 53 HC, 21 IVT. Variable importance in data partition was estimated through Random Forest analysis and accuracy by Receiver Operating Curves. Plasmatic miR-320a showed 0.53 ± 0.04 fold expression difference in ACM vs. HC (p < 0.01). A similar trend was observed when comparing ACM (n = 13) and HC (n = 17) with athletic lifestyle, a ACM precipitating factor. Importantly, ACM patients miR-320a showed 0.78 ± 0.05 fold expression change vs. IVT (p = 0.03). When compared to non-invasive ACM diagnostic parameters, miR-320a ranked highly in discriminating ACM vs. IVT and it increased their accuracy. Finally, miR-320a expression did not correlate with ACM severity. Our data suggest that miR-320a may be considered a novel potential biomarker of ACM, specifically useful in ACM vs. IVT differentiation.
PDF
