Abstract Background The current Risk Score for Life-Threatening Ventricular Tachyarrhythmias (LTVT) in LMNA cardiomyopathy does not consider the frequent association between cardiac and neuromuscular phenotypes as a part of a multisystemic disease. In particular, the prognostic value of tendon retractions (TR) has been recently described. Objectives We aimed to assess the prognostic role of TR in a cohort of probands with LMNA cardiomyopathy undergoing multidisciplinary workup at a referral center. Methods We included 28 probands with LMNA cardiomyopathy undergoing regular, prospective follow-up at a national referral center for laminopathies. All patients underwent extensive baseline characterization, including complete neuromuscular examination and systematic assessment of TR. Indications to implantable cardioverter defibrillators (ICD) for the primary prevention of sudden cardiac death were guideline-based. Patients were clustered in tertiles according to their baseline LMNA-Risk Score. The primary endpoint was the 5-year occurrence of LTVT, namely arrhythmic cardiac death, VF, sustained VT, or appropriate ICD shocks. Results Of the 28 probands with LMNA cardiomyopathy (mean age 33±15 years, 50% males, mean LVEF 55±14 %), neurological assessment identified 14 patients (50%) with TR, including 8 cases with no other signs of neuromuscular involvement. At baseline assessment, the median LMNA-Risk Score was 10% (IQR 6-20%). By 5-year follow-up, 9 patients (32%) met the primary endpoint, including three patients in the lowest tertiles of risk (median LMNA-Risk Score 23, range 6-15%). While other variables showed no remarkable differences between groups, the prevalence of TR was 78% among cases experiencing LTVT and 37% otherwise. The presence of either baseline LMNA-Risk score at the highest tertile (>17%) or TR was 100% predictive of 5-year LTVT (9/9 vs. 7/19, p=0.003). Results did not change after reassessment by the end of follow-up (15±5 years). Conclusions Our preliminary data suggest that the inclusion of TR in risk stratification may result in a better patient selection for primary prevention ICD implant in LMNA cardiomyopathy.
The authors present a clinical report focused on the overlap between myocarditis and genetic cardiomyopathies of the dilated and arrhythmogenic spectrum. Our cohort was composed of 25 patients undergoing extensive baseline characterization and prospective reassessment by a dedicated multidisciplinary disease unit during a median follow-up of 69 months. We showed that the use of multimodal imaging allowed both discrimination of specific genotypes and identification of myocardial inflammation proven using endomyocardial biopsy. In addition, we showed that the use of immunomodulatory therapy was beneficial for most patients.
Abstract Background Early-stage left ventricular non compaction (LVNC) is a nonischemic cardiomyopathy characterized with nondilated phenotype and unpredictable risk of malignant ventricular arrhythmias (MVA). Purpose To report the occurrence of MVA in patients with early-stage LVNC. Methods Consecutive patients (n=63) diagnosed with LVNC according to recognized criteria either on transthoracic echocardiogram or cardiac magnetic resonance were retrospectively enrolled. Patients with late-stage LVNC, defined by a coexistent dilated cardiomyopathy phenotype, were excluded (n=49). Patient-tailored medical treatment, as well as ICD implantation strategies, were based on the updated ESC guidelines integrated by the experience of a referral center for arrhythmia management. The study endpoint was the occurrence of MVA (defined as sustained VT, VF, or appropriate ICD therapy) by 5-year follow-up. Results The study cohort consisted of 14 patients (mean age 37±17 y, 64% males), presenting with palpitation (n=4), syncope (n=4), or dyspnea on effort (n=6). LVNC was diagnosed by echocardiogram and cardiac magnetic resonance in 13 and 1 patients, respectively. Because of nonmalignant VA, seven patients (50%) underwent ICD implant before discharge. By 5-year follow-up, 5 patients (36%) experienced MVA, including VF or appropriate ICD shocks for fast VT. Left ventricular ejection fraction (LVEF) ≥45% was the only factor associated with the occurrence of MVA (5/11 event in cases with LVEF ≥45% vs. 0/3 events in controls with LVEF <45%; p=0.145). Baseline features, including age, gender, NC/C ratio, and clinical presentation were comparable between cases with LVEF ≥45% and controls, all p>0.05. Drug treatment, including RAAS inhibitors, betablockers and antiarrhythmics was also comparable. Conclusions Our preliminary data show that in early-stage LVNC the occurrence of MVA is higher for patients with LVEF ≥45%. Efforts are needed to identify earlier predictors of arrhythmic risk, to improve patient selection for ICD implant. Funding Acknowledgement Type of funding sources: None.
Over recent years, preclinical and clinical evidence has implicated myocardial inflammation (M-Infl) in the pathophysiology and phenotypes of traditionally genetic cardiomyopathies. M-Infl resembling myocarditis on imaging and histology occurs frequently as a clinical manifestation of classically genetic cardiac diseases, including dilated and arrhythmogenic cardiomyopathy. The emerging role of M-Infl in disease pathophysiology is leading to the identification of druggable targets for molecular treatment of the inflammatory process and a new paradigm in the field of cardiomyopathies. Cardiomyopathies constitute a leading cause of heart failure and arrhythmic sudden death in the young population. The aim of this review is to present, from bedside to bench, the current state of the art about the genetic basis of M-Infl in nonischemic cardiomyopathies of the dilated and arrhythmogenic spectrum in order to prompt future research towards the identification of novel mechanisms and treatment targets, with the ultimate goal of lowering disease morbidity and mortality.
Abstract Background Preclinical data support the rationale for targeting myocardial inflammation in genetic nonischemic cardiomyopathies. However, no consistent clinical reports have been provided so far. Methods We describe a series of patients (n=25) with genetic cardiomyopathy and active myocardial inflammation (AMI) proven by multimodal diagnostic workup. Patient-tailored immunosuppressive therapy was empirically started to target myocardial inflammation whenever feasible. Multiple outcomes were retrospectively assessed by a dedicated multidisciplinary disease unit. Results Patients carrying desmosomal (DGV), cytoskeletal (CGV) and membrane gene variants (MGV), were 12 (48%), 10 (40%), and 3 (12%), respectively. DGV carriers uniformly presented with myocarditis-like chest pain and ventricular arrhythmias, whereas heart failure symptoms were found only in CGV carriers. Dilated cardiomyopathy phenotype and ring-like pattern on cardiac magnetic resonance allowed the best discrimination among genotypes. AMI was proven by endomyocardial biopsy in all cases, and by noninvasive imaging in 21 (83%). IST was started in 17 patients (71%) with no safety issues. By the end of follow-up (median 69 months, range 21-182), signs of AMI were documented in 6/18 IST receivers (33%) and 4/7 untreated cases (57%). For most genotypes, paucity of adverse events was noted while on immunosuppression as compared to the off-treatment period. Conclusion Our preliminary data provide the clinical rationale for the research and targeting of AMI in a spectrum of genetic nonischemic cardiomyopathies.
Abstract Background Arrhythmic risk of patients with left ventricular arrhythmogenic cardiomyopathy (LVAC) is unpredictable. Purpose To identify risk facors associated with major ventricular tachyarrhythmias (VTA) in clinically-suspected LVAC patients. Methods We enrolled 127 consecutive patients (69% males, age 46±13 y, LVEF 54±7%) with clinically-suspected LVAC. All patients presented with either major (VT, VF) or minor VTA (NSVT, frequent VEB), and underwent extensive diagnostic workup to rule-out alternative diagnoses. Medical treatment and ICD implant were clinically-driven. Prospective follow-up was obtained via sequential 24h-Holter ECG (2–4/y) with or without continuous arrhythmia monitoring (ICD or implantable loop recorders, ILR). The primary endpoint was occurrence of major VTA (VT/VF/ICD therapy) by 24-month follow-up. Results At presentation, 56 (44%) and 71 patients (56%) had, respectively, major and minor VTA. Variants in desmosomal genes were identified in 7 of the 9 patients with clinically-indicated genetic test. Delayed gadolinium enhancement (DGE, average 23±12% of the LV mass) had anteroseptal distribution in 43 cases (34%). Monitoring strategy included ICD (n=64), ILR (n=33), or sequential Holer ECGs (n=30). By 24-month follow-up, major VTA occurred in 32 patients (25%). At univariable anlysis, major VTA onset (HR 16.8, 95% CI 5.4–52.2, p<0.001) and anteroseptal DGE (HR 3.0, 95% CI 1.3–6.9, p=0.010) were significantly associated with major VTA by 24-month follow-up. Among patients presenting with minor VTA, the only factor significantly associated with the primary endpoint was anteroseptal DGE (3/4 vs. 14/67, p=0.004). Conclusion Our preliminary experience suggests that, in patients with clinically-suspected LVAC, major VTA onset and anteroseptal DGE are relevant risk factors for major arrhythmic events by 24-month follow-up. Funding Acknowledgement Type of funding sources: None.
Brugada syndrome (BrS) is an inherited autosomal dominant genetic disorder responsible for sudden cardiac death from malignant ventricular arrhythmia. The term “channelopathy” is nowadays used to classify BrS as a purely electrical disease, mainly occurring secondarily to loss-of-function mutations in the α subunit of the cardiac sodium channel protein Nav1.5. In this setting, arrhythmic manifestations of the disease have been reported in the absence of any apparent structural heart disease or cardiomyopathy. Over the last few years, however, a consistent amount of evidence has grown in support of myocardial structural and functional abnormalities in patients with BrS. In detail, abnormal ventricular dimensions, either systolic or diastolic dysfunctions, regional wall motion abnormalities, myocardial fibrosis, and active inflammatory foci have been frequently described, pointing to alternative mechanisms of arrhythmogenesis which challenge the definition of channelopathy. The present review aims to depict the status of the art of concealed arrhythmogenic substrates in BrS, often resulting from an advanced and multimodal diagnostic workup, to foster future preclinical and clinical research in support of the cardiomyopathic nature of the disease.
Abstract Background Procalcitonin (PCT) is an established predictor of bacterial infections and sepsis. However, PCT involvement in cardiovascular diseases has been scarcely investigated so far. In particular, no studies at all ever addressed the role of PCT in myocarditis patients. We aimed at evaluating PCT in myocarditis patients, as a potential biomarker of: a) aetiologic diagnosis; b) prognosis. Methods A cohort of 130 consecutive patients with a novel diagnosis of myocarditis confirmed by both endomyocardial biopsy and cardiac magnetic resonance were included in the study. Patients with known bacterial infections or bacterial myocarditis were excluded (n=5). PCT concentration was measured on admission in all patients. Prospective follow-up (FU) was performed every 6 months up to 5 years. Results Of 125 patients analyzed (mean age 45±15 years, males 62%, mean LVEF 48±15%), 22 (18%) had fulminant myocarditis (FM). The remaining 103 cases had non-fulminant myocarditis (NFM), including infarct-like presentation and non-malignant arrhythmias. Aetiology was viral or virus-negative in 23 and 102 patients, respectively. The mean PCT value was 0.44±0.18 mcg/ml, with no significant differences between viral and virus-negative myocarditis (0.43±0.19 vs. 0.44±0.18 mcg/ml, p=0.90). Baseline PCT concentration was significantly higher in FM patients (0.69±0.21 vs. 0.39±0.16 mcg/ml, p=0.07). Consistently, PCT was higher in patients with LVEF <60% (0.51±0.20 vs. 0.30±0.14 mcg/ml, p=0.03) and in those with elevated (>400 pg/mL) NT-proBNP (0.55±0.19 vs. 0.36±0.17 mcg/ml, p=0.03). As for inflammatory biomarkers, patients with high ESR (>20 mm/h) had also higher PCT values (0.56±0.20 vs. 0.37±0.16 mcg/ml, p=0.03). By converse, no association was found between PCT and CRP abnormal values (p>0.05). At univariate analysis, high PCT (≥0.20 mcg/ml) was predictive of heart failure recurrence (OR 2.77, 95% CI 1.18–6.48, p=0.02) or arrhythmic cardiac arrest (OR 3.22, 95% CI 1.19–8.71, p=0.02) by discharge, with overall hospitalization prolonged by 10±4 days (p<0.05). Furthermore, patients with high PCT were more prone to myocarditis recurrences (13/80 vs. 4/45, p=0.03) by 5-year FU. Conclusions In myocarditis patients, elevated PCT values at presentation are not associated with myocarditis aetiology. Nonetheless, PCT suggests a worse short-term clinical outcome, and also a higher risk of myocarditis recurrences at long-term FU. Funding Acknowledgement Type of funding source: None
Abstract Background Pentraxin 3 (PTX3) is an acute phase protein, which regulates the outcomes of inflammation. Currently, there are no myocarditis-typical biomarkers that allow a non-invasive diagnosis, and endomyocardial biopsy (EMB) is still the gold standard. Finally, risk stratification is often challenging in these patients. Aim To investigate whether PTX3 could be expressed in cardiomyocytes and released during myocarditis, serving as a novel and independent diagnostic indicator of myocardial inflammation, and contributing to prognosis prediction. Methods Fifty-five patients with a diagnosis of acute or chronic active myocarditis proven by cardiac magnetic resonance (CMR) and/or endomyocardial biopsy (EMB), were included. First, we evaluated tissue PTX3 expression by immunohistochemistry (IHC). Then, we assessed circulating blood PTX3 by ELISA technique. Results On cardiac tissue, PTX3 at IHC did not localize in the interstitium, and showed an inconstant expression in the vascular endothelium, but a marked staining by cardiomyocytes in all myocarditis patients. The only exception was represented by two patients with systemic COVID-19, with SARS-CoV-2 and PVB-19 intracardiac genomes, respectively, who showed a diffuse cardiac PTX3 expression. Remarkably, at semi-quantitative pixel analysis, viral aetiology showed higher levels of tissue expression, rather than the autoimmune one. Circulating PTX3 levels were significantly higher in myocarditis patients than controls, with pathologic values in 87% of myocarditis patients, and none among controls. Remarkably, plasma PTX3 proved to be more sensitive in myocarditis detection than CRP, ESR, troponin T, and NT-proBNP. As regards of prognosis, we observed that patients with heart failure (HF) presentation all had elevated PTX3 levels, as compared with chest pain or arrhythmia. Remarkably, patients with reduced LVEF (<50%) at admission who recovered during follow-up had higher baseline PTX3 levels, rather than those whose systolic function did not improve. Conclusions Tissue PTX3 is mostly expressed by cardiomyocytes in patients with active myocarditis on EMB samples. In addition, plasma PTX3 is a sensitive diagnostic and prognostic marker in patients with inflammatory cardiomyopathy.
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