Truncating variants in the
gene (TTNtv) are the commonest cause of heritable dilated cardiomyopathy. This study aimed to study the phenotypes and outcomes of TTNtv carriers.
Five hundred thirty-seven ...individuals (61% men; 317 probands) with TTNtv were recruited in 14 centers (372 69% with baseline left ventricular systolic dysfunction LVSD). Baseline and longitudinal clinical data were obtained. The primary end point was a composite of malignant ventricular arrhythmia and end-stage heart failure. The secondary end point was left ventricular reverse remodeling (left ventricular ejection fraction increase by ≥10% or normalization to ≥50%).
Median follow-up was 49 (18-105) months. Men developed LVSD more frequently and earlier than women (45±14 versus 49±16 years, respectively;
=0.04). By final evaluation, 31%, 45%, and 56% had atrial fibrillation, frequent ventricular ectopy, and nonsustained ventricular tachycardia, respectively. Seventy-six (14.2%) individuals reached the primary end point (52 68% end-stage heart failure events, 24 32% malignant ventricular arrhythmia events). Malignant ventricular arrhythmia end points most commonly occurred in patients with severe LVSD. Male sex (hazard ratio, 1.89 95% CI, 1.04-3.44;
=0.04) and left ventricular ejection fraction (per 10% decrement from left ventricular ejection fraction, 50%; hazard ratio, 1.63 95% CI, 1.30-2.04;
<0.001) were independent predictors of the primary end point. Two hundred seven of 300 (69%) patients with LVSD had evidence of left ventricular reverse remodeling. In a subgroup of 29 of 74 (39%) patients with initial left ventricular reverse remodeling, there was a subsequent left ventricular ejection fraction decrement. TTNtv location was not associated with statistically significant differences in baseline clinical characteristics, left ventricular reverse remodeling, or outcomes on multivariable analysis (
=0.07).
TTNtv is characterized by frequent arrhythmia, but malignant ventricular arrhythmias are most commonly associated with severe LVSD. Male sex and LVSD are independent predictors of outcomes. Mutation location does not impact clinical phenotype or outcomes.
Aims
‘Hot phases’, characterized by chest pain and troponin release, may represent the first clinical presentation of arrhythmogenic cardiomyopathies. Differential diagnosis with acute myocarditis is ...an unmet challenge for the clinicians. We sought to investigate histological and genetic features in patients with cardiomyopathy presenting with hot phases.
Methods and results
We evaluated a case series of consecutive patients hospitalized for suspected ‘hot‐phase cardiomyopathy’ in two Italian centres from June 2017 to March 2022 (median follow‐up 18 months) that underwent both endomyocardial biopsy (EMB) and genetic testing. Apoptosis was confirmed with TUNEL assay. Among the 17 enrolled patients (mean age 34 ± 15 years, 76% male), only six patients (35%) presented standard histological and immunohistochemical markers for significant cardiac inflammation at EMB. Conversely, apoptosis was found in 13 patients (77%). Genetic testing was positive for a pathogenic/likely pathogenic (P/LP) variant in genes involved in cardiomyopathies (most frequently in DSP) in eight patients (48%), rising to 62% among patients with apoptosis on EMB. Notably, all patients without apoptosis tested negative for P/LP disease‐related variants. Left ventricular ejection fraction was lower in patients showing apoptosis at EMB compared to those without (p = 0.003).
Conclusions
Apoptosis, rather than significant inflammation, was mostly prevalent in this case series of patients with ‘hot‐phase’ presentation, especially in carriers of variants in cardiomyopathy‐related genes. Detecting apoptosis on EMB might guide clinicians in performing genetic testing and in more tailored therapeutic choices in ‘hot‐phase cardiomyopathy’.
Seventeen patients hospitalized for suspected hot‐phase cardiomyopathy underwent both endomyocardial biopsy (EMB) and genetic testing: histological detection of apoptosis at EMB was frequent (77% of cases) and all patients that tested positive for pathogenic/likely pathogenic variants showed apoptosis at EMB. In patients with apoptosis at EMB, left ventricular ejection fraction was lower at first clinical presentation and improved during follow‐up with anti‐neurohormonal therapy.
Abstract
Background
Titin truncating variants (TTNtv) represent the most prevalent genotype underlying dilated cardiomyopathy (DCM). Recent molecular studies provided initial evidence about different ...pathogenic mechanisms produced by different mutation sites of the truncating variant (A-Band vs non-A-band), possibly related to the presence or absence of truncated titin (TTN) peptides. However, to date, clinical studies on DCM patients carrying TTNtv failed to demonstrate any relevant clinical difference according to the titin band affected. We hypothesized this lack of variation could be partially explained by the selection bias of including only DCM phenotype patients. Thus, we studied the clinical phenotypes and outcomes of our entire population of subjects with pathogenic TTNtv regardless of phenotypic expression at the onset.
Methods
We retrospectively analyzed a population of pathogenic TTNtv carriers, enrolled in the Trieste Heart Muscle Disease Registry. TTNtv were classified according to their site (Z disk, I band, A band, A-M junction, M band) and further grouped for analysis in A-band and non-A band. Variables were expressed as mean±SD, median and interquartile range, or counts and percentage, as appropriate. Kaplan-Meier curves were estimated for the composite endpoints of (i) heart failure-related death, heart transplant, and destination left ventricular assist device implantation and (ii) first major ventricular arrhythmia (MVA, defined as SCD or life-threatening ventricular arrhythmia) and compared by the log-rank test.
Results
154 TTNtv carriers were included in the study, of whom 66% were probands. The most prevalent phenotype was DCM (92%). The mean age of subjects at diagnosis was 43±16 years and 70% were males. There was no difference between groups in the first composite outcome of heart failure-related death, heart transplant, and destination left ventricular assist device implantation. Instead, major ventricular arrhythmias were significantly more frequent in the non-A-band group, in which 47% (n=14) of TTNtv carriers experienced MVA as compared to 19% (n=20) of subjects in the A-band group (p=0.001). Interestingly, we observed a tendency in MVA occurrence at a higher mean left ventricular ejection fraction (LVEF) in the non-A-band group as compared to the A-band group (42±13% vs 35±9%, respectively).
Conclusions
Among TTNtv carriers referred to a tertiary center, those with a mutation in the non-A band seem characterized by higher arrhythmic risk. This novel finding highlights the importance of considering the site of TTN truncating variants to guide the most appropriate clinical management for each patient.
Abstract
A 71-year-old man, former smoker, without other cardiovascular risk factors nor previously known cardiological history, was admitted to our emergency department for nonproductive cough and ...right-sided chest pain, worsened by inspiration. ECG documented reduced peripheral QRS voltages. Echocardiography was performed, revealing the presence of an inhomogeneous, hyperechoic neoformation involving the lateral wall of the right ventricle (RV), dislocating the right coronary artery, protruding into the cavity towards the intraventricular septum and reaching the sub-valvular apparatus of the tricuspid valve, without any hemodynamic interference. Pericardial effusion was also documented (maximum 20 mm around the atrioventricular groove), without signs of cardiac tamponade. For better mass characterization, a computed tomography (CT) scan and a cardiac magnetic resonance (CMR) were performed, confirming the presence of a solid neoformation involving the RV and pericardial effusion, also showing right pleural effusion. Furthermore, right hilar and subcarinal lymphadenomegaly with compression of the bronchi was observed. A positron emission tomography (PET) scan showed areas of increased 18-fluorodeoxyglucose (18FDG) uptake in supra- and infra diaphragmatic lymph nodes, adrenal glands, bones, and lungs. Due to the clinical suspicion of a lymphoproliferative neoplasm, corticosteroid therapy was started.
Before a diagnostic lymph node biopsy could be performed, the patient had a syncopal episode due to cardiac tamponade, requiring pericardiocentesis. During hospitalization, continuous heart monitoring revealed intermittent third-degree atrioventricular block, so a permanent pacemaker was implanted. Finally, an excisional lymph node biopsy was obtained, and a diagnosis of diffuse large B-cell lymphoma was established. Treatment with Prednisone, Cyclophosphamide, Vincristine, nonpegylated liposomal Doxorubicin, and Rituximab (R-COMP) was promptly started. Seven months later, after five cycles of chemotherapy, complete remission was documented by PET scan, and the cardiac mass was no longer evident at echocardiography.
Metastatic involvement of the heart is a relatively frequent event in oncologic patients, with an estimated prevalence of 8% at autopsy. Lymphoproliferive neoplasms have a not negligible rate of heart mestastatization (9,4%). Neoplastic invasion secondary to lymphoma tends to infiltrate the myocardium, typically causing arrhythmias and conduction disturbances.
Diagnostic evaluation relies upon echocardiography, CT and CMR. PET/TC is of paramount importance to assess the malignant nature of the mass, to stage the disease and to evaluate the response to chemotherapy. Metastatic cardiac involvement typically occurs as a late manifestation of disseminated lymphoma and the prognosis is usually poor; however, survival is increasing thanks to new chemo-immunotherapy strategies.
Assessing myocardial strain by cardiac magnetic resonance feature tracking (FT) has been found to be useful in patients with overt hypertrophic cardiomyopathy (HCM). Little is known, however, of its ...role in sarcomere gene mutation carriers without overt left ventricular hypertrophy (subclinical HCM).
Thirty-eight subclinical HCM subjects and 42 healthy volunteers were enrolled in this multicenter case-control study. They underwent a comprehensive cardiac magnetic resonance study. Two-dimensional global radial, circumferential, and longitudinal strain of the left ventricle (LV) were evaluated by FT analysis.
The subclinical HCM sample was 41 (22-51) years old and 32% were men. FT analysis revealed a reduction in global radial strain (29±7.2 versus 47.9±7.4;
<0.0001), global circumferential strain (-17.3±2.6 -versus -20.8±7.4;
<0.0001) and global longitudinal strain (-16.9±2.4 versus -20.5±2.6;
<0.0001) in subclinical HCM compared with control subjects. The significant differences persisted when considering the 23 individuals free of all the structural and functional ECG and cardiac magnetic resonance abnormalities previously described. Receiver operating characteristic curve analyses showed that the differential diagnostic performances of FT in discriminating subclinical HCM from normal subjects were good to excellent (global radial strain with optimal cut-off value of 40.43%: AUC, 0.946 95% CI, 0.93-1.00; sensitivity 90.48%, specificity 94.44%; global circumferential strain with cut-off, -18.54%: AUC, 0.849 95% CI, 0.76-0.94; sensitivity, 88.10%; specificity, 72.22%; global longitudinal strain with cut-off, -19.06%: AUC, 0.843 95% CI, 0.76-0.93; sensitivity, 78.57%; specificity, 78.95%). Similar values were found for discriminating those subclinical HCM subjects without other phenotypic abnormalities from healthy volunteers (global radial strain with optimal cut-off 40.43%: AUC, 0.966 95% CI, 0.92-1.00; sensitivity, 90.48%; specificity, 95.45%; global circumferential strain with cut-off, -18.44%: AUC, 0.866 95% CI, 0.76-0.96; sensitivity, 92.86%; specificity, 77.27%; global longitudinal strain with cut-off, -17.32%: AUC, 0.838 95% CI, 0.73-0.94; sensitivity, 90.48%; specificity, 65.22%).
Cardiac magnetic resonance FT-derived parameters are consistently lower in subclinical patients with HCM, and they could emerge as a good tool for discovering the disease during a preclinical phase.
Left ventricular ejection function (LVEF) is not reliable in identifying subtle systolic dysfunction. Speckle Tracking (ST) plays a promising role and hemodynamic forces (HDFs) are emerging as marker ...of LV function. The role of LV myocardial deformation and HDFs was investigated in a cohort of patients with aortic stenosis (AS) and normal LVEF. Two hundred fifty three patients (median age 79 years, IQR 73 – 83 years) with mild (n = 87), moderate (n =77) and severe AS (n =89) were retrospectively enrolled. 2D echocardiographic global longitudinal strain (GLS), circumferential strain (GCS) and HDFs were determined. The worsening of AS was associated with raising inappropriate LV mass (p < 0.001) and declined LVEF, despite being in the normal range (p < 0.001). ST and HDFs parameters declined as the AS became severe (p<0.0001, for all). When patients were grouped based on the median of LV endocardial GLS value (> -19,9%) and LV systolic longitudinal force (LVsysLF) value (< 12,49), patients with impaired ST and lower HDFs components had increased incidence of aortic valve replacement (AVR) and worse survival (p <0.024 and p <0.037, respectively). Among ST and HDFs parameters, only LVsysLF was independently associated with AVR and all causes mortality on multivariable Cox regression analysis (HR 0.94; 95% CI 0.89-0.99; p= 0.012). Reduced values of LVsysLF were associated with AVR and reduced survival in AS patients. LVsysLF could provide useful information in the stratification of patients with AS and possibly in the choice of timing for AVR.
Rationale and Methods: 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 n-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%. Results: 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. n-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 p < 0.05 vs. CHF and p = NS vs. S). Conclusions:n-3-PUFA isocaloric partial dietary replacement for 8 weeks normalizes CHF-induced derangements of muscle mitochondrial dynamics regulators, ROS production and function. n-3-PUFA mitochondrial effects result in preserved skeletal muscle mass, with potential to improve major patient outcomes in clinical settings.
Lymphocytic Myocarditis Artico, Jessica; Merlo, Marco; Delcaro, Giulia ...
Journal of the American College of Cardiology,
06/2020, Letnik:
75, Številka:
24
Journal Article
The early diagnosis of genetically determined dilated cardiomyopathy (DCM) could improve the prognosis in mutation carriers. Left ventricular global longitudinal strain (LV GLS) and peak left atrial ...longitudinal strain (PALS) are promising techniques for the detection of subtle systolic and diastolic dysfunction. We sought to evaluate the prevalence of subtle systolic and diastolic dysfunction by LV GLS and PALS in a cohort of genotype-positive phenotype-negative (GPFN) DCM relatives.
In this retrospective study, we analyzed echocardiograms of forty-one GPFN relatives of DCM patients. They were compared with age and sex matched healthy individuals (control group). Reduced LV GLS and PALS were defined as >18% and <23.1%, respectively. GPFN relatives (37 ± 14 years, 48.8% male) and controls were similar according to standard echocardiographic measurements. Conversely, LV GLS was −18.8 ± 2.7% in the GPFN group vs. −24.0 ± 1.8% in the control group (p < 0.001). Twenty subjects (48.8%) in the GPFN group and no subjects in the control group had a reduced LV GLS. PALS was 29.2 ± 6.7% in the GPFN group vs. 40.8 ± 8.5% in the control group (p < 0.001). Seven subjects (18.4%) in the GPFN group and one (2%) in the control group had a reduced PALS. A cohort of 17 genotype-negative phenotype-negative relatives showed higher values of LV GLS compared to GPFN.
Despite standard echocardiographic parameters are within the normal range, LV GLS and PALS are lower in GPFN relatives of DCM patients when compared to healthy individuals, suggesting a consistent proportion of subtle systolic and diastolic dysfunction in this population.
•LV GLS and PALS are promising tools for detection of subtle systolic and diastolic dysfunction, also in GPFN relatives of DCM patients.•In GPFN relatives of DCM patients have been identified lower values of both LV GLS and PALS, in compared to healthy subjects.•GPFN relatives of DCM patients with subtle systolic and diastolic dysfunction could require a tight follow-up for early identification of disease onset.
Abstract
Background
Familial patterns of inheritance and genetic mutations have been identified as pathogenic in nearly 40-50% of previously defined “idiopathic” Dilated Cardiomyopathy (DCM). Genetic ...testing in the proband allows cascade genetic screening in relatives, in order to promote an early diagnosis even in a pre-clinical stage of the disease, as recommended by international guidelines. This study aims to describe the clinical characteristics of screened relatives of Dilated Cardiomyopathy (DCM) patients, at baseline and during follow-up.
Methods
Screened relatives of patients affected by DCM were enrolled retrospectively and followed from January 2000 to August 2021. At baseline, the family screening included a clinical evaluation, ECG and echocardiogram. If likely pathogenetic (LP) or pathogenetic (P) variant was identified in the proband Genetic testing was offered and performed on relatives according to available consensus documents from the age of 10-12 years. The onset of disease was defined as left ventricular (LV) dilation and/or LV systolic dysfunction. The following information was obtained during the follow-up: all-cause death, cardiovascular death, sudden cardiac death (SCD), hospitalization for heart failure (HF), heart transplantation, ventricular assist device (VAD) implantation, ICD or CRT-D implantation and major ventricular arrhythmias (MVA).
Results
We enrolled 203 relatives from 32 families with DCM. The median follow-up was 94 months. At baseline, symptomatic relatives for dyspnea (NYHA II-III class) were 29 (14%), versus 174 (86%) of asymptomatic (NYHA I). All these subjects showed initial signs of DCM and experienced more frequently adverse outcomes, such as hospitalization for HF (p<0,001) and MVA (p<0,001) during follow-up.
Among asymptomatic relatives, patients with initial signs of disease were 46 (26%), 20 (43%) with LV dilation and dysfunction, 18 (39%) with LV dysfunction and 7 (15%) with LV dilatation. During follow-up, 5 of them (11%) died and 2 (4%) experienced SCD (one carrier of FLNC variant). Globally, affected relatives at baseline carried a LP/P variant in more than half of the cases (57%), the remaining part being relative of proband with no or negative genetic testing.
Non-affected relatives were 128 (74%) at baseline. 15 relatives (12%) developed initial signs of DCM (5 with LV dilation, 5 with LV dysfunction, 5 with LV dilation and dysfunction) during follow-up. Of those, 13 patients (87%) carried a LP/P variant. The genes mostly involved were TTN (9 cases,69%), followed by DSP and FLNC.
Conclusions
Familial screening allows an early diagnosis of DCM-affected patients. Asymptomatic relatives at the baseline showed a better outcome compared with symptomatic ones. However, SCD events were only detected in the asymptomatic group. Moreover, subjects who develop the disease during follow-up were carriers of a LP/P variant. Seriate follow-up is mandatory in relatives independently by symptoms at the baseline: genetic testing supports a focused clinical screening of high-risk relatives.
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