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Dilated cardiomyopathy is a primary disease of the heart muscle, which affects relatively young patients with a low comorbidity profile. It is characterized by structural and/or functional abnormalities leading to systolic dysfunction of the left ventricle or of both ventricles, often associated with dilatation, in the absence of an ischaemic, valvular, or pressure overload cause sufficient to explain the phenotype. Although the prognosis of the disease has greatly improved over the last few decades, prognostic stratification remains a fundamental objective, especially about the prediction of potentially life-threatening arrhythmic events. An accurate diagnostic work-up and an appropriate aetiopathogenetic characterization affect the patients' outcome and represent the essential basis of an adequate prognostic stratification. It is necessary to adopt a multiparametric approach, especially when the aim is the prediction of arrhythmic risk; it includes an integration of medical history and physical examination with cardiac imaging and genetic testing, in order to obtain a personalized diagnosis and therapeutic strategies. Furthermore, the evaluation should be repeated at every clinical check-up, considering the dynamic trend of the pathology and the arrhythmic risk changes over time. This article aims to illustrate how, starting from an exhaustive aetiological and clinical-instrumental characterization, including all diagnostic methods available at present time, it is possible to obtain a tailored diagnostic evaluation and stratification of the arrhythmic risk as accurate as possible.
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BACKGROUND: Filamin C truncating variants (FLNCtv) cause a form of arrhythmogenic cardiomyopathy: the mode of presentation, natural history, and risk stratification of FLNCtv remain incompletely explored. We aimed to develop a risk profile for refractory heart failure and life-threatening arrhythmias in a multicenter cohort of FLNCtv carriers. METHODS: FLNCtv carriers were identified from 10 tertiary care centers for genetic cardiomyopathies. Clinical and outcome data were compiled. Composite outcomes were all-cause mortality/heart transplantation/left ventricle assist device (D/HT/LVAD), nonarrhythmic death/HT/LVAD, and sudden cardiac death/major ventricular arrhythmias. Previously established cohorts of 46 patients with LMNA and 60 with DSP-related arrhythmogenic cardiomyopathies were used for prognostic comparison. RESULTS: Eighty-five patients carrying FLNCtv were included (42±15 years, 53% men, 45% probands). Phenotypes were heterogeneous at presentation: 49% dilated cardiomyopathy, 25% arrhythmogenic left dominant cardiomyopathy, 3% arrhythmogenic right ventricular cardiomyopathy. Left ventricular ejection fraction was <50% in 64% of carriers and 34% had right ventricular fractional area changes (RVFAC=(right ventricular end-diastolic area - right ventricular end-systolic area)/right ventricular end-diastolic area) <35%. During follow-up (median time 61 months), 19 (22%) carriers experienced D/HT/LVAD, 13 (15%) experienced nonarrhythmic death/HT/LVAD, and 23 (27%) experienced sudden cardiac death/major ventricular arrhythmias. The sudden cardiac death/major ventricular arrhythmias incidence of FLNCtv carriers did not significantly differ from LMNA carriers and DSP carriers. In FLNCtv carriers, left ventricular ejection fraction was associated with the risk of D/HT/LVAD and nonarrhythmic death/HT/LVAD. CONCLUSIONS: Among patients referred to tertiary referral centers, FLNCtv arrhythmogenic cardiomyopathy is phenotypically heterogeneous and characterized by a high risk of life-threatening arrhythmias, which does not seem to be associated with the severity of left ventricular dysfunction.
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Cardiomiopatias/etiologia , Filaminas/genética , Predisposição Genética para Doença , Variação Genética , Fenótipo , Adulto , Alelos , Cardiomiopatias/diagnóstico , Cardiomiopatias/epidemiologia , Cardiomiopatias/terapia , Terapia Combinada , Gerenciamento Clínico , Ecocardiografia , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Prognóstico , Sistema de RegistrosRESUMO
BACKGROUND: Physiological cardiac remodelling in highly trained athletes may overlap with dilated cardiomyopathy (DCM). OBJECTIVES: The aim of this study was to investigate the role of the electrocardiogram (ECG) in differentiating between physiological and pathological remodelling. METHODS: The study population consisted of 30 patients with DCM who revealed a pathogenic variant at genetic testing and 30 elite athletes with significant cardiac remodelling defined by a left ventricular (LV) end-diastolic diameter >62 mm and/or LV ejection fraction between 45% and 50%. RESULTS: The ECG was abnormal in 22 (73%) patients with DCM. The most common abnormalities were low voltages (n = 14, 47%), lateral T-wave inversion (TWI) (n = 6, 20%), ventricular ectopic beats (n = 5, 17%) and anterior TWI (n = 4, 13). Two athletes revealed an abnormal ECG: complete left bundle branch block (LBBB) in one case and atrial flutter in the other. The sensitivity, specificity and accuracy of the ECG in differentiating DCM from physiological adaptation to exercise in athletes was 73% (confidence interval [CI]: 54%-88%), 93% (CI: 78%-99%) and 0.83 (CI: 0.71-0.92) respectively. CONCLUSIONS: While the ECG is usually normal in athletes exhibiting significant LV dilatation and/or systolic dysfunction, this test is often abnormal in patients with DCM harbouring a pathogenic variant. Low voltages in the limb leads and lateral TWI are the most common abnormalities.
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Cardiomegalia Induzida por Exercícios , Cardiomiopatia Dilatada , Arritmias Cardíacas , Atletas , Bloqueio de Ramo , Cardiomiopatia Dilatada/diagnóstico , Cardiomiopatia Dilatada/genética , Eletrocardiografia , Humanos , Remodelação Ventricular/genéticaRESUMO
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.
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Cardiomiopatias , Desfibriladores Implantáveis , Cardiomiopatias/genética , Morte Súbita Cardíaca/etiologia , Morte Súbita Cardíaca/prevenção & controle , Humanos , FenótipoRESUMO
BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a heart muscle disease that affects predominantly the right ventricle and is part of the spectrum of arrythmogenic cardiomyopathies (ACMs). ARVC is a genetic condition; however, a pathogenic gene variant is found in only half of patients. OBJECTIVE: Filamin C gene truncations (FLNCtv) have recently been identified in dilated cardiomyopathy with ventricular arrhythmia and sudden cardiac death, a phenotype partially overlapping with ARVC and part of the ACM spectrum. We hypothesised that FLNCtv could be a novel gene associated with ARVC. METHODS: One hundred fifty-six patients meeting 2010 ARVC Task Force Criteria and lacking variants in known ARVC genes were evaluated for FLNC variants. Available family members were tested for cosegregation. RESULTS: We identified two unique FLNCtv variants in two families (c.6565 G>T, p.Glu2189Ter and c.8107delG, p.Asp2703ThrfsTer69), with phenotypes of dominant RV disease fulfilling 'definite' diagnosis of ARVC according to the 2010 Task Force Criteria. Variants in other cardiomyopathy genes were excluded in both kindreds, and segregation analysis revealed that p.Asp2703ThrfsTer69 was a de novo variant. In both families, the disease phenotype was characterised by prominent ventricular arrhythmias and sudden cardiac arrest. CONCLUSION: The identification of FLNCtv as a novel cause of ARVC in two unrelated families expands the spectrum of ARVC non-desmosome disease genes for this disorder. Our findings should prompt inclusion of FLNC genetic testing in ARVC to improve diagnostic yield and testing of at-risk relatives in ARVC.
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Displasia Arritmogênica Ventricular Direita/genética , Filaminas/genética , Predisposição Genética para Doença , Adulto , Idoso , Displasia Arritmogênica Ventricular Direita/patologia , Feminino , Testes Genéticos , Ventrículos do Coração , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , FenótipoRESUMO
BACKGROUND: Functional mitral regurgitation (FMR) is associated with reduced survival in dilated cardiomyopathy (DCM). Cardiac resynchronization therapy (CRT) can improve FMR. We sought to identify the predictors of FMR improvement after CRT in DCM. METHODS: From January 2003 to December 2013, 430 DCM patients consecutively enrolled were retrospectively analyzed. Inclusion criteria were successful CRT implantation in the presence of conventional indications (i.e., left bundle branch block, left ventricular ejection fraction ≤35%, New York Heart Association functional class ≥II) and moderate-to-severe FMR at the time of procedure. Early echocardiographic evaluation after CRT implantation (median 2.5 days) has been performed in each patient. Improvement in FMR (absent/mild) at midterm (7 months; interquartile range 4-10) was considered as the primary study end point. RESULTS: A total of 44 patients (10% of the overall cohort) were included. A significant reduction in FMR severity was observed in 21 patients (48%) at midterm after CRT (median time 7 months). No preimplantation variables predicted FMR evolution, but FMR improvement at midterm was strongly predicted by an acute favorable hemodynamic response (persistence/development of normal right ventricular function and 10-mm Hg decrease or normalization [≤35 mm Hg] of systolic pulmonary artery pressure) at postimplantation echocardiography (odds ratio: 13.7; 95% confidence interval: 1.27-42.8; P = 0.016). FMR improvement at midterm was stable during follow-up and was associated with superior long-term transplant-free survival (P = 0.022). CONCLUSIONS: Stable FMR improvement frequently occurs after CRT implantation in DCM and is associated with improved transplant-free survival. Echocardiographic evaluation of acute hemodynamic response to CRT is helpful to early identification of the favorable FMR evolution.
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Terapia de Ressincronização Cardíaca , Cardiomiopatia Dilatada/fisiopatologia , Cardiomiopatia Dilatada/terapia , Hemodinâmica , Insuficiência da Valva Mitral/fisiopatologia , Insuficiência da Valva Mitral/terapia , Cardiomiopatia Dilatada/complicações , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Insuficiência da Valva Mitral/complicações , Estudos Retrospectivos , Fatores de TempoRESUMO
BACKGROUND: Patients with nonischemic dilated cardiomyopathy (DCM), severe left ventricular (LV) dysfunction, and complete left bundle branch block benefit from cardiac resynchronization therapy (CRT). However, a large heterogeneity of response to CRT is described. Several predictors of response to CRT have been identified, but the role of the underlying genetic background is still poorly explored. OBJECTIVES: In the present study, the authors sought to define differences in LV remodeling and outcome prediction after CRT when stratifying patients according to the presence or absence of DCM-causing genetic background. METHODS: From our center, 74 patients with DCM subjected to CRT and available genetic testing were retrospectively enrolled. Carriers of causative monogenic variants in validated DCM-causing genes, and/or with documented family history of DCM, were classified as affected by genetically determined disease (GEN+DCM) (n = 25). Alternatively, by idiopathic dilated cardiomyopathy (idDCM) (n = 49). The primary outcome was long-term LV remodeling and prevalence of super response to CRT (evaluated at 24-48 months after CRT); the secondary outcome was heart failure-related death/heart transplant/LV assist device. RESULTS: GEN+DCM and idDCM patients were homogeneous at baseline with the exception of QRS duration, longer in idDCM. The median follow-up was 55 months. Long-term LV reverse remodeling and the prevalence of super response were significantly higher in the idDCM group (27% in idDCM vs 5% in GEN+DCM; P = 0.025). The heart failure-related death/heart transplant/LV assist device outcome occurred more frequently in patients with GEN+DCM (53% vs 24% in idDCM; P = 0.028). CONCLUSIONS: Genotyping contributes to the risk stratification of patients with DCM undergoing CRT implantation in terms of LV remodeling and outcomes.
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Terapia de Ressincronização Cardíaca , Cardiomiopatia Dilatada , Remodelação Ventricular , Humanos , Feminino , Masculino , Cardiomiopatia Dilatada/genética , Cardiomiopatia Dilatada/terapia , Cardiomiopatia Dilatada/fisiopatologia , Pessoa de Meia-Idade , Estudos Retrospectivos , Remodelação Ventricular/genética , Remodelação Ventricular/fisiologia , Idoso , Resultado do Tratamento , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/terapia , Insuficiência Cardíaca/fisiopatologia , Adulto , Disfunção Ventricular Esquerda/genética , Disfunção Ventricular Esquerda/fisiopatologia , Disfunção Ventricular Esquerda/terapia , Bloqueio de Ramo/genética , Bloqueio de Ramo/terapia , Bloqueio de Ramo/fisiopatologiaRESUMO
AIMS: Dilated cardiomyopathy (DCM) with arrhythmic phenotype combines phenotypical aspects of DCM and predisposition to ventricular arrhythmias, typical of arrhythmogenic cardiomyopathy. The definition of DCM with arrhythmic phenotype is not universally accepted, leading to uncertainty in the identification of high-risk patients. This study aimed to assess the prognostic impact of arrhythmic phenotype in risk stratification and the correlation of arrhythmic markers with high-risk arrhythmogenic gene variants in DCM patients. METHODS AND RESULTS: In this multicentre study, DCM patients with available genetic testing were analysed. The following arrhythmic markers, present at baseline or within 1 year of enrolment, were tested: unexplained syncope, rapid non-sustained ventricular tachycardia (NSVT), ≥1000 premature ventricular contractions/24 h or ≥50 ventricular couplets/24 h. LMNA, FLNC, RBM20, and desmosomal pathogenic or likely pathogenic gene variants were considered high-risk arrhythmogenic genes. The study endpoint was a composite of sudden cardiac death and major ventricular arrhythmias (SCD/MVA). We studied 742 DCM patients (45 ± 14 years, 34% female, 410 [55%] with left ventricular ejection fraction [LVEF] <35%). During a median follow-up of 6 years (interquartile range 1.6-12.1), unexplained syncope and NSVT were the only arrhythmic markers associated with SCD/MVA, and the combination of the two markers carried a significant additive risk of SCD/MVA, incremental to LVEF and New York Heart Association class. The probability of identifying an arrhythmogenic genotype rose from 8% to 30% if both early syncope and NSVT were present. CONCLUSION: In DCM patients, the combination of early detected NSVT and unexplained syncope increases the risk of life-threatening arrhythmic outcomes and can aid the identification of carriers of malignant arrhythmogenic genotypes.
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Cardiomiopatia Dilatada , Morte Súbita Cardíaca , Fenótipo , Humanos , Feminino , Cardiomiopatia Dilatada/genética , Cardiomiopatia Dilatada/fisiopatologia , Cardiomiopatia Dilatada/diagnóstico , Cardiomiopatia Dilatada/complicações , Masculino , Pessoa de Meia-Idade , Prognóstico , Morte Súbita Cardíaca/epidemiologia , Morte Súbita Cardíaca/etiologia , Adulto , Medição de Risco/métodos , Síncope/genética , Síncope/etiologia , Síncope/fisiopatologia , Arritmias Cardíacas/genética , Arritmias Cardíacas/fisiopatologia , Arritmias Cardíacas/diagnóstico , Volume Sistólico/fisiologia , Taquicardia Ventricular/genética , Taquicardia Ventricular/fisiopatologia , Taquicardia Ventricular/diagnóstico , Testes Genéticos/métodosRESUMO
BACKGROUND: Nondilated left ventricular cardiomyopathy (NDLVC) has been recently differentiated from dilated cardiomyopathy (DCM). A comprehensive characterization of these 2 entities using cardiac magnetic resonance (CMR) and genetic testing has never been performed. OBJECTIVES: This study sought to provide a thorough characterization and assess clinical outcomes in a large multicenter cohort of patients with DCM and NDLVC. METHODS: A total of 462 patients with DCM (227) or NDLVC (235) with CMR data from 4 different referral centers were retrospectively analyzed. The study endpoint was a composite of sudden cardiac death or major ventricular arrhythmias. RESULTS: In comparison to DCM, NDLVC had a higher prevalence of pathogenic or likely pathogenic variants of arrhythmogenic genes (40% vs 23%; P < 0.001), higher left ventricular (LV) systolic function (LV ejection fraction: 51% ± 12% vs 36% ± 15%; P < 0.001) and higher prevalence of free-wall late gadolinium enhancement (LGE) (27% vs 14%; P < 0.001). Conversely, DCM showed higher prevalence of pathogenic or likely pathogenic variants of nonarrhythmogenic genes (23% vs 12%; P = 0.002) and septal LGE (45% vs 32%; P = 0.004). Over a median follow-up of 81 months (Q1-Q3: 40-132 months), the study outcome occurred in 98 (21%) patients. LGE with septal location (HR: 1.929; 95% CI: 1.033-3.601; P = 0.039) was independently associated with the risk of sudden cardiac death or major ventricular arrhythmias together with LV dilatation, older age, advanced NYHA functional class, frequent ventricular ectopic activity, and nonsustained ventricular tachycardia. CONCLUSIONS: In a multicenter cohort of patients with DCM and NDLVC, septal LGE together with LV dilatation, age, advanced disease, and frequent and repetitive ventricular arrhythmias were powerful predictors of major arrhythmic events.
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Cardiomiopatia Dilatada , Imagem Cinética por Ressonância Magnética , Humanos , Masculino , Feminino , Cardiomiopatia Dilatada/diagnóstico por imagem , Cardiomiopatia Dilatada/fisiopatologia , Pessoa de Meia-Idade , Estudos Retrospectivos , Imagem Cinética por Ressonância Magnética/métodos , Adulto , Idoso , Morte Súbita Cardíaca/epidemiologia , Morte Súbita Cardíaca/etiologia , SeguimentosRESUMO
Background: Patients with likely pathogenic/pathogenic desmoplakin (DSP) variants are poorly characterized. Some of them meet diagnostic criteria for arrhythmogenic right ventricular cardiomyopathy (ARVC), but it is unclear how risk stratification strategies for ARVC perform in this setting. Objectives: The purpose of this study was to characterize arrhythmic outcomes and to test the performance of the recently validated ARVC risk calculator in patients with DSP likely pathogenic/pathogenic variants fulfilling definite 2010 ARVC Task Force Criteria (DSP-TFC+). Methods: DSP-TFC+ patients were enrolled from 20 institutions across 3 continents. Ventricular arrhythmias (VA), defined as a composite of sustained ventricular tachycardia (VT), appropriate implantable cardioverter defibrillator therapies, and ventricular fibrillation/sudden cardiac death events in follow-up, were reported as the primary outcome. We tested the performance of the ARVC risk calculator for VA prediction, reporting c-statistics. Results: Among 252 DSP-TFC+ patients (age 39.6 ± 16.9 years, 35.3% male), 94 (37.3%) experienced VA over 44.5 [IQR: 19.6-78.3] months. Patients with left ventricle involvement (n = 194) were at higher VA risk (log-rank P = 0.0239). History of nonsustained VT (aHR 2.097; P = 0.004) showed the strongest association with VA occurrence during the first 5-year follow-up. Neither age (P = 0.723) nor male sex (P = 0.200) was associated with VAs at follow-up. In 204 patients without VA at diagnosis, incident VA rate was high (32.8%; 7.37%/y). The ARVC risk calculator performed poorly overall (c-statistic 0.604 [0.594-0.614]) and very poorly in patients with left ventricular disease (c-statistic 0.558 [0.556-0.560]). Conclusions: DSP-TFC+ patients are at substantial risk for VAs. The ARVC risk calculator performs poorly in DSP-TFC+ patients suggesting need for a gene-specific risk algorithm. Meanwhile, DSP-TFC+ patients with nonsustained VT should be considered as high-risk.
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Background: Cardiac involvement in amyloid light-chain (AL) amyloidosis usually represents a brick in the wall of a multi-system disease. The presence of cardiac deposition of free light chains (FLCs) is the main determinant of survival. Isolated cardiac AL is an uncommon scenario characterized by a challenging diagnostic and therapeutic workup. Case summary: A 57-year-old asymptomatic man was presented for an incidental finding of myocardial necrosis at the electrocardiogram (ECG) performed for newly diagnosed arterial hypertension. Alongside signs of previous myocardial infarction, transthoracic echocardiography showed a severely increased left ventricular (LV) wall thickness not consistent with ECG voltages, segmental akinaesia with normal LV systolic function with 'apical sparing' pattern. Laboratory assessment showed an unexpectedly high level of natriuretic peptide and persistently abnormal troponin in the absence of symptoms or signs of heart failure or ongoing ischaemia. Coronary angiogram confirmed the coronary artery disease. Before revascularization, a complete diagnostic workup was carried. Serum electrophoresis detected a monoclonal gammopathy that was further investigated by serum immunofixation, revealing high lambda FLCs concentration. Fat pad, bone marrow, and salivary glands biopsies resulted negative for amyloid deposition. Finally, endomyocardial biopsy was consistent with AL amyloidosis. Urgent percutaneous revascularization was performed, and the patients was timely started on chemotherapy. Discussion: The diagnosis of isolated cardiac AL amyloidosis is challenging and carries important therapeutic implications. As the short-term prognosis might be severely compromised, an accurate diagnostic flowchart has to be systematically pursued to obtain a precise diagnosis and address the optimal, tailored management.
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BACKGROUND: Hereditary cardiovascular diseases comprise several different entities. In this study, we focused on cardiomyopathies (i.e., hypertrophic, dilated, arrhythmogenic, and left ventricular non-compaction), channelopathies (i.e., Brugada syndrome and long QT syndrome), and aortopathies and pulmonary arterial hypertension (i.e., thoracic/abdominal aortic aneurysm and pulmonary arterial hypertension), and genetically characterized 200 Italian patients affected by these diseases. METHODS: We employed whole-exome sequencing (WES), focused on four in silico gene panels, and the MLPA method for hypertrophic and arrhythmogenic right ventricular cardiomyopathy cases. RESULTS: Cardiomyopathies affected 87.5% of analyzed patients, channelopathies 7%, and aortopathies and pulmonary arterial hypertension 5.5%. The molecular diagnosis was confirmed for 21.5% of cases with a higher detection rate in familial forms (34%) than sporadic ones (14%). We highlighted the importance of family segregation to better understand the pathogenic role of the identified variants and their involvement in the clinical phenotype. Negative results could be ascribed to the high genetic and clinical heterogeneity of hereditary cardiovascular diseases; clinical follow-up and revaluation of WES data will be essential. CONCLUSION: This study highlights the importance of a multi-step approach (WES and MLPA) to characterize hereditary cardiovascular diseases, provides crucial information for clinical management and recurrence risk estimation, and lays the foundation for future personalized therapies.
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Cardiomiopatias , Doenças Cardiovasculares , Canalopatias , Hipertensão Arterial Pulmonar , Humanos , Testes Genéticos/métodos , Mutação , Doenças Cardiovasculares/genética , Sequenciamento do Exoma , Canalopatias/genética , Cardiomiopatias/genéticaRESUMO
FLNC truncating mutations (FLNCtv) are prevalent causes of inherited dilated cardiomyopathy (DCM), with a high risk of developing arrhythmogenic cardiomyopathy. We investigated the molecular mechanisms of mutant FLNC in the pathogenesis of arrhythmogenic DCM (a-DCM) using patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). We demonstrated that iPSC-CMs from two patients with different FLNCtv mutations displayed arrhythmias and impaired contraction. FLNC ablation induced a similar phenotype, suggesting that FLNCtv are loss-of-function mutations. Coimmunoprecipitation and proteomic analysis identified ß-catenin (CTNNB1) as a downstream target. FLNC deficiency induced nuclear translocation of CTNNB1 and subsequently activated the platelet-derived growth factor receptor alpha (PDGFRA) pathway, which were also observed in human hearts with a-DCM and FLNCtv. Treatment with the PDGFRA inhibitor, crenolanib, improved contractile function of patient iPSC-CMs. Collectively, our findings suggest that PDGFRA signaling is implicated in the pathogenesis, and inhibition of this pathway is a potential therapeutic strategy in FLNC-related cardiomyopathies.
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AIMS: Cardiac implantable electronic device (CIED) therapy is fundamental to the management of LMNA cardiomyopathy due to the high frequency of atrioventricular block and ventricular tachyarrhythmias. We aimed to define the role of cardiac resynchronization therapy (CRT) in impacting heart failure in LMNA cardiomyopathy. METHODS AND RESULTS: From nine referral centres, LMNA cardiomyopathy patients who underwent CRT with available pre- and post-echocardiograms were identified retrospectively. Factors associated with CRT response were identified (defined as improvement in left ventricular ejection fraction [LVEF] ≥5% 6 months post-implant) and the associated impact on the primary outcome of death, implantation of a left ventricular assist device or cardiac transplantation was assessed. We identified 105 patients (mean age 51 ± 10 years) undergoing CRT, including 70 (67%) who underwent CRT as a CIED upgrade. The mean change in LVEF â¼6 months post-CRT was +4 ± 9%. A CRT response occurred in 40 (38%) patients and was associated with lower baseline LVEF or a high percentage of right ventricular pacing prior to CRT in patients with pre-existing CIED. In patients with a European Society of Cardiology class I guideline indication for CRT, response rates were 61%. A CRT response was evident at thresholds of LVEF ≤45% or percent pacing ≥50%. There was a 1.3 year estimated median difference in event-free survival in those who responded to CRT (p = 0.04). CONCLUSION: Systolic function improves in patients with LMNA cardiomyopathy who undergo CRT, especially with strong guideline indications for implantation. Post-CRT improvements in LVEF are associated with survival benefits in this population with otherwise limited options.
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Terapia de Ressincronização Cardíaca , Cardiomiopatias , Insuficiência Cardíaca , Adulto , Cardiomiopatias/terapia , Humanos , Lamina Tipo A , Pessoa de Meia-Idade , Estudos Retrospectivos , Volume Sistólico , Resultado do Tratamento , Função Ventricular EsquerdaRESUMO
BACKGROUND: 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. OBJECTIVES: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.
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Cardiomiopatias , Cardiomiopatia Dilatada , Humanos , Arritmias Cardíacas/diagnóstico , Cardiomiopatias/diagnóstico , Cardiomiopatia Dilatada/genética , Morte Súbita Cardíaca/epidemiologia , Morte Súbita Cardíaca/etiologia , Genótipo , Fenótipo , PrognósticoRESUMO
IMPORTANCE: Dilated cardiomyopathy (DCM) is frequently caused by genetic factors. Studies identifying deleterious rare variants have predominantly focused on early-onset cases, and little is known about the genetic underpinnings of the growing numbers of patients with DCM who are diagnosed when they are older than 60 years (ie, late-onset DCM). OBJECTIVE: To investigate the prevalence, type, and prognostic impact of disease-associated rare variants in patients with late-onset DCM. DESIGN, SETTING, AND PARTICIPANTS: A population of patients with late-onset DCM who had undergone genetic testing in 7 international tertiary referral centers worldwide were enrolled from March 1990 to August 2020. A positive genotype was defined as the presence of pathogenic or likely pathogenic (P/LP) variants. MAIN OUTCOMES AND MEASURES: The study outcome was all-cause mortality. RESULTS: A total of 184 patients older than 60 years (103 female [56%]; mean [SD] age, 67 [6] years; mean [SD] left ventricular ejection fraction, 32% [10%]) were studied. Sixty-six patients (36%) were carriers of a P/LP variant. Titin-truncating variants were the most prevalent (present in 46 [25%] of the total population and accounting for 46 [69%] of all genotype-positive patients). During a median (interquartile range) follow-up of 42 (10-115) months, 23 patients (13%) died; 17 (25%) of these were carriers of P/LP variants, while 6 patients (5.1%) were genotype-negative. CONCLUSIONS AND RELEVANCE: Late-onset DCM might represent a distinct subgroup characterized by and a high genetic variation burden, largely due to titin-truncating variants. Patients with a positive genetic test had higher mortality than genotype-negative patients. These findings support the extended use of genetic testing also in older patients.
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Cardiomiopatia Dilatada , Idoso , Cardiomiopatia Dilatada/genética , Conectina/genética , Feminino , Genótipo , Humanos , Masculino , Volume Sistólico , Função Ventricular EsquerdaRESUMO
BACKGROUND: 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. METHODS AND RESULTS: 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. CONCLUSIONS: 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.
Assuntos
Cardiomiopatia Dilatada , Disfunção Ventricular Esquerda , Cardiomiopatia Dilatada/diagnóstico por imagem , Cardiomiopatia Dilatada/epidemiologia , Cardiomiopatia Dilatada/genética , Feminino , Genótipo , Humanos , Masculino , Fenótipo , Prevalência , Estudos Retrospectivos , Volume Sistólico , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/epidemiologia , Disfunção Ventricular Esquerda/genética , Função Ventricular EsquerdaRESUMO
BACKGROUND: Titin (TTN)-related dilated cardiomyopathy (DCM) has a higher likelihood of left ventricular reverse remodelling compared with other genetic etiologies. No data regarding the evolution of right ventricular dysfunction (RVD) according to genetic background are available. METHODS: Consecutive 104 DCM patients with confirmed pathogenic genetic variants (51 TTN-related DCM; 53 other genetic DCM) and a control group of 139 patients with negative genetic testing and available follow-up data at 12-24 months were analysed. RVD was defined as a right ventricular fractional area change (RVFAC) < 35%. The main study end point was the comparison of the evolution of RVD and the change of RVFAC throughout the follow-up according to etiology. A composite of all-cause mortality and heart transplantation was included as outcome measure. RESULTS: At enrollment, RVD was present in 29.1% of genetically positive DCM without differences between genetic cohorts. At 14 months follow-up, 5.9% of TTN-related DCM patients vs 35.8% of other genetic DCM patients had residual RVD after treatment (P < 0.001). Accordingly, RVFAC significantly improved in the TTN-related DCM cohort and remained stably impaired in other genetic DCM patients. However, the evolution of RVD was similar between TTN-related DCM and patients without a genetic mutation. After adjusting for RVD at follow-up, no differences in the outcome measure were seen in the study cohorts. CONCLUSIONS: The evolution of RVD in DCM is heterogeneous in different genetic backgrounds. TTN-related DCM is associated with a higher chance of RVD recovery compared with other genetic etiologies.
Assuntos
Cardiomiopatia Dilatada/genética , Disfunção Ventricular Direita/epidemiologia , Função Ventricular Direita/fisiologia , Remodelação Ventricular/fisiologia , Adulto , Cardiomiopatia Dilatada/complicações , Cardiomiopatia Dilatada/fisiopatologia , Conectina/genética , Conectina/metabolismo , Feminino , Seguimentos , Patrimônio Genético , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Fenótipo , Prevalência , Estudos Retrospectivos , Disfunção Ventricular Direita/etiologia , Disfunção Ventricular Direita/fisiopatologiaRESUMO
AIMS: Primary prevention implantable cardioverter defibrillator (ICD) is not generally recommended in New York Heart Association (NYHA) I class patients with dilated cardiomyopathy (DCM). This study sought to assess the competing risk of sudden cardiac death (SCD) in DCM patients with left ventricular ejection fraction (EF) ≤35% and NYHA I class. METHODS: A total of 272 DCM patients with EF ≤35% and NYHA class I-III after ≥3 months of guideline-directed medical therapy were included. The risk of SCD and SCD/malignant ventricular arrhythmias (MVA) was assessed in NYHA I vs. NYHA II and NYHA III groups by competing risk analysis. RESULTS: NYHA I patients were younger, had higher EF and smaller left atrium, were less likely receiving mineral corticoid receptor antagonists. The cumulative incidence of SCD (p = 0.92) and SCD/MVA (p = 0.42) did not differ between NYHA I vs NYHA II-III classes. NYHA class did not influence the association between ICD and SCD risk (p for interaction = 0.125). CONCLUSIONS: In this cohort of DCMs, patients with EF ≤35% and NYHA I class were exposed to a risk of SCD and life-threatening arrhythmias not different from NYHA II-III. Therefore, inclusion of asymptomatic patients with DCM and systolic dysfunction should be strongly considered in future randomized studies on primary prevention ICD.
Assuntos
Cardiomiopatia Dilatada , Desfibriladores Implantáveis , Cardiomiopatia Dilatada/diagnóstico , Cardiomiopatia Dilatada/epidemiologia , Morte Súbita Cardíaca/epidemiologia , Morte Súbita Cardíaca/prevenção & controle , Humanos , New York , Medição de Risco , Fatores de Risco , Volume Sistólico , Função Ventricular EsquerdaRESUMO
AIM: Contemporary survival trends in dilated cardiomyopathy (DCM) are largely unknown. The aim of this study is to investigate clinical descriptors, survival trends and the prognostic impact of aetiological characterization in DCM patients. METHODS AND RESULTS: Dilated cardiomyopathy patients were consecutively enrolled and divided into four groups according to the period of enrolment (1978-1984; 1985-1994; 1995-2004; and 2005-2015). A subset of patients with DCM of specific aetiology, enrolled from 2005 to 2015, was also analysed. Over a mean follow-up of 12 ± 8 years, 1284 DCM patients (52 in the 1978-1984 group, 326 in the 1985-1994 group, 379 in the 1995-2004 group, and 527 in the 2005-2015 group) were evaluated. Despite older age (mean age 51 ± 15, 43 ± 15, 45 ± 14, and 52 ± 15 years for the 1978-1984, 1985-1994, 1995-2004, and 2005-2015 groups, respectively; P < 0.001), most of the baseline clinical characteristics improved in the 2005-2015 group, suggesting a less advanced disease stage at diagnosis. Similarly, at competing risk analysis, the annual incidence of all outcome parameters progressively decreased over time (global P < 0.001). At multivariable analysis, the last period of enrolment emerged as independently associated with a reduction in all-cause mortality/heart transplantation (HTx)/ventricular assist device (VAD) implantation (1.46 events/100 patients/year), cardiovascular death/HTx/VAD implantation (0.82 events/100 patients/year) and sudden cardiac death (0.15 events/100 patients/year). Lastly, in 287 patients with DCM of specific aetiology, patients with environmental, toxic, or removable factors appeared to have different phenotypes and prognosis compared to those with genetic, post-myocarditis, or idiopathic DCM (P < 0.001). CONCLUSIONS: Contemporary survival trends in DCM significantly improved, mainly due to a reduction of cardiovascular events. Appropriate aetiological characterization might help in prognostication of DCM patients.