Acometimento do Ventrículo Direito na Cardiomiopatia por Depósito de Glicogênio (PRKAG2): Análise Ecocardiográfica Convencional e Avançada / Right Ventricle Involvement by Glycogen Storage Cardiomyopathy (PRKAG2): Standard and Advanced Echocardiography Analyses

Resumo Fundamento A síndrome do PRKAG2 é uma doença hereditária autossômica dominante rara, de início precoce. Objetivamos descrever os achados ecocardiográficos do ventrículo direito (VD) usando modalidades bi e tridimensionais (2D e 3D), incluindo índices de deformação miocárdica nesta cardiomiopatia. Também objetivamos demonstrar se esta técnica poderia identificar alterações na função do VD que pudessem distinguir quaisquer achados particulares. Métodos Trinta pacientes com síndrome do PRKAG2 (R302Q e H401Q) geneticamente comprovada, 16 (53,3%) do sexo masculino, com idade média de 39,1 ± 15,4 anos, foram submetidos a exame ecocardiográfico completo. A visão de 4 câmaras com foco no VD foi adquirida para medições 2D e 3D. Os testes t de Student ou Wilcoxon-Mann-Whitney foram usados para comparar as variáveis numéricas entre 2 grupos, e p < 0,05 foi considerado significativo. Resultados Doze pacientes (40%) tiveram marca-passo implantado por 12,4 ± 9,9 anos. A espessura diastólica média da parede livre do VD foi de 7,9 ± 2,9 mm. O strain longitudinal de 4 câmaras do VD (SL4VD), incluindo a parede livre e o septo interventricular, foi de -17,3% ± 6,7%, e o strain longitudinal da parede livre do VD (SLPLVD) foi de −19,1% ± 8,5%. A razão apical do SLPLVD mediu 0,63 ± 0,15. A fração de ejeção (FE) 3D média do VD foi de 42,6% ± 10,9% e abaixo dos limites normais em 56,7% dos pacientes. Correlação positiva ocorreu entre FE 3D do VD, SL4VD e SLPLVD, principalmente para pacientes sem marca-passo (p = 0,006). Conclusão O envolvimento do VD em PRKAG2 é frequente e ocorre em diferentes graus. A ecocardiografia é uma ferramenta valiosa na detecção de anormalidades miocárdicas do VD nesta condição. O uso de SL4VD 2D, SLPLVD e FE 3D oferecem indicadores confiáveis de disfunção sistólica do VD nesta cardiomiopatia rara e desafiadora.

Abstract Background PRKAG2 syndrome is a rare, early-onset autosomal dominant inherited disease. We aimed to describe the right ventricle (RV) echocardiographic findings using two and three-dimensional (2D and 3D) modalities including myocardial deformation indices in this cardiomyopathy. We also aimed to demonstrate whether this technique could identify changes in RV function that could distinguish any particular findings. Methods Thirty patients with genetically proven PRKAG2 (R302Q and H401Q), 16 (53.3%) males, mean age 39.1 ± 15.4 years, underwent complete echocardiography examination. RV-focused, 4-chamber view was acquired for 2D and 3D measurements. Student's t or Wilcoxon-Mann-Whitney tests were used to compare numerical variables between 2 groups, and p < 0.05 was considered significant. Results Twelve patients (40%) had a pacemaker implanted for 12.4 ± 9.9 years. RV free wall mean diastolic thickness was 7.9 ± 2.9 mm. RV 4-chamber longitudinal strain (RV4LS), including the free wall and interventricular septum, was -17.3% ± 6.7%, and RV free wall longitudinal strain (RVFWLS) was −19.1% ± 8.5%. The RVFWLS apical ratio measured 0.63 ± 0.15. Mean RV 3D ejection fraction (EF) was 42.6% ± 10.9% and below normal limits in 56.7% of patients. Positive correlation occurred between RV 3DEF, RV4LS, and RVFWLS, especially for patients without a pacemaker (p = 0.006). Conclusion RV involvement in PRKAG2 syndrome is frequent, occurring in different degrees. Echocardiography is a valuable tool in detecting RV myocardial abnormalities in this condition. The use of 2D RV4LS, RVFWLS, and 3DEF offers reliable indicators of RV systolic dysfunction in this rare, challenging cardiomyopathy.

Role of Myocardial Fibrosis in Hypertrophic Cardiomyopathy: A Systematic Review and Updated Meta-Analysis of Risk Markers for Sudden Death / Papel da Fibrose Miocárdica na Cardiomiopatia Hipertrófica: Revisão Sistemática e Metanálise Atualizada de Marcadores de Risco para Morte Súbita

Abstract Background: Hypertrophic cardiomyopathy (HCM) is associated with sudden death (SD). Myocardial fibrosis is reportedly correlated with SD. Objective: We performed a systematic review with meta-analysis, updating the risk markers (RMs) in HCM emphasizing myocardial fibrosis. Methods: We reviewed HCM studies that addressed severe arrhythmic outcomes and the certain RMs: SD family history, severe ventricular hypertrophy, unexplained syncope, non-sustained ventricular tachycardia (NSVT) on 24-hour Holter monitoring, abnormal blood pressure response to exercise (ABPRE), myocardial fibrosis and left ventricular outflow tract obstruction (LVOTO) in the MEDLINE, LILACS, and SciELO databases. We used relative risks (RRs) as an effect measure and random models for the analysis. The level of significance was set at p < 0.05. Results: Twenty-one studies were selected (14,901 patients aged 45 ± 16 years; men, 62.8%). Myocardial fibrosis was the major RISK MARKER (RR, 3.43; 95% CI, 1.95-6.03). The other RMs, except for LVOTO, were also predictors: SD family history (RR, 1.75; 95% CI, 1.39-2.20), severe ventricular hypertrophy (RR, 1.86; 95% CI, 1.26-2.74), unexplained syncope (RR, 2.27; 95% CI, 1.69-3.07), NSVT (RR, 2.79; 95% CI, 2.29-3.41), and ABPRE (RR, 1.53; 95% CI, 1.12-2.08). Conclusions: We confirmed the association of myocardial fibrosis and other RMs with severe arrhythmic outcomes in HCM and emphasize the need for new prediction models in managing these patients.

Resumo Fundamento: A cardiomiopatia hipertrófica (CMH) está associada à morte súbita (MS). A fibrose miocárdica está supostamente correlacionada à MS. Objetivo: Realizamos uma revisão sistemática com metanálise, atualizando os marcadores de risco (MR) em CMH enfatizando a fibrose miocárdica. Métodos: Revisamos estudos de CMH que abordaram desfechos arrítmicos graves e certos MR: história familiar de MS, hipertrofia ventricular grave, síncope inexplicada, taquicardia ventricular não sustentada (TVNS) na monitorização com Holter de 24 horas, resposta anormal da pressão arterial ao exercício (ABPRE), fibrose miocárdica e obstrução da via de saída do ventrículo esquerdo (VSVE) nas bases de dados MEDLINE, LILACS e SciELO. Utilizamos os riscos relativos (RRs) como uma medida de efeito e modelos aleatórios para a análise. O nível de significância foi estabelecido em p < 0,05. Resultados: Vinte e um estudos foram selecionados (14.901 pacientes com idade de 45 ± 16 anos; homens, 62,8%). A fibrose miocárdica foi o principal MARCADOR DE RISCO (RR, 3,43; IC95%, 1,95-6,03). Os outros MR, exceto obstrução da VSVE, também foram preditores: história familiar de MS (RR, 1,75; IC95%, 1,39-2,20), hipertrofia ventricular grave (RR, 1,86; IC95%, 1,26-2,74), síncope inexplicada (RR, 2,27; IC95%, 1,69-3,07), TVNS (RR, 2,79; IC95%, 2,29-3,41) e ABPRE (RR, 1,53; IC95%, 1,12-2,08). Conclusões: Confirmamos a associação de fibrose miocárdica e outros MR com desfechos arrítmicos graves na CMH e enfatizamos a necessidade de novos modelos de previsão no manejo desses pacientes.

Chronic Calmodulin-Kinase II Activation Drives Disease Progression in Mutation-Specific Hypertrophic Cardiomyopathy.

BACKGROUND: Although the genetic causes of hypertrophic cardiomyopathy (HCM) are widely recognized, considerable lag in the development of targeted therapeutics has limited interventions to symptom palliation. This is in part attributable to an incomplete understanding of how point mutations trigger pathogenic remodeling. As a further complication, similar mutations within sarcomeric genes can result in differential disease severity, highlighting the need to understand the mechanism of progression at the molecular level. One pathway commonly linked to HCM progression is calcium homeostasis dysregulation, though how specific mutations disrupt calcium homeostasis remains unclear. METHODS: To evaluate the effects of early intervention in calcium homeostasis, we used 2 mouse models of sarcomeric HCM (cardiac troponin T R92L and R92W) with differential myocellular calcium dysregulation and disease presentation. Two modes of intervention were tested: inhibition of the autoactivated calcium-dependent kinase (calmodulin kinase II [CaMKII]) via the AC3I peptide and diltiazem, an L-type calcium channel antagonist. Two-dimensional echocardiography was used to determine cardiac function and left ventricular remodeling, and atrial remodeling was monitored via atrial mass. Sarcoplasmic reticulum Ca2+ATPase activity was measured as an index of myocellular calcium handling and coupled to its regulation via the phosphorylation status of phospholamban. RESULTS: We measured an increase in phosphorylation of CaMKII in R92W animals by 6 months of age, indicating increased autonomous activity of the kinase in these animals. Inhibition of CaMKII led to recovery of diastolic function and partially blunted atrial remodeling in R92W mice. This improved function was coupled to increased sarcoplasmic reticulum Ca2+ATPase activity in the R92W animals despite reduction of CaMKII activation, likely indicating improvement in myocellular calcium handling. In contrast, inhibition of CaMKII in R92L animals led to worsened myocellular calcium handling, remodeling, and function. Diltiazem-HCl arrested diastolic dysfunction progression in R92W animals only, with no improvement in cardiac remodeling in either genotype. CONCLUSIONS: We propose a highly specific, mutation-dependent role of activated CaMKII in HCM progression and a precise therapeutic target for clinical management of HCM in selected cohorts. Moreover, the mutation-specific response elicited with diltiazem highlights the necessity to understand mutation-dependent progression at a molecular level to precisely intervene in disease progression.

Nonobstructive hypertrophic cardiomyopathy with left ventricular aneurysm: the role of cardiac magnetic resonance.

Hypertrophic cardiomyopathy with concomitant left ventricular aneurysm is rare and has important clinical implications, including an increased risk of sudden cardiac death. Most patients with this rare combination have obstructive hypertrophic cardiomyopathy, but we treated a 26-year-old woman who had nonobstructive hypertrophic cardiomyopathy and a family history of probable sudden cardiac death. In our patient, coronary angiograms showed distal occlusion of the left anterior descending coronary artery. Late gadolinium-enhanced cardiac magnetic resonance images showed scattered fibrosis within and beyond the left ventricular aneurysm. Precautionary therapy with an implantable cardioverter-defibrillator yielded an uneventful outcome. Cardiac magnetic resonance has emerged as a promising method for diagnosing these aneurysms and detecting associated myocardial fibrosis, thereby enabling patient risk stratification and the determination of appropriate therapeutic options. We discuss the role of cardiac magnetic resonance imaging in the management of this rare clinical entity.

Avaliação diagnóstica da cardiomiopatia hipertrófica em fase clínica e pré-clínica: [revisão] / Diagnostic evaluation of hipertrophic cardiomyopathy in its clinical and preclinical phases: [review]

A cardiomiopatia hipertrófica é uma doença de origem genética e caráter familiar, causada por mutações em genes codificantes de proteínas do sarcômero. Determina hipertrofia ventricular esquerda de grau variável, geralmente difusa, com predominante acometimento do septo interventricular. A ocorrência de formas assintomáticas com hipertrofia segmentar, de grau leve ou ausente, dificulta o diagnóstico e o rastreamento de formas familiares. A penetrância elevada costuma ser incompleta, o que faz com que 20 por cento a 30 por cento dos adultos carreadores de mutações gênicas não expressem o fenótipo. A suscetibilidade à morte súbita e a possibilidade de expressão tardia tornam relevante o diagnóstico em fase pré-clínica. A investigação por meio do ecocardiograma Doppler e da ressonância magnética adicionada à análise detalhada do eletrocardiograma pode contribuir nesse processo. O diagnóstico genético-molecular identifica mutações em 60 por cento a 80 por cento dos casos. A complexidade, a demora e o elevado custo, aliados à insuficiente avaliação das relações genótipo/fenótipo restringem sua aplicação de rotina. O aprimoramento dos métodos de imagem e a introdução de técnicas moleculares mais simplificadas devem favorecer o diagnóstico clínico e pré-clínico da cardiomiopatia hipertrófica e possibilitar a futura introdução de medidas terapêuticas que possam impedir ou retardar o desenvolvimento da doença.

Hypertrophic cardiomyopathy is a familial, genetic disease caused by mutations in genes encoding sarcomeric proteins. It is characterized by various deGrees of left ventricular hypertrophy, usually diffuse, predominantly involving the interventricular septum. The asymptomatic forms with mild or no segmental hypertrophy makes it difficult to establish the diagnosis and screening for familial forms. Its high penetrance is often incomplete and, as a result, 20 percent to 30 percent of adults who carry disease-causing gene mutations do not express the phenotype. The susceptibility to sudden death and likelihood of late expression makes establishing a preclinical diagnosis all the more important. The use of Doppler echocardiography and magnetic resonance imaging, in conjunction with a detailed ECG analysis, may be useful in this process. Molecular genetic studies can identify mutations in 60 percent to 80 percent of the cases. However, its complex, time-consuming and costly nature, coupled with an inadequate assessment of genotype-phenotype relationships, limits its routine application. Major advances in imaging methods and the introduction of more simplified molecular techniques may contribute to clinical and preclinical diagnosis of hypertrophic cardiomyopathy, in addition to allowing implementation of therapeutic strategies to prevent or delay the development of the disease.