Xusto Fernández

Prognostic Value of Exercise Echocardiography in Patients with Hypertrophic Cardiomyopathy

BACKGROUND Although exercise echocardiography may assess left ventricular (LV) function and LV outflow tract (LVOT) gradients during exercise in patients with hypertrophic cardiomyopathy (HCM), its value for predicting outcomes has not been studied. The aim of this study was to determine whether exercise echocardiography predicts outcomes in patients with HCM. METHODS LV function and LVOT gradients were evaluated during exercise echocardiography in 239 patients with HCM. RESULTS Sixty patients (25.1%) had LVOT obstruction at rest, and 43 (18%) developed exercise-induced LVOT obstruction. The mean resting LV ejection fraction was 69 ± 9%, and the mean resting wall motion score index was 1.00 ± 0.06. Wall motion abnormalities during exercise were seen in 19 patients (7.9%). During follow-up of 4.1 ± 2.6 years, 19 patients had hard events (cardiac death, cardiac transplantation, appropriate discharge of a defibrillator, stroke, myocardial infarction, or hospitalization for heart failure), and 41 patients had composite end points of hard or soft events (including atrial fibrillation and syncope). Exercise wall motion abnormalities occurred in 31.5% of patients with hard events compared with 5.9% of patients without hard events (P < .001). After adjustment, LV wall thickness (hazard ratio [HR], 1.13; 95% confidence interval [CI], 1.05-1.21; P = .002), resting wall motion score index (HR, 21.59; 95% CI, 2.38-196.1, P = .006), and metabolic equivalents (HR, 0.74; 95% CI, 0.63-0.88; P = .001) remained independent predictors of hard events. Change in wall motion score index was also independently associated with hard events (HR, 52.30; 95% CI, 3.81-718.5; P = .003) and with the composite end point (HR, 39.51; 95% CI, 3.79-412.4; P = .002). LVOT obstruction was not associated with either end point. CONCLUSIONS Assessment of exercise capacity and LV systolic function during exercise echocardiography may have a role in risk stratification of patients with HCM.

Significado clínico del realce tardío de gadolinio con resonancia magnética en pacientes con miocardiopatía hipertrófica

Introduccion y objetivos La fibrosis miocardica puede ser detectada en la miocardiopatia hipertrofica (MCH) mediante resonancia magnetica cardiaca (RM) con realce tardio de gadolinio (RT). Analizamos la relacion entre la extension del RT y la morfologia y funcion del ventriculo izquierdo (VI) y los datos clinicos. Metodos Estudiamos con RM a 104 pacientes diagnosticados de MCH. Se obtuvieron secuencias de cine-RM y secuencias de realce tardio. Resultados Cincuenta pacientes presentaron RT (48%; rango: 1-11 segmentos). La extension del RT se correlaciono positivamente con el grosor maximo (r = 0,53; p Conclusiones La extension del RT refleja una mayor expresion de esta enfermedad. Se asocia con un dano miocardico mas severo (menor fraccion de eyeccion y mayor numero de segmentos hipocineticos) y con parametros clinicos adversos (edad mas joven en el momento del diagnostico, hipertrofia severa, TVNS y respuesta isquemica al ejercicio), lo que indica que podria vincularse al pronostico.

Clinical significance of late gadolinium enhancement on cardiovascular magnetic resonance in patients with hypertrophic cardiomyopathy

INTRODUCTION AND OBJECTIVES In patients with hypertrophic cardiomyopathy, myocardial fibrosis can be detected by late gadolinium enhancement (LGE) on cardiac magnetic resonance imaging. We investigated the relationships between the extent of LGE, left ventricular morphology and function, and clinical characteristics. METHODS Both cine and gadolinium-enhanced magnetic resonance imaging were performed in 104 patients with hypertrophic cardiomyopathy. RESULTS Fifty patients (48%) showed LGE (range: 1-11 segments). The extent of LGE was positively correlated with maximum left ventricular wall thickness (r=0.53, P< .001), left ventricular mass (r=0.41, P< .001), and the number of hypokinetic segments (r=0.51, P< .001), and inversely correlated with ejection fraction (r=-0.32, P=.001), the magnitude of the subaortic gradient increase during exercise echocardiography (r=-0.26, P=.023), and age at diagnosis (r=-0.20, P=.04). Four of the five patients with an ischemic response on exercise echocardiography had > or =3 segments showing LGE (P=.003). Severe hypertrophy (i.e., > or =30 mm) and nonsustained ventricular tachycardia occurred more frequently as the number of LGE segments increased (P< .001 and P=.04, respectively). CONCLUSIONS Extensive LGE reflects greater disease expression. It is associated with more severe myocardial damage (i.e., a lower ejection fraction and a larger number of hypokinetic segments) and with adverse clinical characteristics (e.g., young age at diagnosis, severe hypertrophy, nonsustained ventricular tachycardia, and an ischemic response on exercise), suggesting that it may be closely linked to prognosis.

Mutaciones en el gen de la cadena pesada de la betamiosina en pacientes con miocardiopatía hipertrófica

Introduction and objectives. To determine the frequency of mutations in the beta-myosin heavy-chain gene (MYH7) in a cohort of patients with hypertrophic cardiomyopathy (HCM) and their families, and to investigate correlations between genotype and phenotype. Methods. Single-strand conformation polymorphism analysis and sequencing of fragments with abnormal MYH7 gene mobility were carried out in 128 consecutive index patients with HCM. The phenotypes of patients with and without mutations were compared and the phenotypes of identified families were recorded. Results. A total of 11 mutations were found in 13 families (10%); 7/11 had been previously described. The I736T mutation was found in 3 families and the A797T in 2. One patient had 2 mutations (i.e., I736T and R787H). Mutations were more frequent in patients with a family history of sudden death (31%) and in those with severe hypertrophy (39% had a thickness ≥30 mm). Mutations were found in 29 of 42 members of the 13 families, including 6 family members (20%) who were healthy carriers and aged ≤36 years. Sudden death had occurred in 8 members of 4 families: four in 2 families with the I736T mutation, 1 in a family with A797T, 1 in a family with R870H, and 2 in a family with A901P. Conclusions. MYH7 mutations were present in 10% of our families. Mutations were more frequent in patients with a family history of sudden death and in those with severe hypertrophy. Most mutations had been described previously. Some appeared in several families. For some mutations, the correlation between genotype and phenotype was stable, while for others, there were marked differences between the phenotypes of the index

Screening mutations in myosin binding protein C3 gene in a cohort of patients with Hypertrophic Cardiomyopathy

BackgroundMyBPC3 mutations are amongst the most frequent causes of hypertrophic cardiomyopathy, however, its prevalence varies between populations. They have been associated with mild and late onset disease expression. Our objectives were to establish the prevalence of MyBPC3 mutations and determine their associated clinical characteristics in our patients.MethodsScreening by Single Strand Conformation Polymorphisms (SSCP) and sequencing of the fragments with abnormal motility of the MyBPC3 gene in 130 unrelated consecutive HCM index cases. Genotype-Phenotype correlation studies were done in positive families.Results16 mutations were found in 20 index cases (15%): 5 novel [D75N, V471E, Q327fs, IVS6+5G>A (homozygous), and IVS11-9G>A] and 11 previously described [A216T, R495W, R502Q (2 families), E542Q (3 families), T957S, R1022P (2 families), E1179K, K504del, K600fs, P955fs and IVS29+5G>A]. Maximum wall thickness and age at time of diagnosis were similar to patients with MYH7 mutations [25(7) vs. 27(8), p = 0.16], [46(16) vs. 44(19), p = 0.9].ConclusionsMutations in MyBPC3 are present in 15% of our hypertrophic cardiomyopathy families. Severe hypertrophy and early expression are compatible with the presence of MyBPC3 mutations. The genetic diagnosis not only allows avoiding clinical follow up of non carriers but it opens new possibilities that includes: to take preventive clinical decisions in mutation carriers than have not developed the disease yet, the establishment of genotype-phenotype relationship, and to establish a genetic diagnosis routine in patients with familial HCM.

Cardiotrophin-1 plasma levels are associated with the severity of hypertrophy in hypertrophic cardiomyopathy

Aims Cardiotrophin-1 (CT-1) is a cytokine that induces hypertrophy in cardiomyocytes and is associated with left ventricular hypertrophy (LVH) in hypertensive patients. The objective of this study was to evaluate whether plasma CT-1 is associated with hypertrophic cardiomyopathy (HCM). Methods and results The study was performed in 124 patients with HCM. All patients underwent a full clinical evaluation and an echocardiogram. Left ventricular hypertrophy was evaluated by the measurement of the maximal LV wall thickness and the Spiritos LVH score. Plasma CT-1 was measured by an enzyme-linked immunosorbent assay. Compared with controls, patients with HCM exhibited higher (P < 0.001) plasma CT-1 levels. Significant correlations were found between CT-1 and maximal LV wall thickness (r = 0.284, P = 0.001) and the Spiritos LVH score (r = 0.287, P = 0.006) in HCM patients. In addition, the levels of CT-1 were higher (P = 0.02) in patients with severe LVH (maximal LV wall thickness ≥30 mm) than in patients with mild or moderate LVH (maximal LV wall thickness <30 mm). Conclusions These findings show that plasma CT-1 is associated with the severity of LVH in patients with HCM. Further studies are required to ascertain whether CT-1 is a diagnostic biomarker of this cardiomyopathy.

Exercise echocardiography and cardiac magnetic resonance imaging to predict outcome in patients with hypertrophic cardiomyopathy

AIMS We have observed that wall motion abnormalities (WMAs) during exercise echocardiography (ExE) are associated to events in hypertrophic cardiomyopathy (HCM). Our objective was to evaluate ExE and cardiac magnetic resonance (CMR) to predict outcome in HCM. METHODS AND RESULTS ExE and CMR were performed in 148 patients with HCM. During follow-up (7.1 ± 2.7 years), there were 7 hard events (Hard-E) and 26 combined events (Comb-E). Exercise WMAs were observed in 13 patients (8.8%), perfusion defects in 10 (6.8%), and late gadolinium enhancement (LGE) in 48 (32.4%). WMAs were seen in 57% of patients with Hard-E vs. 6% without (P = 0.001) and in 23 and 6% with and without Comb-E (P = 0.005). Perfusion defects were also more frequent in patients with Hard-E than without (43 vs. 5%, P = 0.007) and in patients with Comb-E than without (23 vs. 5%, P = 0.002). LGE (g) was greater in patients with Comb-E than without [median (25th-75th percentile) 0 (0-21.1) vs. 0 (0-9.3) g P = 0.04]. Univariable predictors of Comb-E included NYHA class ≥2, peak double product, ΔWMSI, and CMR data. Peak double product [Hazard ratios (HR) = 0.99, confidence intervals (CI) 95% 0.99-0.99, P = 0.02] and ΔWMSI (HR = 404, CI 95% 12-13681, P = 0.001) remained independent predictors. Peak WMSI correlated with myocardial mass with LGE (r = 0.20, P = 0.02) and with perfusion defect area (r = 0.40, P < 0.001). LGE affecting ≥15% of the left ventricle was observed in 38% of patients with exercise WMAs vs. 12% without (P = 0.009). CONCLUSION CMR data are associated to exercise WMAs in patients with HCM. ExE and CMR may help to predict outcome in them.

Mutación en homocigosis en el gen MYBPC3 asociada a fenotipos severos y alto riesgo de muerte súbita en una familia con miocardiopatía hipertrófica

El estudio genetico puede resultar una pieza clave en la evaluacion integral de la miocardiopatia hipertrofica familiar y en el desarrollo de una medicina individualizada. Hay pocos casos descritos, pero existe un grupo de pacientes con genotipos complejos asociados a manifestacion severa de la enfermedad y alto riesgo de muerte subita. Presentamos una familia caracterizada por evolucion precoz a disfuncion sistolica y diastolica en algunos de sus integrantes y muerte subita a edades tempranas en otros. Se detecto una mutacion en homocigosis (IVS6+5G>A) en el gen de la proteina C de union a la miosina, no descrita previamente, que nos permitio explicar el fenotipo de los afectados, estimar el riesgo en otros familiares y ofrecer consejo genetico.

Phenotype and prognostic correlations of the converter region mutations affecting the β myosin heavy chain

Objectives The prognostic value of genetic studies in cardiomyopathies is still controversial. Our objective was to evaluate the outcome of patients with cardiomyopathy with mutations in the converter domain of β myosin heavy chain (MYH7). Methods Clinical characteristics and survival of 117 affected members with mutations in the converter domain of MYH7 were compared with 409 patients described in the literature with mutations in the same region. Results Twenty-five mutations were evaluated (9 in our families including 3 novel (Ile730Asn, Asp717Gly and Arg719Pro)). Clinical diagnoses were hypertrophic (n=407), dilated (n=15), non-compaction (n=4) and restrictive (n=5) cardiomyopathies, unspecified cardiomyopathy (n=11), sudden death (n=50) and 35 healthy carriers. One hundred eighty-four had events (cardiovascular death or transplant). Median event-free survival was 50±2 years in our patients and 53±3 years in the literature (p=0.27). There were significant differences in the outcome between mutation: Ile736Thr had fewer events than other mutations in the region (p=0.01), while Arg719Gln (p<0.01) had reduced event-free survival. Conclusions Mutations in the converter region are generally associated with adverse prognosis although there are differences between mutations. The identification of a mutation in this particular region provides important prognostic information that should be considered in the clinical management of affected patients.

A homozygous MYBPC3 gene mutation associated with a severe phenotype and a high risk of sudden death in a family with hypertrophic cardiomyopathy.

Genetic studies can play a key role in the comprehensive evaluation of familiar hypertrophic cardiomyopathy and in the development of individualized medicine. Although only a few cases have been described, there exists a group of patients with complex genotypes that are associated with severe disease manifestations and a high risk of sudden death. We describe a family in which some members experienced the early development of systolic and diastolic dysfunction while others experienced sudden death at a young age. We identified a novel homozygous mutation (IVS6+5G>A) in the myosin-binding protein-C gene that explained the phenotype of affected individuals and that enabled us to estimate the risk in other family members and to offer genetic counseling.