Juan R. Gimeno

Non-sustained ventricular tachycardia in hypertrophic cardiomyopathy: An independent marker of sudden death risk in young patients

OBJECTIVES The aim of this study was to examine the characteristics of non-sustained ventricular tachycardia (NSVT) episodes during Holter monitoring and to determine their relationship to age and prognosis. BACKGROUND It has been suggested that NSVT is only of prognostic importance in patients with hypertrophic cardiomyopathy (HCM) when repetitive, prolonged, or associated with symptoms. METHODS We studied 531 patients with HCM (323 male, 39 +/- 15 years). All underwent ambulatory electrocardiogram monitoring (41 +/- 11 h). RESULTS A total of 104 patients (19.6%) had NSVT. The proportion of patients with NSVT increased with age (p = 0.008). Maximum left ventricular wall thickness and left atrial size were greater in patients with NSVT. Mean follow-up was 70 +/- 40 months. Sixty-eight patients died, 32 from sudden cardiac death (SCD). Twenty-one patients received an implantable cardioverter defibrillator (ICD). There were four appropriate ICD discharges. In patients < or =30 years (but not >30), five-year freedom from sudden death was lower in those with NSVT (77.6% [95% confidence interval (CI): 59.8 to 95.4] vs. 94.1% [95% CI: 90.2 to 98.0]; p = 0.003). There was no relation between the duration, frequency, or rate of NSVT runs and prognosis at any age. The odds ratio of sudden death in patients < or =30 years of age with NSVT was 4.35 (95% CI: 1.54 to 12.28; p = 0.006) compared with 2.16 (95% CI: 0.82 to 5.69; p = 0.1) in patients >30 years of age. CONCLUSIONS Non-sustained ventricular tachycardia is associated with a substantial increase in sudden death risk in young patients with HCM. A relation between the frequency, duration, and rate of NSVT episodes could not be demonstrated.

Prospective evaluation of relatives for familial arrhythmogenic right ventricular cardiomyopathy/dysplasia reveals a need to broaden diagnostic criteria.

OBJECTIVES We sought to ascertain the prevalence and mode of expression of familial disease in a consecutive series of patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D). BACKGROUND Autosomal-dominant inheritance is recognized in ARVC. The prevalence and mode of expression of familial disease in consecutive, unselected families is uncertain. METHODS First- and second-degree relatives of 67 ARVC index patients underwent cardiac evaluation with history and examination, 12-lead and signal-averaged electrocardiogram (ECG), two-dimensional and Doppler echocardiography, metabolic exercise testing and Holter monitoring. Diagnoses were made in accordance with published criteria. RESULTS Of 298 relatives, 29 (10%; mean age 37.4 +/- 16.4 years) had ARVC. These were from 19 of the 67 families, representing familial involvement in 28%. Of these affected relatives, 72% were asymptomatic, 17% had ventricular tachycardia (sustained VT 10%, nonsustained VT 7%) and 21% had left ventricular involvement. A further 32 relatives (11%; 37.7 +/- 12.4 years) exhibited nondiagnostic ECG, echocardiographic or Holter abnormalities. Fifteen of these relatives were from families with only the proband affected, and inclusion of this subset of relatives would have resulted in familial ARVC in 48% of index cases. Four additional relatives (1% to 3%) fulfilled diagnostic criteria for dilated cardiomyopathy without any features of right ventricular disease. CONCLUSIONS By using current diagnostic criteria, familial disease was present in 28% of index patients. A further 11% of their relatives had minor cardiac abnormalities, which, in the context of a disease whose mode of inheritance is autosomal dominant, are likely to represent early or mild disease expression. We advocate that the current ARVC diagnostic criteria are modified to reflect the broader spectrum of disease that is observed in family members.

Anticoagulant and antiplatelet therapy use in 426 patients with atrial fibrillation undergoing percutaneous coronary intervention and stent implantation implications for bleeding risk and prognosis.

OBJECTIVES This study was designed to review outcomes in relation to antithrombotic therapy management strategies for patients with atrial fibrillation (AF) who undergo percutaneous coronary intervention (PCI) with stenting. BACKGROUND There is limited evidence on the optimal antithrombotic therapy management strategies for patients with AF who undergo PCI with stenting. METHODS We reviewed 426 patients (70.9% men, mean age 71.5 +/- 8.5 years) with AF undergoing PCI with stenting between 2001 and 2006. We recorded clinical and demographic characteristics of the patients, stroke risk factors, and antithrombotic therapy use before PCI and at discharge. Clinical follow-up was performed, and all bleeding episodes, thromboembolism, and major adverse cardiac events (MACE) (i.e., death, acute myocardial infarction, or target lesion revascularization) were recorded. RESULTS The most commonly associated comorbidities were hypertension (74.5%), diabetes mellitus (40.2%), chronic renal failure (14.9%), and congestive heart failure (26.7%); 80% of patients had >or=2 stroke risk factors. Of the drugs prescribed at discharge, aspirin plus clopidogrel were used in 174 patients (40.8%), whereas 213 patients (50%) were discharged with triple therapy (coumarins, aspirin, and clopidogrel). Complete follow-up was achieved in 87.5% (median 594 days; range 0 to 2,190). The incidence of adverse events was high (36.6%), with major bleeding in 12.3%, thromboembolic events in 4.2%, and MACE in 32.3%. All-cause mortality was high (22.6%). In a multivariate analysis, non-anticoagulation with coumarins increased mortality (17.8% vs. 27.8%; hazard ratio [HR] = 3.43; 95% confidence interval [CI] 1.61 to 7.54; p = 0.002) and MACE (26.5% vs. 38.7%; HR = 4.9; 95% CI 2.17 to 11.1; p < 0.01) In a Cox-regression analysis, non-anticoagulation (p < 0.01) and age (p = 0.02) were independent predictors of MACE. CONCLUSIONS Patients with AF undergoing PCI with stenting represent a high-risk population because of age, comorbidities, and presence of stroke risk factors. These patients have a high mortality and MACE rate, which is reduced by anticoagulation therapy.

Idiopathic restrictive cardiomyopathy is part of the clinical expression of cardiac troponin I mutations

Restrictive cardiomyopathy (RCM) is an uncommon heart muscle disorder characterized by impaired filling of the ventricles with reduced volume in the presence of normal or near normal wall thickness and systolic function. The disease may be associated with systemic disease but is most often idiopathic. We recognized a large family in which individuals were affected by either idiopathic RCM or hypertrophic cardiomyopathy (HCM). Linkage analysis to selected sarcomeric contractile protein genes identified cardiac troponin I (TNNI3) as the likely disease gene. Subsequent mutation analysis revealed a novel missense mutation, which cosegregated with the disease in the family (lod score: 4.8). To determine if idiopathic RCM is part of the clinical expression of TNNI3 mutations, genetic investigations of the gene were performed in an additional nine unrelated RCM patients with restrictive filling patterns, bi-atrial dilatation, normal systolic function, and normal wall thickness. TNNI3 mutations were identified in six of these nine RCM patients. Two of the mutations identified in young individuals were de novo mutations. All mutations appeared in conserved and functionally important domains of the gene. This article was published online in advance of the print edition. The date of publication is available from the JCI website, http://www.jci.org.

Mutations in the NOTCH pathway regulator MIB1 cause left ventricular noncompaction cardiomyopathy

Left ventricular noncompaction (LVNC) causes prominent ventricular trabeculations and reduces cardiac systolic function. The clinical presentation of LVNC ranges from asymptomatic to heart failure. We show that germline mutations in human MIB1 (mindbomb homolog 1), which encodes an E3 ubiquitin ligase that promotes endocytosis of the NOTCH ligands DELTA and JAGGED, cause LVNC in autosomal-dominant pedigrees, with affected individuals showing reduced NOTCH1 activity and reduced expression of target genes. Functional studies in cells and zebrafish embryos and in silico modeling indicate that MIB1 functions as a dimer, which is disrupted by the human mutations. Targeted inactivation of Mib1 in mouse myocardium causes LVNC, a phenotype mimicked by inactivation of myocardial Jagged1 or endocardial Notch1. Myocardial Mib1 mutants show reduced ventricular Notch1 activity, expansion of compact myocardium to proliferative, immature trabeculae and abnormal expression of cardiac development and disease genes. These results implicate NOTCH signaling in LVNC and indicate that MIB1 mutations arrest chamber myocardium development, preventing trabecular maturation and compaction.

Historical trends in reported survival rates in patients with hypertrophic cardiomyopathy

Objective: To determine the range of survival rates of patients with hypertrophic cardiomyopathy (HCM) by comparing and contrasting the natural history of a cohort of patients seen between 1988 and 2002 with that of other published series. Methods: 956 adult (⩾ 16 years old) patients with HCM (572 men, mean (SD) age 42 (15) years, range 16–88) were evaluated by ECG, Holter, exercise testing, and echocardiography. Patient characteristics and survival data were compared with those in natural history studies from referral and non-referral centres published between 1960 and January 2003. Results: The duration of follow up was 69 (45) months. 120 (12.6%) patients died or underwent cardiac transplantation. Sudden cardiac death (n  =  48) was the most common mode of death. The annual rate of sudden death or implantable cardioverter-defibrillator discharge was 1.02 (95% confidence interval (CI) 0.76 to 1.26). Annual rates for heart failure death or transplantation and stroke related death were 0.55% (95% CI 0.37% to 0.78%) and 0.07% (95% CI 0.02% to 0.19%), respectively. When studies published within the last 10 years of the study period were compared with earlier reports, the size of individual study cohorts was larger (309 (240.6) v 136.5 (98.8), p  =  0.058) and the proportion with severe functional limitation NYHA class III/IV lower (12.4% v 24.8%, p < 0.0001), and fewer patients underwent septal myotomy-myectomy (5.2% v 18.7%, p < 0.0001). Published sudden death rates over the last 10 years were lower than previously published figures (median 1.0% (range 0.1–1.7) v 2.0% (0–3.5)). Conclusion: Published survival rates in HCM cohorts have improved progressively over the past 40 years. In the modern era the prevalence of disease related complications is similar in all reporting centres.

Proposal for a revised definition of dilated cardiomyopathy, hypokinetic non-dilated cardiomyopathy, and its implications for clinical practice: a position statement of the ESC working group on myocardial and pericardial diseases

In this paper the Working Group on Myocardial and Pericardial Disease proposes a revised definition of dilated cardiomyopathy (DCM) in an attempt to bridge the gap between our recent understanding of the disease spectrum and its clinical presentation in relatives, which is key for early diagnosis and the institution of potential preventative measures. We also provide practical hints to identify subsets of the DCM syndrome where aetiology directed management has great clinical relevance.

Prevalence and clinical significance of systolic impairment in hypertrophic cardiomyopathy

Objectives: To determine the frequency of systolic impairment (SI) and its impact on the natural history of hypertrophic cardiomyopathy (HCM). Methods: 1080 patients (mean (SD) age 43 (15) years, 660 men) with HCM were evaluated. Initial assessment included history, examination, 48 hour Holter monitoring, cardiopulmonary exercise testing, and echocardiography; SI was defined as a fractional shortening (FS) ⩽ 25%. Survival data were collected at clinic visits or by direct communication with patients and their general practitioners. The results of serial echocardiography in 462 patients with normal FS at presentation are also reported. Results: 26 (2.4%) patients (49 (14) years, 18 men) had SI at the initial visit. During follow up (58 (49) months), nine (34.6%) died or underwent cardiac transplantation compared with 108 (10.2%) patients with normal FS (p  =  0.01). Five year survival from death (any cause) or transplantation was 90.1% (95% confidence interval (CI) 87.8 to 92.4) in patients with normal systolic function versus 52.4% (95% CI 25.2 to 79.6, p < 0.0001) in patients with SI. In patients who underwent serial echocardiography, 22 (4.8%, aged 41 (15) years) developed SI over 66 (40) months; the annual incidence of SI was 0.87% (95% CI 0.54 to 1.31). On initial evaluation patients who developed SI had a higher frequency of syncope (67 (15.2%) v 10 (45.5%) of those who did not develop SI, p  =  0.001), non-sustained ventricular tachycardia (91 (20.6%) v 11 (50%), p  =  0.002), and an abnormal blood pressure response on exercise (131 (29.7%) v 15 (68.2%), p  =  0.001). Patients with SI had greater wall thinning (p  =  0.001), left ventricular cavity enlargement (p < 0.0005), and deterioration in New York Heart Association functional class (p  =  0.001) during follow up. Thirteen (59.1%) patients who progressed to SI died or underwent transplantation compared with 38 (8.6%) patients who maintained normal systolic function. Conclusions: SI is an infrequent complication of HCM but, when present, is associated with a poor prognosis.

Exercise-induced ventricular arrhythmias and risk of sudden cardiac death in patients with hypertrophic cardiomyopathy

BACKGROUND Non-sustained ventricular tachycardia (NSVT) during ambulatory electrocardiographic monitoring (typically occurring at rest or during sleep) is associated with an increased risk of sudden cardiac death in patients with hypertrophic cardiomyopathy. The prevalence and prognostic significance of ventricular arrhythmias during exercise is unknown. METHODS AND RESULTS This was a cohort study, with prospective data collection. We studied 1380 patients, referred to a cardiomyopathy clinic in London, UK [mean age 42 years (SD 15); 62% male; mean follow-up 54 (SD 49) months]. Patients underwent two-dimensional and Doppler echocardiography, upright exercise testing, and Holter monitoring. Twenty-seven patients [mean age 40 (SD 14) years (18-64); 22 (81.5%) male] had NSVT (24) or ventricular fibrillation (VF) (3) during exercise. During exercise, 13 (54.2%) had more than one run of NSVT (maximum 5) with a mean heart rate of 221 (SD 48) b.p.m. Patients with exercise NSVT/VF had more severe hypertrophy (22.6 vs. 19.5 mm, P = 0.009) and larger left atria (47.3 vs. 43.7 mm, P = 0.03). Male gender was significantly associated with exercise NSVT/VF [22 (81.5%) vs. 832 (61.5%), P = 0.03]. Eight (29.6%) of the exercise NSVT/VF patients died or had a cardiac event (SD/ICD discharge/transplant) compared with 150 (11.1%) patients without exercise NSVT/VF, P = 0.008. Patients with NSVT/VF had a 3.73-fold increase in risk of SD/ICD discharge (HR 95% CI: 1.61-8.63, P = 0.002). Exercise NSVT alone was associated with a 2.82-fold increased risk (HR 95% CI: 1.02-7.75, P = 0.049). In multivariable analysis with other risk markers, exercise NSVT/VF (but not NSVT alone) was independently associated with an increased risk of SD/ICD [HR 3.14 (95% CI: 1.29-7.61, P = 0.01)]. CONCLUSION Ventricular arrhythmia during symptom limited exercise is rare in patients with hypertrophic cardiomyopathy, but is associated with an increased risk of sudden cardiac death.

Pregnancy related complications in women with hypertrophic cardiomyopathy

Objectives: To determine whether pregnancy is well tolerated in hypertrophic cardiomyopathy. Setting: Referral clinic. Design: The study cohort comprised 127 consecutively referred women with hypertrophic cardiomyopathy. Forty (31.5%) underwent clinical evaluation before pregnancy. The remaining 87 (68.5%) were referred after their first pregnancy. All underwent history, examination, electrocardiography, and echocardiography. Pregnancy related symptoms and complications were determined by questionnaire and review of medical and obstetric records where available. Results: There were 271 pregnancies in total. Thirty six (28.3%) women reported cardiac symptoms in pregnancy. Over 90% of these women had been symptomatic before pregnancy. Symptoms deteriorated during pregnancy in fewer than 10%. Of the 36 women with symptoms during pregnancy, 30 had further pregnancies. Symptoms reoccurred in 18 (60%); symptomatic deterioration was not reported. Heart failure occurred postnatally in two women (1.6%). No complications were reported in 19 (15%) women who underwent general anaesthesia and in 22 (17.4%) women who received epidural anaesthesia, three of whom had a significant left ventricular outflow tract gradient at diagnosis after pregnancy. Three unexplained intrauterine deaths occurred in women taking cardiac medication throughout pregnancy. No echocardiographic or clinical feature was a useful indicator of pregnancy related complications. Conclusions: Most women with hypertrophic cardiomyopathy tolerate pregnancy well. However, rare complications can occur and therefore planned delivery and fetal monitoring are still required for some patients.