Niall Mahon

Sudden death in hypertrophic cardiomyopathy: identification of high risk patients

OBJECTIVES We sought to identify patients with hypertrophic cardiomyopathy (HCM) at high risk of sudden death (SD). BACKGROUND Relatively low mortality rates in HCM make conventional analysis of multiple clinical risk markers for SD problematic. This study used a referral center registry to investigate a smaller number of generally accepted noninvasive risk markers. METHODS We studied 368 patients (14 to 65 years old, 239 males) with HCM. There were five variables: nonsustained ventricular tachycardia (NSVT), syncope, exercise blood pressure response (BPR), family history of sudden death (FHSD) and left ventricular wall thickness (LVWT). RESULTS During follow-up (3.6+/-2.5 years [range 2 days to 9.6 years]), 36 patients (9.8%) died, 22 of them suddenly. Two patients received heart transplants. The six-year SD-free survival rate was 91% (95% confidence interval [CI] 87% to 95%). In the Cox model, there was a significant pairwise interaction between FHSD and syncope (p = 0.01), and these were subsequently considered together. The multivariate SD risk ratios (with 95% CIs) were 1.8 for BPR (0.7 to 4.4) (p = 0.22); 5.3 for FHSD and syncope (1.9 to 14.9) (p = 0.002); 1.9 for NSVT (0.7 to 5.0) (p = 0.18) and 2.9 for LVWT (1.1 to 7.1) (p = 0.03). Patients with no risk factors (n = 203) had an estimated six-year SD-free survival rate of 95% (95% CI 91% to 99%). The corresponding six-year estimates (with 95% CIs) for one (n = 122), two (n = 36) and three (n = 7) risk factors were 93% (87% to 99%), 82% (67% to 96%) and 36% (0% to 75%), respectively. Patients with two or more risk factors had a lower six-year SD survival rate (95% CI) compared with patients with one or no risk factors (72% [56% to 88%] vs. 94% [91% to 98%]) (p = 0.0001). CONCLUSIONS This study demonstrates that patients with multiple risk factors have a substantially increased risk of SD sufficient to warrant consideration for prophylactic therapy.

Relation between severity of left-ventricular hypertrophy and prognosis in patients with hypertrophic cardiomyopathy

BACKGROUND A previous study suggested that severe left-ventricular hypertrophy (maximum wall thickness > or = 30 mm) in patients with hypertrophic cardiomyopathy is associated with a risk of sudden cardiac death sufficient to warrant consideration for implantation of a cardioverter defibrillator (ICD). However, the prognostic significance of left-ventricular hypertrophy in relation to other clinical risk factors is poorly characterised. METHODS We studied 630 patients consecutively referred to one hospital in London, UK (mean age 37 years [SD 16]; 382 male; mean follow-up 59 months). Patients underwent two-dimensional and doppler echocardiography, upright exercise testing, and Holter monitoring. FINDINGS 39 patients died suddenly or had an appropriate ICD discharge; nine died from progressive heart failure; 11 from other cardiovascular causes and 23 from non-cardiac causes. There was a trend towards higher probability of sudden death or ICD discharge with increasing wall thickness (p=0.029, relative risk per 5 mm increment 1.31 [95% CI 1.03-1.66]). Of the 39 patients who died suddenly or had an ICD discharge, ten had a wall thickness of 30 mm or more. Patients with wall thickness of 30 mm or more had higher probability of sudden death or ICD discharge than patients with wall thickness less than 30 mm (p=0.049, 2.07 [1.00-4.25]. When considered together, the number of additional risk factors (one to three) was a better predictor of risk of sudden death or ICD discharge than wall thickness (p=0.0001, relative risk per additional factor 2.00 [1.43-2.79] vs p=0.058, 1.26 per 5 mm increment [0.99-1.60]). There was no relation between the pattern of hypertrophy and survival. INTERPRETATION The risk of sudden death associated with a wall thickness of 30 mm or more in patients without other risk factors is insufficient to justify aggressive prophylactic therapy. Most sudden deaths occurred in patients with wall thickness less than 30 mm, so the presence of mild hypertrophy cannot be used to reassure patients that they are at low risk.

Relation between myocyte disarray and outcome in hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HC) is associated with an increased risk of sudden cardiac death or death from heart failure. Little is known of the pathologic substrate for risk of premature death in this disease. We therefore set out to correlate the pathologic findings with the mode of death and risk profile in 75 patients with HC. Hearts with HC were obtained after death or transplantation. The clinical details were correlated with the macroscopic findings and the percent fibrosis, disarray, and small-vessel disease across 19 sections of each heart. Thirty-nine patients died suddenly, 28 had end-stage heart failure, and 8 died of other causes. Myocyte disarray correlated positively with evidence of ischemia (r = 0.5, p <0.0001), and was greater in patients who died before age 21 years (mean disarray 33% vs 18%, p <0.0001) and in those with an abnormal vascular response to exercise (mean disarray and 30% vs 19%, p = 0.04). Myocardial fibrosis was greater in patients who died in heart failure (mean percent fibrosis was 2.8% versus 0.9%, p = 0.003), and in patients with nonsustained ventricular tachycardia or a high risk fractionation study (4.9% vs 2.7%, p = 0.04, and 6.84% vs 2.8%, p = 0.03, respectively). In conclusion, young patients who die with HC have greater disarray than their older counterparts. In contrast, myocardial fibrosis is the substrate for premature deaths from heart failure and is associated with an increased risk of a primary ventricular arrhythmia.

The prognostic value of estimated creatinine clearance alongside functional capacity in ambulatory patients with chronic congestive heart failure

OBJECTIVES The goal of this study was to determine the prognostic significance of estimated creatinine clearance (CrCl) in relation to 6-min walk distance in ambulatory patients with congestive heart failure (HF). BACKGROUND Although measurement of renal function is integral to the management of chronic congestive HF, its prognostic implications are not well described and have not been formally evaluated relative to measures of functional capacity. METHODS We analyzed outcomes of the 585 participants of the 6-min walk substudy of the Digitalis Investigation Group (DIG) trial. The CrCl was estimated using the Cockcroft-Gault equation. Predictors of all-cause mortality were identified using semiparametric Cox proportional hazards regression and completely parametric hazard analyses. RESULTS Most subjects (85%) were New York Heart Association functional class II and III. Mean age was 65 (+/-12) years and mean ejection fraction (EF) 35% (+/-13%). There were 153 (26%) deaths during a median of 2.6 years of follow-up. Mortality by increasing quartiles of estimated CrCl was 37% (18 to 48 ml/min), 29% (47 to 64 ml/min), 18% (64 to 86 ml/min), and 21% (86 to 194 ml/min) with corresponding hazard ratios (HRs) relative to the top quartile of 2.1 (95% confidence interval [CI], 1.4 to 3.3), 1.6 (95% CI, 1.0 to 2.5), and 0.9 (95% CI, 0.5 to 1.5), respectively. In Cox regression analyses, independent predictors of mortality were estimated CrCl (adjusted HR [quartile 1:quartile 4] 1.5; 95% CI, 1.1 to 2.1), 6-min walk distance < or =262 m [adjusted HR, 1.63; 95% CI, 1.12 to 2.27]), EF, recent hospitalization for worsening HF, and need for diuretic treatment. Parametric (hazard) analysis confirmed consistent effects of estimated CrCl on mortality in several subgroups including that of patients with EF >45%. CONCLUSION In ambulatory patients with congestive HF, estimated CrCl predicts all-cause mortality independently of established prognostic variables.

Working formulation for the standardization of definitions of infections in patients using ventricular assist devices

In 2009, the International Society for Heart and Lung Transplantation (ISHLT) recognized the importance of infectionrelated morbidity and mortality in patients using ventricular assist devices (VADs) and the growing need for a consensusbased expert opinion to provide standard definitions of infections in these patients. The aim of these standard definitions is to improve clinical-investigator communication, allowing meaningful comparison in practice and outcomes between different centers and different VAD devices. In 2010, a core group of experts, including infectious diseases specialists, cardiologists, pathologists, radiologists, and cardiothoracic surgeons, formed an ISHLT Infectious Diseases Working Group to develop agreed criteria for definitions of infections in VAD patients. These definitions have been created by adapting and expanding on existing standardized definitions, which are based on the pathophysiology of equivalent infectious processes in prosthetic devices, such as cardiac prosthetic valve infections, intravascular catheter-related infections, and prosthetic joint infections. These definitions have been divided into 3 sections: VAD-specific infections, VAD-related infections, and non-VAD infections. Owing to the constant shortage of donor organs, new allocation systems, and improved medical therapies for congestive cardiac failure, the overwhelming trend in cardiac transplantation has been toward listing principally the most critically ill patients, that is, those requiring inpatient inotropic therapy for mechanical circulatory support (MCS). The ventricular assist device (VAD) has an expanding role in the management of these patients, both as a bridge to transplantation and as a destination therapy (ie, alternative to transplantation). According to United Network of Organ Sharing (UNOS) registry data, 9,000 transplant candidates have undergone MCS since 1999, comprising 33% of all listed patients and 75% of all listed inpatients. 1

Prospective Familial Assessment in Dilated Cardiomyopathy Cardiac Autoantibodies Predict Disease Development in Asymptomatic Relatives

Background— In autoimmune disorders, circulating autoantibodies identify healthy relatives at risk years before clinical presentation. Healthy relatives of patients with dilated cardiomyopathy (DCM) who have echocardiographic changes, including left ventricular enlargement or depressed fractional shortening at baseline, have increased medium-term risk for DCM development. Approximately one third of relatives have serum anti-heart autoantibodies (AHAs) at baseline; we intended to assess their potential role in predicting DCM development. Methods and Results— Baseline evaluation, including electrocardiography, echocardiography, and AHA, was performed in 592 asymptomatic relatives of 169 consecutive DCM patients (291 males and 301 females; mean age 36±16 years). Relatives were classified in accordance with published echocardiographic criteria; those who did not have DCM were followed up (median of 58 months). DCM among relatives was diagnosed by echocardiography at follow-up. Of the 592 individuals evaluated, 77% were assessed as normal, 4.4% as having DCM, and 19% as possibly affected on the basis of depressed fractional shortening without ventricular dilatation in 17 and left ventricular enlargement without systolic dysfunction in 94. Five-year follow-up of 311 relatives revealed that 26 had progressed (13 to DCM, 11 to left ventricular enlargement, and 2 to depressed fractional shortening). Relatives who developed DCM were more frequently AHA-positive than those who did not (69% versus 37%, P=0.02). Five-year probability of progression to DCM, among normal or possibly affected relatives, was higher in AHA-positive cases (P=0.03). By Cox regression, positive AHAs at baseline were independent predictors of progression (RR 2.26, CI 1 to 5.1, P=0.03). Conclusions— Among healthy relatives of DCM patients, AHAs are independent predictors of disease development within 5 years.

Echocardiographic Evaluation in Asymptomatic Relatives of Patients with Dilated Cardiomyopathy Reveals Preclinical Disease

Context Idiopathic dilated cardiomyopathy is familial in 25% of cases. However, identifying asymptomatic affected relatives is difficult because there is no specific molecular marker for the disease and penetrance of the genetic defect is incomplete. The natural history of asymptomatic disease is poorly defined. Contribution Clinical evaluation of asymptomatic relatives of patients with dilated cardiomyopathy showed that those with left ventricular enlargement or depressed fractional shortening were nearly 8 times as likely to progress to dilated cardiomyopathy as those with normal findings. Implications Screening of asymptomatic relatives of patients with dilated cardiomyopathy seems useful since early treatment may improve prognosis in affected individuals. The Editors Idiopathic dilated cardiomyopathy frequently presents at an advanced stage as severe heart failure or a catastrophic event, such as sudden death or stroke (1). The preclinical stage of dilated cardiomyopathy may last several years, even when the eventual clinical syndrome is acute. Although advances in heart failure management have improved the prognosis for patients presenting late, additional benefit might result from treatment before the onset of symptoms, making the identification of at-risk individuals a major focus of current research in heart failure. Recent studies have demonstrated that dilated cardiomyopathy is familial in at least 25% of cases (2-5). Most families exhibit an autosomal dominant mode of inheritance. Genetic analyses in extended kindreds have defined several dilated cardiomyopathy disease loci and genes (6-16). However, in most families with dilated cardiomyopathy, disease penetrance is incomplete and age-related, hampering attempts to identify the responsible gene defects. Without molecular markers, the diagnosis of familial dilated cardiomyopathy and the detection of early asymptomatic disease depend on clinical evaluation. Initial echocardiographic studies of the family members of patients with dilated cardiomyopathy noted an unusually high incidence of asymptomatic minor abnormalities of the left ventricle (3-5). These abnormalities may represent preclinical disease or formes frustes of dilated cardiomyopathy. We prospectively examined a large series of unselected patients with dilated cardiomyopathy and their family members to determine the prevalence and natural history of echocardiographic abnormalities among asymptomatic, apparently healthy relatives. Methods The human research committee at St. Georges Hospital Medical School, London, United Kingdom, reviewed and approved the entire study protocol. We obtained informed consent from each patient to contact family members and subsequently from each family member who agreed to participate in the study. Echocardiographic Criteria Experienced operators, who were unaware of the clinical context, performed all study echocardiography. We obtained chamber measurements at the mitral valve tip level from 2-dimensional guided M-mode or short-axis view recordings. We corrected dimensions for age and body surface area according to the formula of Henry and colleagues (17): percentage of predicted left ventricular end-diastolic dimension = measured left ventricular diastolic dimension/predicted left ventricular diastolic dimension 100; and predicted left ventricular diastolic dimension = (45.3 body surface area0.3) (0.03 age) 7.2. We classified individuals in accordance with earlier reports as follows. Dilated cardiomyopathy was defined as percentage of predicted left ventricular diastolic dimension of 112% or greater and fractional shortening less than 25%; left ventricular enlargement was defined as percentage of predicted left ventricular diastolic dimension of 112% or greater and fractional shortening of 25% or greater; depressed fractional shortening was defined as percentage of predicted left ventricular diastolic dimension less than 112% and fractional shortening less than 25%; and healthy was defined as percentage of predicted left ventricular diastolic dimension less than 112% and fractional shortening of 25% or greater. Proband Enrollment We recruited probands from 370 consecutive patients with dilated cardiomyopathy who were referred to the heart failure clinic at St. Georges Hospital. All patients underwent a comprehensive evaluation, including clinical history, physical examination, 12-lead electrocardiography, 2-dimensional echocardiography, 24-hour Holter monitoring, symptom-limited metabolic exercise testing, and laboratory investigation (including creatine kinase level measurement), to screen for asymptomatic skeletal muscle disease and iron studies to exclude hemochromatosis. We performed coronary angiography to exclude atherosclerotic heart disease in those older than 40 years of age or in those with features suggestive of coronary disease. We excluded individuals with documented coronary disease, systemic arterial hypertension, primary valvular disease, pericardial disease, cor pulmonale, or a history of excess alcohol consumption (regular intake >40 g/d for women and >80 g/d for men). Family Member Enrollment We offered family screening to all patients with dilated cardiomyopathy, regardless of an overt family history, and we based inclusion on the willingness to participate and geographic availability. Of the patients, 189 probands and their families fulfilled inclusion criteria, resided in the United Kingdom, and were willing to participate. A trained research nurse constructed extended pedigrees based on each proband by using Cyrillic 2.1 (Cherwell Scientific Ltd., Oxford, United Kingdom), and we contacted at-risk first- and second-degree relatives and offered them noninvasive evaluation. Assessment of asymptomatic relatives who agreed to participate included medical history, clinical examination, 12-lead electrocardiography, and 2-dimensional echocardiography. Relatives with abnormalities proceeded to a full evaluation as described for probands. We reviewed medical records and autopsy findings to confirm or refute the diagnosis of dilated cardiomyopathy for all deceased relatives. Definition of Familial Dilated Cardiomyopathy We classified dilated cardiomyopathy as familial if at least 1 relative (in addition to the proband) had documented disease during life or at postmortem or if there was a history of unexplained sudden cardiac death before the age of 30 years. Follow-up of Asymptomatic Relatives All relatives with left ventricular enlargement and depressed fractional shortening (but not initially healthy relatives) underwent prospective annual evaluation. They were asymptomatic and did not receive treatment unless criteria for dilated cardiomyopathy developed. After initial observation of progression to dilated cardiomyopathy (approximately 9% over 40 months) among this group, we determined that initially healthy individuals should also be reevaluated to verify that left ventricular enlargement and depressed fractional shortening were risk markers for development of dilated cardiomyopathy. Accordingly, a nurse who had not been involved in the original screening project and who did not know the families randomly contacted 238 relatives whose initial echocardiograms were entirely normal from a list of all initially healthy relatives and invited them for reevaluation at a median of 57 months from their initial assessment. Follow-up evaluations consisted of repeated history and physical examination, 12-lead electrocardiography, and 2-dimensional echocardiography. Statistical Analysis To determine the number of initially healthy relatives requiring follow-up, we based power calculations for analysis of progression on the 9% rate of progression over 40 months observed among 140 study participants with left ventricular enlargement and depressed fractional shortening, a hypothesized rate of progression of 2% or less among those relatives with initially normal echocardiograms, and an level of 0.05. We determined the requirement of follow-up of 235 relatives or more who were initially classified as healthy at a power of 0.85 (that is, total population of 375 patients, with 140 patients with left ventricular enlargement and depressed fractional shortening and 235 healthy patients). We confirmed all quantitative variables to be normally distributed by using a 1-sample KolmogorovSmirnoff test and expressed them as means and SDs. For comparisons of continuous and discrete variables, we used the Student t-test, chi-square test, or Fisher exact test as appropriate. To account for the nesting of individuals within families, we estimated 95% CIs for prevalence of dilated cardiomyopathy, left ventricular enlargement, and depressed fractional shortening among relatives by fitting a hierarchical model for each condition using WinBUGS 1.4 (Imperial College and Medical Research Council, London, United Kingdom). We estimated prediction intervals from the posterior distribution for mean disease prevalence and presented them as 95% CIs. We used the KaplanMeier method to construct survival curves for risk for progression for relatives with left ventricular enlargement and depressed fractional shortening and healthy relatives. We fitted a Cox proportional hazards regression model to perform further analysis of progression to dilated cardiomyopathy. We used the Efron approximation to deal with ties. Covariates included in the initial model were initial diagnosis and age. A backward stepwise procedure converged upon a model, which only included initial diagnosis. To account for the clustering of related individuals within families, we used frailty models. A frailty model is a random-effects model that accounts for a familial effect in the analysis. These models allow for the lack of independence between events observed in members of the same family. Henderson and Oman (18) have discussed their use in more detail. The frailty was introduced into the model as an unobserved, no

Contemporary management of and outcomes from cardiac device related infections

AIMS To describe the incidence and management of cardiac device infection. Infection is a serious, potentially fatal complication of device implantation. The numbers of device implants and infections are rising. Optimal care of device infection is not well defined. METHODS AND RESULTS We retrospectively identified cases of device infection at our institution between 2000 and 2007 by multiple source record review, and active surveillance. Device infection was related to demographics, clinical, and procedural characteristics. Descriptive analysis was performed. From 2000 to 2007, a total of 2029 permanent pacemakers and 1076 biventricular/implantable cardioverter-defibrillators (ICDs) or ICDs were implanted. Thirty-nine cases of confirmed device infections were identified--27 pacemaker and 12 bivent/ICD or ICD infections, giving an infection rate of 1.25%. Median time from implant or revision to presentation was 150 days (range 2915 days, IQR25% 35-IQR75% 731). Ninety percent of patients presented with generator-site infections. The most common organism was methicillin-sensitive Staphylococcus aureus (30.8%), followed by coagulase negative Staphylococcus (20.5%). Complete device extraction occurred in 82%. Of these, none had relapse, and mortality was 7.4% (n = 2/27). With partial removal or conservative therapy (n = 13), relapse occurred in 67% (n = 8/12), with mortality of 8.4% (n = 1/12). Median duration of antibiotics was 42 days (range 47 days, IQR25% 28-IQR75% 42 days). Re-implantation of a new device occurred in 54%, at a median of 28 days (range 73 days, IQR25% 8.5-IQR75% 35 days). Methicillin-Resistant Staphylococcus Aureus infection predicted mortality (P < 0.004, RR 37, 95% CI 5.3-250). Median follow-up was 36 months. CONCLUSION Cardiac device infection is a rare complication, with significant morbidity and mortality. Complete hardware removal with appropriate duration of antimicrobial therapy results in the best outcomes for patients.

Utility of cardiopulmonary exercise in the assessment of clinical determinants of functional capacity in hypertrophic cardiomyopathy.

The utility of metabolic gas exchange measurements in evaluating the severity and determinants of exercise limitation was studied during upright symptom-limited cardiopulmonary exercise in 135 consecutive patients with hypertrophic cardiomyopathy (HC) and 50 healthy age- and gender-matched volunteers. Peak oxygen consumption (VO(2)) was less than predicted (age, gender, and size) in 99% patients. Peak VO(2) was significantly associated with New York Heart Association functional class; however, there was considerable overlap of peak VO(2) between classes I and III (70 +/- 15%, 56 +/- 15%, 35 +/- 11%, respectively). Patients with abnormal blood pressure responses and patients with chronotropic incompetence during exercise had lower percent-predicted peak VO(2) than patients with normal blood pressure and heart rate responses during exercise (p = 0.0001 and p <0.001, respectively). Percent-predicted peak VO(2) was similar in patients with and without resting left ventricular outflow obstruction. Of those patients with resting gradients, however, there was a strong inverse correlation between the magnitude of the gradient and peak VO(2) (r = 0.5; p <0.001). In conclusion, peak VO(2) is significantly related to New York Heart Association functional class in this group of patients with HC, but peak VO(2) is a superior measure of cardiovascular performance in individual patients. Our peak VO(2) data indicate that mechanical obstruction has an adverse pathophysiologic effect on functional capacity and provide the rationale to support treatments aimed at gradient reduction. Low peak VO(2) characteristics including those with normal or near-normal left ventricular wall thickness suggests that measurement of peak VO(2) may aid in the differential diagnosis between HC and athletes heart.

Genetic polymorphisms in the renin-angiotensin-aldosterone system associated with expression of left ventricular hypertrophy in hypertrophic cardiomyopathy: a study of five polymorphic genes in a family with a disease causing mutation in the myosin binding protein C gene

Background: Hypertrophic cardiomyopathy (HCM) is an inherited disease of the sarcomere characterised clinically by myocardial hypertrophy and its consequences. Phenotypic expression is heterogeneous even within families with the same aetiological mutation and may be influenced by additional genetic factors. Objective: To determine the influence of genetic polymorphisms of the renin-angiotensin-aldosterone system (RAAS) on ECG and two dimensional echocardiographic left ventricular hypertrophy (LVH) in genetically identical patients with HCM. Patients and methods: Polymorphisms of five RAAS components were determined in 26 gene carriers from a single family with HCM caused by a previously identified myosin binding protein C mutation. Genotypes associated with a higher activation status of the RAAS were labelled “pro-LVH genotypes”. Results: There was a non-biased distribution of pro-LVH genotypes in the gene carriers. Those without pro-LVH genotypes did not manifest cardiac hypertrophy whereas gene carriers with pro-LVH genotypes did (mean (SD) left ventricular muscle mass 190 (48) v 320 (113), p = 0.002; interventricular septal thickness 11.5 (2.0) v 16.4 (6.7), p = 0.01; pathological ECG 0% (0 of 10) v 63% (10 of 16), respectively). Multivariate analysis controlling for age, sex, and hypertension confirmed an independent association between the presence of pro-LVH polymorphisms and left ventricular mass. When each polymorphism was assessed individually, carriers of each pro-LVH genotype had a significantly greater left ventricular mass than those with no pro-LVH mutation; these associations, with the exception of cardiac chymase A AA polymorphism (p = 0.06), remained significant in multivariate analysis. Conclusion: Genetic polymorphisms of the RAAS influence penetrance and degree of LVH in 26 gene carriers from one family with HCM caused by a myosin binding protein C mutation.