Amanda Varnava

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.

Association of Angiotensin-Converting Enzyme Gene I/D Polymorphism With Change in Left Ventricular Mass in Response to Physical Training

BACKGROUND The absence (deletion allele [D]) of a 287-base pair marker in the ACE gene is associated with higher ACE levels than its presence (insertion allele [I]). If renin-angiotensin systems regulate left ventricular (LV) growth, then individuals of DD genotype might show a greater hypertrophic response than those of II genotype. We tested this hypothesis by studying exercise-induced LV hypertrophy. METHODS AND RESULTS Echocardiographically determined LV dimensions and mass (n=140), electrocardiographically determined LV mass and frequency of LV hypertrophy (LVH) (n=121), and plasma brain natriuretic peptide (BNP) levels (n=49) were compared at the start and end of a 10-week physical training period in male Caucasian military recruits. Septal and posterior wall thicknesses increased with training, and LV mass increased by 18% (all P<.0001). Response magnitude was strongly associated with ACE genotype: mean LV mass altered by +2.0, +38.5, and +42.3 g in II, ID and DD, respectively (P<.0001). The prevalence of electrocardiographically defined LVH rose significantly only among those of DD genotype (from 6 of 24 before training to 11 of 24 after training, P<.01). Plasma brain natriuretic peptide levels rose by 56.0 and 11.5 pg/mL for DD and II, respectively (P<.001). CONCLUSIONS Exercise-induced LV growth in young males is strongly associated with the ACE I/D polymorphism.

Hypertrophic cardiomyopathy: the interrelation of disarray, fibrosis, and small vessel disease

OBJECTIVE To make a quantitative assessment of the relation between disarray, fibrosis, and small vessel disease in hypertrophic cardiomyopathy. DESIGN Detailed macroscopic and histological examination at 19 segments of the left and right ventricle and the left atrial free wall. PATIENTS 72 patients with hypertrophic cardiomyopathy who had suffered sudden death or progression to end stage cardiac failure (resulting in death or heart transplantation). MAIN OUTCOME MEASURES The presence of scarring, atrial dilatation, and a mitral valve impact lesion were noted, and heart weight, wall thickness, per cent disarray, per cent fibrosis, and per cent small vessel disease quantitated for each heart. RESULTS Within an individual heart the magnitude of hypertrophy correlated with the severity of fibrosis (p = 0.006) and disarray (p = 0.0002). Overall, however, total heart weight related weakly but significantly to fibrosis (r = 0.4, p = 0.0001) and small vessel disease (r = 0.3, p = 0.03), but not to disarray. Disarray was greater in hearts with mild left ventricular hypertrophy (maximum wall thickness < 20 mm) and preserved systolic function (60.9 (26)% v 43 (20.4)% respectively, p = 0.02) and hearts without a mitral valve impact lesion (26.3% v 18.9%, p = 0.04), but was uninfluenced by sex. Fibrosis was influenced by sex (7% in male patients and 4% in female, p = 0.04), but not by the presence of an impact lesion. No relation was found between disarray, fibrosis, and small vessel disease. CONCLUSIONS Myocyte disarray is probably a direct response to functional or structural abnormalities of the mutated sarcomeric protein, while fibrosis and small vessel disease are secondary phenomena unrelated to disarray, but modified by factors such as left ventricular mass, sex, and perhaps local autocrine factors.

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.

Survival after cardiac arrest or sustained ventricular tachycardia in patients with hypertrophic cardiomyopathy.

OBJECTIVES The aim of this study was to evaluate the survival of patients with hypertrophic cardiomyopathy (HCM) after resuscitated ventricular fibrillation or syncopal sustained ventricular tachycardia (VT/VF) when treated with low dose amiodarone or implantable cardioverter defibrillators (ICDs). BACKGROUND Prospective data on clinical outcome in patients with HCM who survive a cardiac arrest are limited, but studies conducted before the widespread use of amiodarone and/or ICD therapy suggest that over a third die within seven years from sudden cardiac death or progressive heart failure. METHODS Sixteen HCM patients with a history of VT/VF (nine male, age at VT/VF 19 +/- 8 years [range 10 to 36]) were studied. Syncopal sustained ventricular tachycardia/ventricular fibrillation occurred during or immediately after exertion in eight patients and was the initial presentation in eight. One patient had disabling neurologic deficit after VT/VF. Before VT/VF, two patients had angina, four had syncope and six had a family history of premature sudden cardiac death. After VT/VF all patients were in New York Heart Association class I or II, three had nonsustained VT during ambulatory electrocardiography and 11 had an abnormal exercise blood pressure response. After VT/VF eight patients were treated with low dose amiodarone and six received an ICD. Prophylactic therapy was declined by two patients. RESULTS Mean follow-up was 6.1 +/- 4.0 years (range 0.5 to 14.5). Cumulative survival (death or ICD discharge) for the entire cohort was 59% at five years (95% confidence interval: 33% to 84%). Thirteen (81%) patients were alive at last follow-up. Two patients died suddenly while taking low dose amiodarone, and one died due to neurologic complications of his initial cardiac arrest. Three patients had one or more appropriate ICD discharges during follow-up; the times to first shock after ICD implantation were 23, 197 and 1,124 days. CONCLUSIONS This study shows that patients with HCM who survive an episode of VT/VF remain at risk for a recurrent event. Implantable cardioverter defibrillator therapy appears to offer the best potential benefit regarding outcome.

A new mutation of the cardiac troponin T gene causing familial hypertrophic cardiomyopathy without left ventricular hypertrophy

AIM To screen for a mutation of the cardiac troponin T gene in two families where there had been sudden deaths without an increase in left ventricular mass but with myocardial disarray suggesting hypertrophic cardiomyopathy. METHODS DNA from affected individuals from both families was used to screen the cardiac troponin T gene on an exon by exon basis. Mutation screening was achieved by polymerase chain reaction and direct sequencing. Where appropriate, a mutation was confirmed by restriction digest. RESULTS A novel missense mutation of exon 9 was found in the affected individuals of one of the families. This mutation at amino acid 94 resulted in the substitution of arginine for leucine and was not found in 100 normal control samples. A mutation of the cardiac troponin T gene was excluded in the second family. CONCLUSIONS A mutation of the gene for the sarcomeric protein cardiac troponin T can cause familial hypertrophic cardiomyopathy with marked myocyte disarray and frequent premature sudden death in the absence of myocardial hypertrophy at clinical or macroscopic level.

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.

Role of late gadolinium enhancement cardiovascular magnetic resonance in the risk stratification of hypertrophic cardiomyopathy

Objective Myocardial fibrosis identified by late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) in patients with hypertrophic cardiomyopathy (HCM) is associated with adverse cardiovascular events, but its value as an independent risk factor for sudden cardiac death (SCD) is unknown. We investigated the role of LGE-CMR in the risk stratification of HCM. Methods We conducted a prospective cohort study in a tertiary referral centre. Consecutive patients with HCM (n=711, median age 56.3 years, IQR 46.7–66.6; 70.0% male) underwent LGE-CMR and were followed for a median 3.5 years. The primary end point was SCD or aborted SCD. Results Overall, 471 patients (66.2%) had myocardial fibrosis (median 5.9% of left ventricular mass, IQR: 2.2–13.3). Twenty-two (3.1%) reached the primary end point. The extent but not the presence of fibrosis was a significant univariable predictor of the primary end point (HR per 5% LGE: 1.24, 95% CI 1.06 to 1.45; p=0.007 and HR for LGE: 2.69, 95% CI 0.91 to 7.97; p=0.073, respectively). However, on multivariable analysis, only LV-EF remained statistically significant (HR: 0.92, 95% CI 0.89 to 0.95; p<0.001). For the secondary outcome of cardiovascular mortality/aborted SCD, the presence and the amount of fibrosis were significant predictors on univariable but not multivariable analysis after adjusting for LV-EF and non-sustained ventricular tachycardia. Conclusions The amount of myocardial fibrosis was a strong univariable predictor of SCD risk. However, this effect was not maintained after adjusting for LV-EF. Further work is required to elucidate the interrelationship between fibrosis and traditional predictors of outcome in HCM.

Cytosine methylation confers instability on the cardiac troponin T gene in hypertrophic cardiomyopathy

Editor—Hypertrophic cardiomyopathy (HCM) is an inherited disease (MIM 192600, 115195) of the heart muscle, characterised by unexplained left ventricular hypertrophy. HCM is also one of the major causes of sudden cardiac death,1sometimes occurring in young asymptomatic people.2-4Although sporadic forms do rarely occur,5 generally HCM has an autosomal dominant pattern of inheritance caused by mutations of the genes coding for proteins of the cardiac sarcomere. Subjects with HCM caused by mutations in the cardiac troponin T ( cTNT ) gene have been clinically shown to be at increased risk of sudden death,6 which may occur even in the absence of marked morphological abnormalities.7Since incomplete penetrance of the clinical phenotype, measured by ECG and echocardiographic parameters, is one of the hallmarks of “troponin” disease, the identification of cTNT mutation in probands would facilitate identification of “at risk” relatives who may not fulfil clinical diagnostic criteria. In the course of a study undertaken to characterise the cTNT mutation profile in HCM patients, we identified a cluster of mutations in exons 8 and 9. Five out of the 11 mutations published to date in this gene have been found in exons 88 and 9.7-10 We report here a novel Arg94Cys de novo mutation in a female patient presenting with HCM bringing the total of cTNT mutations to 12. Four of the mutations found in exon 9, Arg92Trp, Arg92Gln, Arg94Cys, and Ala104Val, involve C→T transitions (or G→A transitions in the opposite strand) within CpG dinucleotides. Approximately 70% of the cytosines within CpG dinucleotides in the mammalian genome contain highly mutable 5-methyl-cytosine (5mC) residues. These residues are not randomly distributed and the majority of the genome is CpG depleted.11 Although some CpG dinucleotides are found within coding regions, most CpG residues are in CpG islands, …

ST-Elevation Magnitude Correlates With Right Ventricular Outflow Tract Conduction Delay in Type I Brugada ECG

Background: The substrate location and underlying electrophysiological mechanisms that contribute to the characteristic ECG pattern of Brugada syndrome (BrS) are still debated. Using noninvasive electrocardiographical imaging, we studied whole heart conduction and repolarization patterns during ajmaline challenge in BrS individuals. Methods and Results: A total of 13 participants (mean age, 44±12 years; 8 men), 11 concealed patients with type I BrS and 2 healthy controls, underwent an ajmaline infusion with electrocardiographical imaging and ECG recordings. Electrocardiographical imaging activation recovery intervals and activation timings across the right ventricle (RV) body, outflow tract (RVOT), and left ventricle were calculated and analyzed at baseline and when type I BrS pattern manifested after ajmaline infusion. Peak J-ST point elevation was calculated from the surface ECG and compared with the electrocardiographical imaging–derived parameters at the same time point. After ajmaline infusion, the RVOT had the greatest increase in conduction delay (5.4±2.8 versus 2.0±2.8 versus 1.1±1.6 ms; P=0.007) and activation recovery intervals prolongation (69±32 versus 39±29 versus 21±12 ms; P=0.0005) compared with RV or left ventricle. In controls, there was minimal change in J-ST point elevation, conduction delay, or activation recovery intervals at all sites with ajmaline. In patients with BrS, conduction delay in RVOT, but not RV or left ventricle, correlated to the degree of J-ST point elevation (Pearson R, 0.81; P<0.001). No correlation was found between J-ST point elevation and activation recovery intervals prolongation in the RVOT, RV, or left ventricle. Conclusions: Magnitude of ST (J point) elevation in the type I BrS pattern is attributed to degree of conduction delay in the RVOT and not prolongation in repolarization time.