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Introduction: The role of copy-number variants (CNV) as a cause of hypertrophic cardiomyopathy (HCM) is poorly studied. The aim of this study was to use high-throughput sequence (HTS) data combined with a read-depth strategy, to screen for CNV in cardiomyopathy-associated genes in a large consecutive cohort of HCM patients., Methods: Five-hundred-and-five unrelated HCM patients were genotyped using a HTS approach for 41 cardiovascular genes. We used a previously validated read-depth strategy (ExomeDepth) to call CNVs from the short-read sequence data. Detected CNVs in 19 cardiomyopathy-associated genes were then validated by comparative genomic hybridization array., Results: Twelve CNVs were identified. Four CNVs in 4 patients (0.8% of the cohort) were validated: one large deletion in MYBPC3, one large deletion in PDLIM3, one duplication of the entire TNNT2 gene and one large duplication in LMNA., Conclusions: Our data suggest that the proportion of HCM cases with pathogenic CNVs is small (<1%). For the small subset of patients with clearly interpretable CNVs, our findings have direct clinical implications. Short read sequence data can be used for CNV calling, but the high false positive rate requires a validation step. The two-step strategy described here is effective at identifying novel genetic causes of HCM and similar techniques should be applied whenever possible., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Hypertrophic cardiomyopathy (HCM) is an inherited disorder of cardiac sarcomeric proteins characterised by the presence of myocardial hypertrophy in the absence of abnormal loading conditions. Individuals with HCM can remain asymptomatic throughout their lives but many experience chest pain, symptoms of heart failure, syncope and sudden ventricular arrhythmias. Cardiopulmonary exercise testing is an important part of the assessment of patients with HCM who often have reduced peak oxygen consumption and a lower anaerobic threshold compared with healthy age-matched controls. This review will focus on mechanisms of exercise limitation, which are complex and multifactorial, and the options for medical management.

Symptoms of impaired consciousness (syncope and pre-syncope) occur in 15-25% of patients with hypertrophic cardiomyopathy (HCM).1 In young patients a history of recurrent syncope is associated with an increased risk of sudden death.2(-)5 Syncope usually occurs without warning or symptoms suggestive of the cause. Detailed investigations identify a probable mechanism in a minority, usually paroxysmal atrial fibrillation or ventricular tachycardia. In the majority however no likely mechanism is found despite repeated 24-hour ambulatory echocardiography (ECG) or patient-activated monitoring, exercise testing and invasive electrophysiological studies.1 6 Empirical treatment with amiodarone, a pacemaker or an implantable cardioverter-defibrillator is commonly employed, but is often unsuccessful in relieving the symptoms. We have previously observed that approximately 30% of patients with HCM have abnormal blood pressure response during maximal upright exercise.7 8 This was due in the majority of patients to an exaggerated fall in systemic vascular resistance, possibly arising from abnormal activation of stretch-sensitive left ventricular mechanoreceptors,9 10 by a mechanism similar to that described in aortic stenosis.11 However, in some patients an inadequate cardiac output response to exercise may be responsible.12 We hypothesised that abnormal vasodepressor-mediated hypotension may also occur during daily life in patients with HCM, and that this may be an important mechanism of syncope when conventional investigations fail to reveal a cause.

Background: Resting left ventricular outflow tract obstruction (LVOTO) occurs in 25% of patients with hypertrophic cardiomyopathy (HCM) and is an important cause of symptoms and disease progression. The prevalence and clinical significance of exercise induced LVOTO in patients with symptomatic non-obstructive HCM is uncertain., Methods and Results: 87 symptomatic patients (43.3 (13.7) years, 67.8% males) with HCM and no previously documented LVOTO (defined as a gradient >or=30 mm Hg) underwent echocardiography during upright cardiopulmonary exercise testing: 54 patients (62.1%; 95% CI 51.5 to 71.6) developed LVOTO during exercise (latent LVOTO); 33 (37.9%; 95% CI 28.4 to 48.5) had neither resting nor exercise LVOTO (non-obstructive). Patients with latent LVOTO were more likely to have systolic anterior motion of the mitral valve (SAM) at rest (relative risk 2.1, 95% CI 1.2 to 3.8; p = 0.01), and higher peak oxygen consumption (mean difference: 10.3%, 95% CI 2.1 to 18.5; p = 0.02) than patients with non-obstructive HCM. The only independent predictors of Delta gradient during exercise were a history of presyncope/syncope, incomplete/complete SAM at rest and Wigle score (all p<0.05). Subsequent invasive reduction of LVOTO in 10 patients with latent obstruction and drug refractory symptoms resulted in improved functional class and less syncope/presyncope (all p<0.05)., Conclusions: Approximately two-thirds of patients with symptomatic non-obstructive HCM have latent LVOTO. This study suggests that all patients with symptomatic non-obstructive HCM should have exercise stress echocardiography.

Background: In adults with hypertrophic cardiomyopathy (HCM), plasma B-type natriuretic peptide (BNP) levels correlate with dyspnoea class and other markers of disease severity. In children with HCM, symptoms are a poor guide to disease severity and no studies have evaluated the clinical utility of BNP testing., Objective: To assess the relation of BNP levels to symptoms and markers of disease severity in children with HCM., Methods: Forty-four consecutive patients with HCM (27 male, age 10 (area under the receiver operator characteristic curve = 0.875 (p<0.001))., Conclusions: BNP levels correlate with non-invasive parameters of disease severity in children with HCM, including measures of raised LV filling pressures. For patients in whom evaluation of symptoms is difficult, BNP may be a useful additional tool in the assessment of disease severity.

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 (> or = 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.

Objective: To examine the influence of genotype on late gadolinium enhancement (LGE) and the potential of cardiovascular magnetic resonance (CMR) to detect preclinical hypertrophic cardiomyopathy., Design: Prospective, blinded cohort study of myocardial LGE in a genetically homogeneous population., Patients: 30 patients with disease causing mutations in the recognised hypertrophic cardiomyopathy gene for cardiac troponin I (TNNI3): 15 with echocardiographically determined left ventricular hypertrophy (LVH+) and 15 without (LVH-)., Main Outcome Measures: CMR measures of regional left ventricular function, wall thickness, and mass, and the extent and distribution of LGE., Results: LGE was found in 12 (80%) LVH+ patients but with variable extent (mean 15%, range 3-48%). LGE was also found in two (13%) LVH- patients but the extent was limited (3.6%) and both patients were found to have an abnormal ECG and regional hypertrophy by cine CMR. The extent of LGE was positively associated with clinical markers of sudden death risk (21% with > or = 2 risk factors v 7% with < or = 1 risk factor, p = 0.02) and left ventricular mass (r = 0.56, p < 0.001) and was inversely associated with ejection fraction (r = -0.58, p < 0.001). Segmental analysis showed that as regional wall thickness increased, LGE was more prevalent (p < 0.0001) and more extensive (r = 0.98, p = 0.001)., Conclusion: In patients with disease causing mutations in TNNI3, focal fibrosis was not detected by LGE CMR before LVH and ECG abnormalities were present. Once LVH is present, LGE is common and the extent correlates with adverse clinical parameters. This suggests that focal fibrosis is closely linked to disease development.

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) < or = 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.

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.

Aims: Surgical myectomy has been successfully used to treat patients with symptomatic obstructive hypertrophic cardiomyopathy (HCM). More recently, alcohol septal ablation has been advocated as a less invasive, but equally effective alternative therapy. The aim of this non-randomized cohort study was to compare subjective and objective outcomes in patients undergoing these therapies., Methods: Forty-four patients (25 male; age 41+/-15 years) with symptomatic drug-refractory obstructive HCM were studied. Twenty-four patients underwent surgical myectomy and 20 alcohol septal ablation. All patients underwent clinical evaluation, echocardiography and upright maximal cardiopulmonary exercise testing using a cycle ergometer before and following their intervention., Results: Peak gradient was reduced to a similar extent by both modalities (myectomy: 83+/-23 to 15+/-10 mmHg (P<0.000001); ablation: 91+/-18 to 22+/-14 mmHg (P<0.000002);P =0.48 for myectomy vs ablation) and led to similar improvements in NYHA class (myectomy: 2.4+/-0.6 to 1.5+/-0.7 (P<0.00001); ablation: 2.3+/-0.5 to 1.7+/-0.8 (P<0.0001);P=0.3 for myectomy vs ablation). Myectomy resulted in a greater improvement in peak oxygen consumption (myectomy: 16.4+/-5.8 to 23.1+/-7.1 ml.kg(-1) min(-1) (P<0.00002); ablation: 16.2+/-5.2 to 19.3+/-6.1 ml.kg(-1) min(-1) (P<0.05);P <0.05 for myectomy vs ablation) and work rate achieved (myectomy: 130+/-57 to 161+/-60 watts (P<0.04); ablation: 121+/-53 to 137+/-51 watts (P=0.11);P <0.05 for myectomy vs ablation)., Conclusion: Surgical myectomy and alcohol septal ablation are equally effective at reducing obstruction and subjective exercise limitation in appropriately selected patients. However, the superior effect of surgical myectomy on exercise test parameters suggests that surgery remains the gold standard against which new treatment modalities should be compared., (Copyright 2002 The European Society of Cardiology. Published by Elsevier Science Ltd. All rights reserved.)

Background: Although studies have suggested that "late-onset" hypertrophic cardiomyopathy (HCM) may be caused by sarcomeric protein gene mutations, the cause of HCM in the majority of patients is unknown. This study determined the prevalence of a potentially treatable cause of hypertrophy, Anderson-Fabry disease, in a HCM referral population., Methods and Results: Plasma alpha-galactosidase A (alpha-Gal) was measured in 79 men with HCM who were diagnosed at > or =40 years of age (52.9+/-7.7 years; range, 40-71 years) and in 74 men who were diagnosed at <40 years (25.9+/-9.2 years; range, 8-39 years). Five patients (6.3%) with late-onset disease and 1 patient (1.4%) diagnosed at <40 years had low alpha-Gal activity. Of these 6 patients, 3 had angina, 4 were in New York Heart Association class 2, 5 had palpitations, and 2 had a history of syncope. Hypertrophy was concentric in 5 patients and asymmetric in 1 patient. One patient had left ventricular outflow tract obstruction. All patients with low alpha-Gal activity had alpha-Gal gene mutations., Conclusion: Anderson-Fabry disease should be considered in all cases of unexplained hypertrophy. Its recognition is important given the advent of specific replacement enzyme therapy.

Background: Conventional Doppler indices of left ventricular diastolic function do not correlate with symptoms or exercise capacity in patients with hypertrophic cardiomyopathy, because of their dependence on loading conditions. Diastolic mitral annular velocity measured using Doppler tissue imaging has been reported to be a preload independent index of left ventricular diastolic function., Objective: To determine the relation between diastolic annular velocities combined with conventional Doppler indices and symptoms or exercise capacity in hypertrophic cardiomyopathy., Methods: 85 patients with hypertrophic cardiomyopathy and 60 normal controls were studied. Diastolic mitral annular velocities, transmitral left ventricular filling, and pulmonary venous velocities were measured., Results: Early diastolic velocities at lateral and septal annulus were lower in patients with hypertrophic cardiomyopathy than in controls (lateral Ea: 10 (3) v 18 (4) cm/s, p < 0.0001; septal Ea: 7 (2) v 12 (3) cm/s, p < 0.0001). Unlike conventional Doppler indices alone, transmitral early left ventricular filling velocity (E) to lateral Ea ratio correlated inversely with peak oxygen consumption (r = -0.42, p < 0.0001). Patients in New York Heart Association (NYHA) class III had a higher transmitral E to lateral Ea ratio (12.0 (4.6)) than those in NYHA class II (7.6 (3.1), p < 0.005) or class I (6.6 (2.6), p < 0.0001)., Conclusions: Early diastolic mitral annular velocities are reduced in patients with hypertrophic cardiomyopathy. Unlike conventional Doppler indices alone, the transmitral E to lateral Ea ratio correlates with NYHA functional class and exercise capacity.

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.

QT dispersion is significantly greater in patients with hypertrophic cardiomyopathy (HCM) than that in healthy subjects. Few data exist regarding the prognostic value of QT dispersion in HCM. In this study, we retrospectively investigated the association between QT dispersion and sudden cardiac death in 46 patients with HCM (mean 33.1 +/- 15.5 years, 32 men). The case group consisted of 23 HCM patients who died suddenly, and the control group consisted of 23 HCM patients who survived uneventfully during follow-up. Study patients were pair-matched for age, gender, and maximum left ventricular wall thickness. QT dispersion (maximum minus minimum QT interval) was manually measured on early 12-lead ECGs using a digitizing board. An in-house program was used for calculating QT interval, QT dispersion, JT interval, and JT dispersion (maximum minus minimum J point to T end interval). Patients in the case group tended to have shorter RR intervals than those in the control group (777 +/- 171 vs 856 +/- 192 ms, P = 0.08). Maximum corrected QT and JT intervals did not discriminate the case group from controls (489 +/- 29 vs 479 +/- 27 ms, P = NS; 375 +/- 36 vs 366 +/- 22 ms, P = NS, respectively). Greater QT dispersion and JT dispersion were found in the case group compared with controls (74 +/- 28 vs 59 +/- 21 ms, P = 0.02 and 76 +/- 32 vs 59 +/- 26 ms, P = 0.03, respectively). The measurements of maximum QT, JT, and T peak to T end intervals, precordial QT and JT dispersion, and T peak and T end dispersion were all comparable between the two groups (P = NS for all). No systematic changes in ECG measurements were found from late ECGs of the case group compared to those from early ECGs (P = NS). No correlation between maximum left ventricular wall thickness and QT dispersion, JT dispersion, maximum QTc or JTc intervals was observed (r < 0.29, P > 0.05 for all). Our results show that increased QT dispersion and JT dispersion is weakly associated with sudden cardiac death in the selected patients with HCM.

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.

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.

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.

Premature sudden cardiac death (SD) is a critical event in the natural history of hypertrophic cardiomyopathy (HCM), and occurs during or just after physical exertion in approximately 60% of instances. Abnormalities in ventricular repolarization may not be present at rest in some patients but may become apparent under certain conditions. This study was performed to examine whether dynamic QT dispersion during exercise is associated with SD in HCM. Twenty-four HCM patients with catastrophic events (group I; 18 SD, 6 ventricular fibrillation) and 24 event-free survivors (group II) were studied. The two groups were pair-matched for age, gender, and maximum left ventricular wall thickness. QT intervals were manually measured from 12-lead exercise electrocardiogram (ECG) with a digitizing board. A custom-developed program was used to calculate QT and JT dispersion. The QT/RR relationship was evaluated by the slope of linear regression analysis. Before exercise, significant differences in heart rate and JT dispersion were found between group I and II. During exercise, heart rate increased and QT decreased significantly in both groups. QT and JT dispersion decreased in both groups, though the magnitude of reduction was greater in group I than in group II. No significant differences in QTc interval and QT or JT dispersion were found between the groups at any stages. At 3 minutes of recovery, heart rate had decreased but remained higher than before exercise, and all measurements of QT components remained shorter compared with those made before exercise in both groups. There was a strong correlation between QT and RR interval during exercise in all study patients (r = 0.95). No difference in the slope of QT against RR intervals was found between the groups (0.317 vs 0.319). In conclusion, exercise reduced QT dispersion in patients with HCM. The dynamic changes in QT dispersion examined by this method on exercise ECG did not make additional contributions in their risk stratification.

Objectives: This study evaluated the role of metabolic (cardiopulmonary gas exchange) exercise testing in differentiating physiologic LVH in athletes from HCM., Background: Regular intensive training may cause mild increases in left ventricular wall thickness (LVWT). Although the degree of left ventricular hypertrophy (LVH) is typically less than that seen in hypertrophic cardiomyopathy (HCM), genetic studies have shown that a substantial minority of patients with HCM have an LVWT in the same range. The differentiation of physiologic and pathologic LVH in this "gray zone" can be problematic using echocardiography and electrocardiography alone., Methods: Eight athletic men with genetically proven HCM and mild LVH (13.9 +/- 1.1 mm) and eight elite male athletes matched for age, size and LVWT (13.4 +/- 0.9 mm) underwent symptom limited metabolic exercise stress testing. Peak oxygen consumption (pVO2), anaerobic threshold, oxygen pulse and respiratory exchange ratios were measured in both groups and compared with those observed in 12 elite and 12 recreational age- and size-matched athletes without LVH., Results: Elite athletes with LVH had significantly greater pVO2 (66.2 +/- 4.1 ml/kg/min vs. 34.3 +/- 4.1 ml/kg/min; p < 0.0001), anaerobic threshold (61.6 +/- 1.8% of the predicted maximum VO2 vs. 41.4 +/- 4.9% of the predicted maximum VO2; p < 0.001) and oxygen pulse (27.1 +/- 3.2 ml/beat vs. 14.3 +/- 1.8 ml/beat; p < 0.0001) than individuals with HCM. A pVO2 >50 ml/kg/min or >20% above the predicted maximum VO2 differentiated athlete's heart from HCM., Conclusions: Metabolic exercise testing facilitates the differentiation between physiologic LVH and HCM in individuals in the "gray zone."

Percutaneous alcohol ablation of the interventricular septum via the first septal perforator branch of the left anterior descending artery can successfully treat dynamic left ventricular outflow tract obstruction in patients with hypertrophic cardiomyopathy. Increasingly, echocardiographic contrast agents are used before alcohol injection to identify the perfusion bed of the septal perforator vessels. This study describes the unexpected opacification of the left ventricular cavity in three of five consecutive patients following selective injection of the first septal perforator with Optison. This case study demonstrates that direct communication between the first septal perforator vessel and the left ventricle is common, an observation that may have considerable relevance to the technique of alcohol septal reduction.

Hypertrophic cardiomyopathy is a disease of the cardiac sarcomere and is the most common inherited cardiovascular disorder affecting up to 1 in 500 people in the general population. The disease is typified by variable clinical penetrance and heterogeneous clinical expression, resulting in a wide range of clinical manifestations. Most patients have few if any symptoms and a relatively benign clinical course. A minority are at risk of serious complications including ventricular arrhythmia, sudden death, thromboembolism, congestive cardiac failure, heart block, and infective endocarditis. This article reviews the natural history of the disease, with particular emphasis on lessons learned from recent genetic studies.

Dual chamber pacing has been proposed as an alternative to surgery in the management of hypertrophic cardiomyopathy. Reports have documented hemodynamic and symptomatic benefit from dual chamber pacing, raising the question of whether or not all patients with drug-refractory symptoms should undergo a trial of pacing before consideration of surgery. The enthusiasm for pacing in hypertrophic cardiomyopathy has generated a number of investigations addressing this issue, including several recently concluded clinical trials. This article reviews the recent experience with dual chamber pacing in hypertrophic cardiomyopathy.

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.

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.

Disproportionate exercise limitation in patients with cardiovascular disease is a common problem faced by clinical cardiologists and other physicians. Symptoms may be attributed to psychological factors or hypothetical pathophysiological mechanisms that are difficult to confirm clinically. This case report describes how the use of metabolic exercise testing in a 28 year old woman with morphologically and haemodynamically mild hypertrophic cardiomyopathy and severe exercise limitation led to the diagnosis of an alternative cause for the patient's symptoms, namely a primary disturbance of the mitochondrial respiratory chain probably caused by a nuclear encoded gene defect.

Objective: To examine the submaximal and maximal indices of the exercise response of patients with hypertrophic cardiomyopathy., Design and Setting: Prospective examination of cardiopulmonary responses to ramp exercise test of a consecutive group of patients with hypertrophic cardiomyopathy attending a cardiomyopathy outpatient clinic., Methods: 50 patients aged 12 to 76 years (mean (SD) 35 (14)) with diagnosis of hypertrophic cardiomyopathy performed incremental cycle ergometry; 22 sedentary volunteers (seven female, 15 male) aged 14 to 58 years (mean (SD) 31 (12)) served as controls. Respiratory gas was continuously sampled from the mouth-piece, and its concentration profile phase aligned to the respired air flow signals. Following analogue to digital conversion, gas exchange variables were computed breath by breath and the data were averaged every 30 seconds for graphic display. A 12 lead ECG was monitored continuously and recorded every three minutes during the exercise., Results: Both the peak oxygen uptake attained on the test (VO2 peak) and anaerobic threshold were reduced in patients with hypertrophic cardiomyopathy compared with the control group (p < 0.0001). In 29 patients (59%) the VO2 peak was less than 60% and only two patients achieved a peak above 80% of their predicted values. The anaerobic threshold was below 60% of the predicted value in 31 patients and above 80% in only three patients. The slope of oxygen uptake/work rate relation (delta VO2/delta WR) was decreased in 16 patients (32%). The maximum oxygen pulse (VO2/HR) was reduced as a percentage of the predicted value, and became flat at high work rates in 32 patients. There was a significant correlation between anaerobic threshold and VO2 peak (p < 0.0001), work efficiency (p < 0.0001), and maximum oxygen pulse (p < 0.0001). The slope of change in ventilation against change in carbon dioxide output (delta VE/delta VCO2) for the subanaerobic threshold range was increased in 36 patients (72%) and was inversely correlated with anaerobic threshold (p < 0.0002)., Conclusions: There were severe abnormalities in maximal and submaximal indices of pulmonary gas exchange in a cohort of hypertrophic cardiomyopathy patients attending a referral cardiovascular clinic. The pattern of the abnormalities suggests that a reduced stroke volume response, ventilation/perfusion mismatch, and abnormal peripheral oxygen utilisation are the possible mechanisms of exercise intolerance.

Aims: Thallium-201 perfusion abnormalities are common in patients with hypertrophic cardiomyopathy and may be associated with an adverse prognosis in the young. The aim of this study was to prospectively determine the relationship between thallium-201 defects during dipyridamole stress to clinical presentation and outcome in a large consecutive series of patients with hypertrophic cardiomyopathy., Methods/results: Thallium-201 single photon computed tomography was performed in 216 patients with hypertrophic cardiomyopathy during dipyridamole stress (0.5 mg. kg-1). Fixed perfusion defects occurred in 25%, and reversible defects in 22%. A combination of defects was present in 7%. Fixed defects were associated with: a history of syncope (17 of 46 with, vs 36 of 170 without syncope, P = 0.03); larger left ventricular end-diastolic (46.9 +/- 7.4 mm vs 43.3 +/- 6.4 mm; P = 0.001) and end-systolic dimension (30.2 +/- 8.4 mm vs 24.5 +/- 5.9 mm, P < 0.0001); increased left atrial diameter (46.1 +/- 8.1 mm vs 40.5 +/- 7.7 mm, P < 0.0001); lower fractional shortening (35.9 +/- 10.4% vs 43.8 +/- 8.6%, P < 0.0001): and lower maximal exercise oxygen consumption (24.2 +/- 8.1 ml. min-1. kg-1 vs 29.4 +/- 8.8 ml. min-1. kg-1, P < 0.0003). Reversible defects did not correlate with symptomatic status, but were associated with: larger left atrial dimensions (44.5 +/- 8.1 mm vs 41.0 +/- 8.0 mm; P = 0.009) and greater maximal left ventricular wall thickness (24.0 +/- 7.0 mm vs 20.6 +/- 7.0 mm, P = 0.003). The mean follow up time was 41 +/- 21 months, range 0.6-124. There was no association between any thallium-201 abnormality and disease related death in young or adult patients., Conclusion: The present study shows that fixed thallium-201 perfusion defects detected during dipyridamole stress in patients with hypertrophic cardiomyopathy are associated with syncope, larger left ventricular cavity dimensions and reduced exercise capacity. Although the event rate was relatively small, there was no evidence for an association between thallium-201 defects and survival.

Background: Previous studies revealed that an abnormal blood pressure response (ABPR) during exercise was common in young hypertrophic cardiomyopathy (HCM) patients and was associated with a family history of premature sudden cardiac death (SCD). This study was performed prospectively to assess the prognostic significance of blood pressure response during exercise in young patients with HCM., Methods and Results: Maximum symptom-limited treadmill exercise testing with continuous blood pressure monitoring was performed in 161 consecutive patients 8 to 40 years old (27+/-9). A normal blood pressure response, defined as an increase in the systolic pressure of at least 20 mm Hg from rest to peak exercise in the absence of a fall of >20 mm Hg from peak pressure, was seen in 101 (63%). In 60 (37%), the blood pressure response was abnormal. There was no significant difference in patients with normal blood pressure response and ABPR in terms of age, sex, follow-up, or recognized risk factors for SCD. During the follow-up period (mean, 44+/-20 months), SCD occurred in 12 patients: 3 (3%) in the normal blood pressure response group versus 9 (15%) in the ABPR group (P<.009). ABPR had a sensitivity of 75%, a specificity of 66%, a negative predictive value of 97%, and a positive predictive value of 15% for the prediction of SCD. There was no significant difference in the incidence of other recognized risk factors between patients with SCD and the survivors., Conclusions: A normal exercise blood pressure response identifies low-risk young patients with HCM. An ABPR identifies the high-risk cohort; the low positive predictive accuracy, however, indicates that further risk stratification is warranted.

Patients with hypertrophic cardiomyopathy frequently complain of chest pain during daily activities. ST-segment depression is described in association with sudden death and pacing, but its prevalence during ambulatory electrocardiographic monitoring is unknown. The aim of this study was to determine the relation of ambulatory ST-segment depression to clinical characteristics, risk factors for sudden death and thallium-201 perfusion in patients with hypertrophic cardiomyopathy. Continuous 48 h ambulatory electrocardiographic monitoring was performed in 113 patients (age 38 +/- 14 years) with hypertrophic cardiomyopathy. Ninety-four (83%) recordings were suitable for ST-segment analysis. A total of 109 episodes of ST-segment depression (> or = 1 mm from baseline) were recorded in 25 (27%) patients (mean 4 +/- 5). In patients < or = 30 years of age (but not > 30) there was an association between ST-segment depression and a history of exertional chest pain (seven of 12 vs one of 20; P = 0.001), and dyspnoea NYHA class II/III (seven of 15 vs one of 17; P = 0.008). There was no association between ST-segment depression and risk markers for sudden death, i.e. family history of sudden death, syncope and non-sustained ventricular tachycardia, in any group. Reversible thallium-201 defects occurred in 27 (29%) of the 94 patients with analysed recordings but were not associated with symptoms, risk factors for sudden death or ambulatory ST-segment depression. In young patients with hypertrophic cardiomyopathy, ischaemia-like ST-segment depression is common and is associated with a history of typical angina and dyspnoea. Reversible thallium-201 perfusion defects are associated with neither symptomatic status nor ambulatory ST-segment depression.

Objectives: The presence of angina pectoris and myocardial scarring in patients with hypertrophic cardiomyopathy (HCM) suggests that myocardial ischemia is a factor in the pathophysiology of the disease. The clinical evaluation of ischaemia is problematic in HCM as baseline electrocardiographic abnormalities are frequent and thallium-201 perfusion abnormalities correlate poorly with anginal symptoms. Coronary sinus pH measurement using a catheter mounted pH electrode is a validated sensitive technique for the detection of myocardial ischaemia., Methods and Results: 11 patients with HCM and chest pain (eight men; mean (SD) (range) age 36 (11) (19-53) years) and six controls (two men; mean (SD) (range) age 49 (11) (31-62) years) with atypical pain and normal coronary angiograms were studied. Eight patients with HCM had baseline ST segment depression of > or = 1 mm and four had reversible perfusion defects during stress 201TI scintigraphy. A catheter mounted hydrogen ion sensitive electrode was introduced into the coronary sinus and pH monitored continuously during dipyridamole infusion (0.56 mg/kg over four min). The maximal change in coronary sinus pH during dipyridamole stress was greater in patients with HCM than in controls (0.082 (0.083) (0 to -0.275) v 0.005 (0.006) (0 to -0.012), P = 0.02). In six patients (four men; mean (SD) (range) age 29 (9) (19-40 years) the development of chest pain was associated with a gradual decline in coronary sinus pH (mean 0.123 (0.089)), peaking at 442 (106) s. There were no relations among left ventricular dimensions, maximal wall thickness, and maximum pH change. In patients with HCM there was a correlation between maximum pH change and maximum heart rate during dipyridamole infusion (r = 0.70, P = 0.02)., Conclusion: This study provides further evidence that chest pain in patients with HCM is caused by myocardial ischaemia. The role of myocardial ischaemia in the pathophysiology of the disease remains to be determined but coronary sinus pH monitoring provides a method for quantifying and prospectively assessing its effects on clinical presentation and prognosis.

Sarcomere protein mutations in hypertrophic cardiomyopathy induce subtle cardiac structural changes before the development of left ventricular hypertrophy (LVH). We have proposed that myocardial crypts are part of this phenotype and independently associated with the presence of sarcomere gene mutations. We tested this hypothesis in genetic hypertrophic cardiomyopathy pre-LVH (genotype positive, LVH negative [G+LVH-]).A multicenter case-control study investigated crypts and 22 other cardiovascular magnetic resonance parameters in subclinical hypertrophic cardiomyopathy to determine their strength of association with sarcomere gene mutation carriage. The G+LVH- sample (n=73) was 29±13 years old and 51% were men. Crypts were related to the presence of sarcomere mutations (for ≥1 crypt, β=2.5; 95% confidence interval [CI], 0.5-4.4; P=0.014 and for ≥2 crypts, β=3.0; 95% CI, 0.8-7.9; P=0.004). In combination with 3 other parameters: anterior mitral valve leaflet elongation (β=2.1; 95% CI, 1.7-3.1; P<0.001), abnormal LV apical trabeculae (β=1.6; 95% CI, 0.8-2.5; P<0.001), and smaller LV end-systolic volumes (β=1.4; 95% CI, 0.5-2.3; P=0.001), multiple crypts indicated the presence of sarcomere gene mutations with 80% accuracy and an area under the curve of 0.85 (95% CI, 0.8-0.9). In this G+LVH- population, cardiac myosin-binding protein C mutation carriers had twice the prevalence of crypts when compared with the other combined mutations (47 versus 23%; odds ratio, 2.9; 95% CI, 1.1-7.9; P=0.045).The subclinical hypertrophic cardiomyopathy phenotype measured by cardiovascular magnetic resonance in a multicenter environment and consisting of crypts (particularly multiple), anterior mitral valve leaflet elongation, abnormal trabeculae, and smaller LV systolic cavity is indicative of the presence of sarcomere gene mutations and highlights the need for further study. [ABSTRACT FROM AUTHOR]

Mutations in genes coding for sarcomeric proteins cause hypertrophic cardiomyopathy. Subtle abnormalities of the myocardium may be present in mutation carriers without left ventricular hypertrophy (G+LVH-) but are difficult to quantify. Fractal analysis has been used to define trabeculae in left ventricular noncompaction and to identify normal racial variations. We hypothesized that trabeculae measured by fractal analysis of cardiovascular magnetic resonance images are abnormal in G+LVH- patients, providing a preclinical marker of disease in hypertrophic cardiomyopathy.Cardiovascular magnetic resonance was performed on 40 G+LVH- patients (33±15 years, 38% men), 67 patients with a clinical diagnosis of hypertrophic cardiomyopathy (53±15 years, 76% men; 31 with a pathogenic mutation [G+LVH+]), and 69 matched healthy volunteers (44±15 years, 57% men). Trabeculae were quantified by fractal analysis of cine slices to calculate the fractal dimension, a unitless index of endocardial complexity calculated from endocardial contours after segmentation. In G+LVH- patients, apical left ventricular trabeculation was increased compared with controls (maximal apical fractal dimension, 1.249±0.07 versus 1.199±0.05; P=0.001). In G+LVH+ and G-LVH+ cohorts, maximal apical fractal dimension was greater than in controls (P<0.0001) irrespective of gene status (G+LVH+: 1.370±0.08; G-LVH+: 1.380±0.09). Compared with controls, G+LVH- patients also had a higher frequency of clefts (28% versus 8%; P=0.02), longer anterior mitral valve leaflets (23.5±3.0 versus 19.7±3.1 mm; P<0.0001), greater septal systolic wall thickness (12.6±3.2 versus 11.2±2.1 mm; P=0.03), higher ejection fraction (71±4% versus 69±4%; P=0.03), and smaller end-systolic volumes (38±9 versus 43±12 mL; P=0.03).Increased myocardial trabecular complexity is one of several preclinical abnormalities in hypertrophic cardiomyopathy sarcomere gene mutation carriers without LVH. [ABSTRACT FROM AUTHOR]