Identification of Fabry Disease in a Tertiary Referral Cohort of Patients with Hypertrophic Cardiomyopathy.

BACKGROUND: Fabry disease is an X-linked lysosomal storage disorder caused by the deficient activity of α-galactosidase A due to mutations in the GLA gene, which may be associated with increased left ventricular wall thickness and mimic the morphologic features of hypertrophic cardiomyopathy. Management strategies for these 2 diseases diverge, with Fabry disease-specific treatment utilizing recombinant α-galactosidase A enzyme replacement therapy. METHODS: We studied a prospectively assembled consecutive cohort of 585 patients (71% male) from 2 hypertrophic cardiomyopathy tertiary referral centers by screening for low α-galactosidase A activity in dried blood spots. Male patients with low α-galactosidase A activity levels and all females were tested for mutations in the GLA gene. RESULTS: In 585 patients previously diagnosed with hypertrophic cardiomyopathy, we identified 2 unrelated patients (0.34%), both with the GLA mutation encoding P.N215S, the most common mutation causing later-onset Fabry disease phenotype. These patients were both asymptomatic, a man aged 53 years and a woman aged 69 years, and demonstrated a mild cardiac phenotype with symmetric distribution of left ventricular hypertrophy. After family screening, a total of 27 new Fabry disease patients aged 2-81 years were identified in the 2 families, including 12 individuals who are now receiving enzyme replacement therapy. CONCLUSIONS: These observations support consideration for routine prospective screening for Fabry disease in all patients without a definitive etiology for left ventriclar hypertrophy. This strategy would likely result, through cascade family testing, in the earlier identification of new Fabry disease-affected males and female heterozygotes who may benefit from monitoring and/or enzyme replacement therapy.

Death and Cardiac Arrest in U.S. Triathlon Participants, 1985 to 2016: A Case Series.

BACKGROUND: Reports of race-related triathlon fatalities have raised questions regarding athlete safety. OBJECTIVE: To describe death and cardiac arrest among triathlon participants. DESIGN: Case series. SETTING: United States. PARTICIPANTS: Participants in U.S. triathlon races from 1985 to 2016. MEASUREMENTS: Data on deaths and cardiac arrests were assembled from such sources as the U.S. National Registry of Sudden Death in Athletes (which uses news media, Internet searches, LexisNexis archival databases, and news clipping services) and USA Triathlon (USAT) records. Incidence of death or cardiac arrest in USAT-sanctioned races from 2006 to 2016 was calculated. RESULTS: A total of 135 sudden deaths, resuscitated cardiac arrests, and trauma-related deaths were compiled; mean (±SE) age of victims was 46.7 ± 12.4 years, and 85% were male. Most sudden deaths and cardiac arrests occurred in the swim segment (n = 90); the others occurred during bicycling (n = 7), running (n = 15), and postrace recovery (n = 8). Fifteen trauma-related deaths occurred during the bike segment. Incidence of death or cardiac arrest among USAT participants (n = 4 776 443) was 1.74 per 100 000 (2.40 in men and 0.74 in women per 100 000; P < 0.001). In men, risk increased substantially with age and was much greater for those aged 60 years and older (18.6 per 100 000 participants). Death or cardiac arrest risk was similar for short, intermediate, and long races (1.61 vs. 1.41 vs. 1.92 per 100 000 participants). At autopsy, 27 of 61 decedents (44%) had clinically relevant cardiovascular abnormalities, most frequently atherosclerotic coronary disease or cardiomyopathy. LIMITATIONS: Case identification may be incomplete and may underestimate events, particularly in the early study period. In addition, prerace medical history is unknown in most cases. CONCLUSION: Deaths and cardiac arrests during the triathlon are not rare; most have occurred in middle-aged and older men. Most sudden deaths in triathletes happened during the swim segment, and clinically silent cardiovascular disease was present in an unexpected proportion of decedents. PRIMARY FUNDING SOURCE: Minneapolis Heart Institute Foundation.

Lack of Phenotypic Differences by Cardiovascular Magnetic Resonance Imaging in MYH7 (ß-Myosin Heavy Chain)- Versus MYBPC3 (Myosin-Binding Protein C)-Related Hypertrophic Cardiomyopathy.

BACKGROUND: The 2 most commonly affected genes in hypertrophic cardiomyopathy (HCM) are MYH7 (ß-myosin heavy chain) and MYBPC3 (ß-myosin-binding protein C). Phenotypic differences between patients with mutations in these 2 genes have been inconsistent. Scarce data exist on the genotype-phenotype association as assessed by tomographic imaging using cardiac magnetic resonance imaging. METHODS AND RESULTS: Cardiac magnetic resonance imaging was performed on 358 consecutive genotyped hypertrophic cardiomyopathy probands at 5 tertiary hypertrophic cardiomyopathy centers. Genetic testing revealed a pathogenic mutation in 159 patients (44.4%). The most common genes identified were MYH7 (n=53) and MYBPC3 (n=75); 33.1% and 47% of genopositive patients, respectively. Phenotypic characteristics by cardiac magnetic resonance imaging of these 2 groups were similar, including left ventricular volumes, mass, maximal wall thickness, morphology, left atrial volume, and mitral valve leaflet lengths (all P=non-significant). The presence of late gadolinium enhancement (65% versus 64%; P=0.99) and the proportion of total left ventricular mass (%late gadolinium enhancement; 10.4±13.2% versus 8.5±8.5%; P=0.44) were also similar. CONCLUSIONS: This multicenter multinational study shows lack of phenotypic differences between MYH7- and MYBPC3-associated hypertrophic cardiomyopathy when assessed by cardiac magnetic resonance imaging. Postmutational mechanisms appear more relevant to thick-filament disease expression and outcome than the disease-causing variant per se.

Ventricular Tachyarrhythmias in Patients With Hypertrophic Cardiomyopathy and Defibrillators: Triggers, Treatment, and Implications.

INTRODUCTION: Triggers and ICD interventions of ventricular arrhythmias in patients with hypertrophic cardiomyopathy (HCM) offer insight into mechanisms and treatment. METHODS AND RESULTS: Intracardiac ICD electrograms from 71 HCM patients in the HCM I and II studies were analyzed by three individuals. Rhythms were defined as VF (polymorphic ventricular arrhythmia), VT (monomorphic ventricular tachycardia), and ventricular flutter (VFL; VT ≥ 240 bpm). Physical activity and rhythm preceding the arrhythmia were ascertained. Of 149 arrhythmias, VF was present in 74, VT in 57, and VFL in 18. In those whose activity was known, moderate or intense physical activity was associated with over 50% of the tachycardias (57 of 111). Rhythms preceding ventricular arrhythmias were often sinus tachycardia (49 of 149; 33%) or rapid atrial fibrillation (7 of 149; 5%). VF and VFL were more likely preceded by supraventricular rhythms >100 bpm (30 of 68 with VF; 44%; 12 of 16 with VFL 75%, vs. 14 of 50 with VT 28%; P = 0.001). Antitachycardia pacing (ATP) was successful in 39 of 53 (74%). Multiple shocks were more often required to terminate VFL (10 of 18; 56%) compared to VF (10 of 72; 14%) and VT (2 of 25; 8%; P < 0.0001). Of arrhythmias requiring more than one shock to terminate, 16 of 22 were preceded by sinus tachycardia and/or moderate or extreme physical activity. CONCLUSIONS: Rapid supraventricular rhythms, and at least moderate activity, frequently precede VT and VF, and when they occur in these situations often require multiple ICD shocks to restore sinus rhythm. ATP is successful in terminating VT and VFL, and should be a programmed in all HCM patients with ICDs.

Hypertrophic Cardiomyopathy With Left Ventricular Apical Aneurysm: Implications for Risk Stratification and Management.

BACKGROUND: A previously under-recognized subset of hypertrophic cardiomyopathy (HCM) patients with left ventricular (LV) apical aneurysms is being identified with increasing frequency. However, risks associated with this subgroup are unknown. OBJECTIVES: The authors aimed to clarify clinical course and prognosis of a large cohort of HCM patients with LV apical aneurysms over long-term follow-up. METHODS: The authors retrospectively analyzed 1,940 consecutive HCM patients at 2 centers, 93 of which (4.8%) were identified with LV apical aneurysms; mean age was 56 ± 13 years, and 69% were male. RESULTS: Over 4.4 ± 3.2 years, 3 of the 93 patients with LV apical aneurysms (3%) died suddenly or of heart failure, but 22 (24%) survived with contemporary treatment interventions: 18 experienced appropriate implantable cardioverter-defibrillator discharges, 2 underwent heart transplants, and 2 were resuscitated after cardiac arrest. The sudden death (SD) event rate was 4.7%/year, which includes sudden death, successful resuscitation from cardiac arrest or appropriate ICD interventions triggered by VF or rapid VT. Notably, recurrent monomorphic ventricular tachycardia requiring ≥2 implantable cardioverter-defibrillator shocks occurred in 13 patients, including 6 who underwent successful radiofrequency ablation of the arrhythmic focus without ventricular tachycardia recurrence. Five non-anticoagulated patients experienced nonfatal thromboembolic events (1.1%/year), whereas 13 with apical clots and anticoagulation did not incur embolic events. There was no consistent relationship between aneurysm size and adverse HCM-related events. Rate of HCM-related deaths combined with life-saving aborted disease-related events was 6.4%/year, 3-fold greater than the 2.0%/year event rate in 1,847 HCM patients without aneurysms (p < 0.001). CONCLUSIONS: HCM patients with LV apical aneurysms are at high risk for arrhythmic sudden death and thromboembolic events. Identification of this phenotype expands risk stratification and can lead to effective treatment interventions for potentially life-threatening complications.

Demographics and Epidemiology of Sudden Deaths in Young Competitive Athletes: From the United States National Registry.

BACKGROUND: Sudden deaths in young competitive athletes are tragic events, with high public visibility. The importance of race and gender with respect to sport and the diagnosis and causes of sudden death in athletes has generated substantial interest. METHODS: The US National Registry of Sudden Death in Athletes, 1980-2011, was accessed to define the epidemiology and causes of sudden deaths in competitive athletes. A total of 2406 deaths were identified in young athletes aged 19 ± 6 years engaged in 29 diverse sports. RESULTS: Among the 842 athletes with autopsy-confirmed cardiovascular diagnoses, the incidence in males exceeded that in females by 6.5-fold (1:121; 691 vs 1:787,392 athlete-years; P ≤.001). Hypertrophic cardiomyopathy was the single most common cause of sudden death, occurring in 302 of 842 athletes (36%) and accounting for 39% of male sudden deaths, almost 4-fold more common than among females (11%; P ≤.001). More frequent among females were congenital coronary artery anomalies (33% vs 17% of males; P ≤.001), arrhythmogenic right ventricular cardiomyopathy (13% vs 4%; P = .002), and clinically diagnosed long QT syndrome (7% vs 1.5%; P ≤.002). The cardiovascular death rate among African Americans/other minorities exceeded whites by almost 5-fold (1:12,778 vs 1:60; 746 athlete-years; P <.001), and hypertrophic cardiomyopathy was more common among African Americans/other minorities (42%) than in whites (31%; P ≤.001). Male and female basketball players were 3-fold more likely to be African American/other minorities than white. CONCLUSIONS: Within this large forensic registry of competitive athletes, cardiovascular sudden deaths due to genetic and/or congenital heart diseases were uncommon in females and more common in African Americans/other minorities than in whites. Hypertrophic cardiomyopathy is an under-appreciated cause of sudden death in male minority athletes.

Relation of Doppler Tissue Imaging Parameters With Heart Failure Progression in Hypertrophic Cardiomyopathy.

Refractory progressive heart failure (HF) is becoming the predominant cause of mortality in nonobstructive hypertrophic cardiomyopathy (HC). To anticipate development of this important and often unpredictable clinical course, we investigated whether left ventricular diastolic dysfunction, assessed by echocardiographic Doppler parameters, could identify a subset of patients with HC without obstruction at rest who would experience progression of HF. Diastolic function parameters, assessed by Doppler tissue imaging (DTI), mitral inflow, and pulmonary venous flow were measured in 274 consecutive adult patients with HC evaluated from 2003 to 2007. DTI and other diastolic and clinical/demographic parameters were measured against the composite end point of HF/death, heart transplantation, or progression to advanced New York Heart Association functional class III/IV symptoms and sudden death (SD)/implantable defibrillator (ICD) interventions. HF end points were reached in 19 of 274 patients (7%) over a follow-up period of 4.0 ± 2.3 years. Variables significantly associated with HF outcome by univariate analysis included male gender, initial New York Heart Association class II, lower ejection fraction, and reduced septal and lateral e' mitral annular tissue velocities. Multivariable analysis showed only a reduced lateral e' mitral annular tissue velocity to be independently associated with the composite HF end points (HR 0.77; 95% CI 0.65 to 0.91; p = 0.003). In addition, estimated pulmonary arterial systolic pressure and extensive late gadolinium enhancement by magnetic resonance were also associated with HF outcome (p = 0.04 and p <0.001, respectively). No Doppler (or clinical) variable was associated with SD/appropriate ICD interventions. In conclusion, in HC without outflow obstruction at rest, diastolic dysfunction, evidenced by DTI-reduced lateral e' mitral annular tissue velocity, was associated with adverse long-term HF outcome but was unrelated to SD. This echocardiographic marker provides a potential noninvasive strategy for anticipating progressive HF in this HC patient group.

Comparison of the Frequency of Sudden Cardiovascular Deaths in Young Competitive Athletes Versus Nonathletes: Should We Really Screen Only Athletes?

The issue of sudden death in young athletes and consideration for the most practical and optimal strategy to identify those genetic and/or congenital heart diseases responsible for these tragic events continues to be debated. However, proponents of broad-based and mandatory national preparticipation screening, including with 12-lead electrocardiograms have confined the focus to a relatively small segment of the youthful population who choose to engage in competitive athletic programs at the high school, college, and elite-professional level. Therefore, lost in this discussion of preparticipation screening of athletes is that the larger population of young people not involved in competitive sports (and, therefore, a priori are excluded from systematic screening) who nevertheless may die suddenly of the same cardiovascular diseases as athletes. To substantiate this hypothesis, we accessed the forensic Hennepin County, Minnesota registry in which cardiovascular sudden deaths were 8-fold more common in nonathletes (n = 24) than athletes (n = 3) and threefold more frequent in terms of incidence. The most common diseases responsible for sudden death were hypertrophic cardiomyopathy (n = 6) and arrhythmogenic right ventricular cardiomyopathy (n = 4). These data raise ethical considerations inherent in limiting systematic screening for unsuspected genetic and/or congenital heart disease to competitive athletes.

Significance of Late Gadolinium Enhancement at Right Ventricular Attachment to Ventricular Septum in Patients With Hypertrophic Cardiomyopathy.

Cardiovascular magnetic resonance (CMR) with extensive late gadolinium enhancement (LGE) is a novel marker for increased risk for sudden death (SD) in patients with hypertrophic cardiomyopathy (HC). Small focal areas of LGE confined to the region of right ventricular (RV) insertion to ventricular septum (VS) have emerged as a frequent and highly visible CMR imaging pattern of uncertain significance. The aim of this study was to evaluate the prognostic significance of LGE confined to the RV insertion area in patients with HC. CMR was performed in 1,293 consecutive patients with HC from 7 HC centers, followed for 3.4 ± 1.7 years. Of 1,293 patients (47 ± 14 years), 134 (10%) had LGE present only in the anterior and/or inferior areas of the RV insertion to VS, occupying 3.7 ± 2.9% of left ventricular myocardium. Neither the presence nor extent of LGE in these isolated areas was a predictor of adverse HC-related risk, including SD (adjusted hazard ratio 0.82, 95% confidence interval 0.45 to 1.50, p = 0.53; adjusted hazard ratio 1.16/10% increase in LGE, 95% confidence interval 0.29 to 4.65, p = 0.83, respectively). Histopathology in 20 HC hearts show the insertion areas of RV attachment to be composed of a greatly expanded extracellular space characterized predominantly by interstitial-type fibrosis and interspersed disorganized myocyte patterns and architecture. In conclusion, LGE confined to the insertion areas of RV to VS was associated with low risk of adverse events (including SD). Gadolinium pooling in this region of the left ventricle does not reflect myocyte death and repair with replacement fibrosis or scarring.

Prognostic value of quantitative contrast-enhanced cardiovascular magnetic resonance for the evaluation of sudden death risk in patients with hypertrophic cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is the most common cause of sudden death in the young, although not all patients eligible for sudden death prevention with an implantable cardioverter-defibrillator are identified. Contrast-enhanced cardiovascular magnetic resonance with late gadolinium enhancement (LGE) has emerged as an in vivo marker of myocardial fibrosis, although its role in stratifying sudden death risk in subgroups of HCM patients remains incompletely understood. METHODS AND RESULTS: We assessed the relation between LGE and cardiovascular outcomes in 1293 HCM patients referred for cardiovascular magnetic resonance and followed up for a median of 3.3 years. Sudden cardiac death (SCD) events (including appropriate defibrillator interventions) occurred in 37 patients (3%). A continuous relationship was evident between LGE by percent left ventricular mass and SCD event risk in HCM patients (P=0.001). Extent of LGE was associated with an increased risk of SCD events (adjusted hazard ratio, 1.46/10% increase in LGE; P=0.002), even after adjustment for other relevant disease variables. LGE of ≥15% of LV mass demonstrated a 2-fold increase in SCD event risk in those patients otherwise considered to be at lower risk, with an estimated likelihood for SCD events of 6% at 5 years. Performance of the SCD event risk model was enhanced by LGE (net reclassification index, 12.9%; 95% confidence interval, 0.3-38.3). Absence of LGE was associated with lower risk for SCD events (adjusted hazard ratio, 0.39; P=0.02). Extent of LGE also predicted the development of end-stage HCM with systolic dysfunction (adjusted hazard ratio, 1.80/10% increase in LGE; P<0.03). CONCLUSIONS: Extensive LGE measured by quantitative contrast enhanced CMR provides additional information for assessing SCD event risk among HCM patients, particularly patients otherwise judged to be at low risk.

Significance of sarcomere gene mutations analysis in the end-stage phase of hypertrophic cardiomyopathy.

End-stage hypertrophic cardiomyopathy (ES-HC) has an ominous prognosis. Whether genotype can influence ES-HC occurrence is unresolved. We assessed the spectrum and clinical correlates of HC-associated mutations in a large multicenter cohort with end-stage ES-HC. Sequencing analysis of 8 sarcomere genes (MYH7, MYBPC3, TNNI3, TNNT2, TPM1, MYL2, MYL3, and ACTC1) and 2 metabolic genes (PRKAG2 and LAMP2) was performed in 156 ES-HC patients with left ventricular (LV) ejection fraction (EF) <50%. A comparison among mutated and negative ES-HC patients and a reference cohort of 181 HC patients with preserved LVEF was performed. Overall, 131 mutations (36 novel) were identified in 104 ES-HC patients (67%) predominantly affecting MYH7 and MYBPC3 (80%). Complex genotypes with double or triple mutations were present in 13% compared with 5% of the reference cohort (p = 0.013). The distribution of mutations was otherwise indistinguishable in the 2 groups. Among ES-HC patients, those presenting at first evaluation before the age of 20 had a 30% prevalence of complex genotypes compared with 19% and 21% in the subgroups aged 20 to 59 and ≥60 years (p = 0.003). MYBPC3 mutation carriers with ES-HC were older than patients with MYH7, other single mutations, or multiple mutations (median 41 vs 16, 26, and 28 years, p ≤0.001). Outcome of ES-HC patients was severe irrespective of genotype. In conclusion, the ES phase of HC is associated with a variable genetic substrate, not distinguishable from that of patients with HC and preserved EF, except for a higher frequency of complex genotypes with double or triple mutations of sarcomere genes.

Significance of left ventricular apical-basal muscle bundle identified by cardiovascular magnetic resonance imaging in patients with hypertrophic cardiomyopathy.

AIMS: Cardiovascular magnetic resonance (CMR) has improved diagnostic and management strategies in hypertrophic cardiomyopathy (HCM) by expanding our appreciation for the diverse phenotypic expression. We sought to characterize the prevalence and clinical significance of a recently identified accessory left ventricular (LV) muscle bundle extending from the apex to the basal septum or anterior wall (i.e. apical-basal). METHODS AND RESULTS: CMR was performed in 230 genotyped HCM patients (48 ± 15 years, 69% male), 30 genotype-positive/phenotype-negative (G+/P-) family members (32 ± 15 years, 30% male), and 126 controls. Left ventricular apical-basal muscle bundle was identified in 145 of 230 (63%) HCM patients, 18 of 30 (60%) G+/P- family members, and 12 of 126 (10%) controls (G+/P- vs. controls; P < 0.01). In HCM patients, the prevalence of an apical-basal muscle bundle was similar among those with disease-causing sarcomere mutations compared with patients without mutation (64 vs. 62%; P = 0.88). The presence of an LV apical-basal muscle bundle was not associated with LV outflow tract obstruction (P = 0.61). In follow-up, 33 patients underwent surgical myectomy of whom 22 (67%) were identified to have an accessory LV apical-basal muscle bundle, which was resected in all patients. CONCLUSION: Apical-basal muscle bundles are a unique myocardial structure commonly present in HCM patients as well as in G+/P- family members and may represent an additional morphologic marker for HCM diagnosis in genotype-positive status.

Strategies for assessing the prevalence of cardiovascular sudden deaths in young competitive athletes.

BACKGROUND/OBJECTIVES: Prevalence/incidence of sudden death due to cardiovascular disease in young competitive athletes has become an important part of the debate over the most effective and practical preparticipation screening strategies for this population. Since event reporting is not mandatory, identification of cases has been achieved largely through publicly available data and internet searches. The accuracy of this methodology has not been studied and deserves scrutiny. METHODS: We assessed recognition of sudden cardiovascular deaths in college (NCAA) athletes with the U.S. National Registry of Sudden Death in Athletes that uses largely public domain sources, and also the NCAA Memorial Resolutions List. RESULTS: For 2002-2011, 64 total sudden death cases were identified by both sources. The Registry identified 56 cases (88%), including 14 not found in the NCAA List. The NCAA List identified 50 cases (78%), including 8 unrecognized by the Registry (p=0.16). Failure to initially recognize these 8 deaths using established Registry search mechanisms was due to the absence of key search terms in media reports. Cases not identified by the 2 methodologies did not differ significantly regarding demographics, cause of death, or sport. CONCLUSIONS: Internet-based, public domain methodology is useful and identified more cases of sudden cardiovascular death in college athletes than did the internal list provided by the NCAA. Nevertheless, these findings support the principle that multiple sources are additive and beneficial in identifying the maximum number of sudden death events.

Incidence and causes of sudden death in U.S. college athletes.

OBJECTIVES: The goal of this study was to reliably define the incidence and causes of sudden death in college student-athletes. BACKGROUND: The frequency with which cardiovascular-related sudden death occurs in competitive athletes importantly influences considerations for pre-participation screening strategies. METHODS: We assessed databases (including autopsy reports) from both the U.S. National Registry of Sudden Death in Athletes and the National Collegiate Athletic Association (2002 to 2011). RESULTS: Over the 10-year study period, 182 sudden deaths occurred (age 20 ± 1.7 years; 85% male; 64% white), 52 resulting from suicide (n = 31) or drug abuse (n = 21) and 64 probably or likely attributable to cardiovascular causes (6/year). Of these 64 athletes, 47 had a confirmed post-mortem diagnosis; the most common were hypertrophic cardiomyopathy in 21 and congenital coronary anomalies in 8. The 4,052,369 athlete participations (in 30 sports over 10 years) incurred mortality risks as follows: suicide and drugs combined, 1.3/100,000 athlete participation-years (5 deaths/year); and documented cardiovascular disease, 1.2/100,000 athlete participation-years (4 deaths/year). Notably, cardiovascular deaths were 5-fold more common in African-American athletes than in white athletes (3.8 vs. 0.7/100,000 athlete participation-years; p < 0.01) but did not differ from the general population of the same age and race (p = 0.6). CONCLUSIONS: In college student-athletes, risk of sudden death due to cardiovascular disease is relatively low, with mortality rates similar to suicide and drug abuse, but less than expected in the general population, although highest in African-American athletes. A substantial minority of confirmed cardiovascular deaths would not likely have been reliably detected by pre-participation screening with 12-lead electrocardiograms.

Risk of sudden death and outcome in patients with hypertrophic cardiomyopathy with benign presentation and without risk factors.

Patients with hypertrophic cardiomyopathy (HC) are reported to have a mortality rate of about 1.0% per year, and those patients without sudden death risk factors and with no or mild symptoms are generally considered to have a benign clinical presentation. However, the risk of sudden death and the outcome in this latter subgroup have not been investigated systematically and remain unresolved. We assessed the risk of sudden death and outcome in 653 consecutive patients with HC without risk factors and with no or mild symptoms. Over a median follow-up of 5.3 years, 35 patients (5.4%) died of HC-related causes. Mean age at death was 46 ± 20 years in patients who died suddenly and 66 ± 15 and 72 ± 9 years, respectively, in patients who died of heart failure or stroke. Event rate was 0.6% per year for sudden death, 0.2% per year for heart failure death, and 0.1% per year for stroke-related death. Sudden death risk was independently and inversely related to age, and risk of heart failure or stroke death was directly related to age (p = 0.020). At 10 years after the initial evaluation, sudden death risk was 5.9%, with sudden death rate being the lowest (0.3% per year) in patients with normal left atrial dimension (≤40 mm). In conclusion, in patients with HC without conventional risk factors and with no or mild symptoms, the risk of sudden death was not negligible, with an event rate of 0.6% per year. Heart failure and stroke-related death were less common and largely confined to older patients. These results underscore the need for a more accurate assessment of the sudden death risk in patients with HC.

Left atrial remodeling in hypertrophic cardiomyopathy and susceptibility markers for atrial fibrillation identified by cardiovascular magnetic resonance.

In hypertrophic cardiomyopathy (HC), atrial fibrillation (AF) is an important determinant of clinical deterioration due to heart failure or embolic stroke. This study characterizes left atrial (LA) structural and functional parameters to establish markers predictive of AF risk, using cardiovascular magnetic resonance (CMR) imaging. We studied 427 consecutive patients with HC in sinus rhythm with CMR (age 44±18 years), including 41 who developed clinically overt AF after study entry (2.6±2.1 years), 49 patients with AF before CMR, 337 patients with HC but without AF, and 244 normal controls. LA chamber was assessed for absolute and indexed end-diastolic volume (LAEDV), end-systolic volume, and percent ejection fraction (LAEF). In the 41 prospectively studied patients with HC who developed AF during follow-up, LAEDV was significantly greater than in patients without AF (146±48 vs 107±37 ml) or in normal controls (81±24 ml, p<0.001). Percent LAEF was lower in patients developing AF (36±10%) than without AF (46±12%) or controls (55±9%, p<0.001). Multivariate analysis identified LAEF (<38%), LAEDV (≥118 ml), and age (≥40 years) as independently associated with AF occurrence. In conclusion, CMR measures of LA remodeling and dysfunction reliably identified patients with HC at risk for future development of AF. Decrease in LAEF represents a strong novel marker of susceptibility to AF in this disease.

Obesity and its association to phenotype and clinical course in hypertrophic cardiomyopathy.

OBJECTIVES: This study sought to assess the impact of body mass index (BMI) on cardiac phenotypic and clinical course in a multicenter hypertrophic cardiomyopathy (HCM) cohort. BACKGROUND: It is unresolved whether clinical variables promoting left ventricular (LV) hypertrophy in the general population, such as obesity, may influence cardiac phenotypic and clinical course in patients with HCM. METHODS: In 275 adult HCM patients (age 48 ± 14 years; 70% male), we assessed the relation of BMI to LV mass, determined by cardiovascular magnetic resonance (CMR) and heart failure progression. RESULTS: At multivariate analysis, BMI proved independently associated with the magnitude of hypertrophy: pre-obese and obese HCM patients (BMI 25 to 30 kg/m(2) and >30 kg/m(2), respectively) showed a 65% and 310% increased likelihood of an LV mass in the highest quartile (>120 g/m(2)), compared with normal weight patients (BMI <25 kg/m(2); hazard ratio [HR]: 1.65; 95% confidence interval [CI]: 0.73 to 3.74, p = 0.22 and 3.1; 95% CI: 1.42 to 6.86, p = 0.004, respectively). Other features associated with LV mass >120 g/m(2) were LV outflow obstruction (HR: 4.9; 95% CI: 2.4 to 9.8; p < 0.001), systemic hypertension (HR: 2.2; 95% CI: 1.1 to 4.5; p = 0.026), and male sex (HR: 2.1; 95% CI: 0.9 to 4.7; p = 0.083). During a median follow-up of 3.7 years (interquartile range: 2.5 to 5.3), obese patients showed an HR of 3.6 (95% CI: 1.2 to 10.7, p = 0.02) for developing New York Heart Association (NYHA) functional class III to IV symptoms compared to nonobese patients, independent of outflow obstruction. Noticeably, the proportion of patients in NYHA functional class III at the end of follow-up was 13% among obese patients, compared with 6% among those of normal weight (p = 0.03). CONCLUSIONS: In HCM patients, extrinsic factors such as obesity are independently associated with increase in LV mass and may dictate progression of heart failure symptoms.

Risk stratification and outcome of patients with hypertrophic cardiomyopathy >=60 years of age.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is prominently associated with risk for sudden death and disease progression, largely in young patients. Whether patients of more advanced age harbor similar risks is unresolved, often creating clinical dilemmas, particularly in decisions for primary prevention of sudden death with implantable defibrillators. METHODS AND RESULTS: We studied 428 consecutive HCM patients presenting at ≥60 years of age and followed for 5.8±4.8 years; 53% were women. Of the 428 patients, 279 (65%) survived to 73±7 years of age (range, 61-96 years), most (n=245, 88%) with no/mild symptoms, including 135 with ≥1 conventional sudden death risk factors and 50 (37%) with late gadolinium enhancement. Over follow-up, 149 (35%) died at 80±8 years of age, mostly from non-HCM-related causes (n=133, 31%), including a substantial proportion from noncardiac disease (n=54). Sixteen patients (3.7%) had HCM-related mortality events (0.64%/y), including embolic stroke (n=6), progressive heart failure or transplantation (n=3), postoperative complications (n=2), and arrhythmic sudden death events (n=5, 1.2% [0.20%/y]). All-cause mortality was increased in HCM patients ≥60 years of age compared with an age-matched US general population, predominantly as a result of non-HCM-related diseases (P<0.001; standard mortality ratio, 1.5). CONCLUSIONS: HCM patients surviving into the seventh decade of life are at low risk for disease-related morbidity/mortality, including sudden death, even with conventional risk factors. These data do not support aggressive prophylactic defibrillator implantation at advanced ages in HCM. Other cardiac or noncardiac comorbidities have a greater impact on survival than HCM in older patients.