Arrhythmogenic Mitral Valve Prolapse Revisited: A Not Uncommon Cause of Youthful Sudden Death in Athletes and Women.

BACKGROUND: Sudden deaths (SD) in young people including competitive athletes, albeit uncommon, are usually attributable to genetic, congenital or acquired cardiovascular conditions. However, it is under-appreciated that mitral valve prolapse (MVP), a relatively common valvular heart disease, is associated with SD in this youthful population. METHODS: Forty-three MVP-related SDs are identified from 2 large cardiovascular registries with pathologic, clinical, and demographic findings reported. RESULTS: Events occurred in both genders, but females were unexpectedly common (49%); median age was 22 ± 8 years, and 29 (67%) were engaged in competitive sports, including 17 with preparticipation examination. Of the 43 MVP cases, 21 died suddenly during or just after vigorous exercise including 6 during organized sports. Sixteen (37%) had been evaluated by a cardiologist resulting in confirmed MVP diagnosis in 11.. Pathologic findings characteristic of MVP included: bileaflet myxomatous involvement in all cases; and areas of interstitial or replacement myocardial fibrosis in 79%, most evident in posterolateral left ventricular wall. CONCLUSIONS: Arrhythmogenic myxomatous degeneration (MVP) is an under-recognized cause of SD in young people including competitive athletes, disproportionally affecting females and requiring requires a high index of clinical suspicion. Frequency of left ventricular fibrosis in these young people with MVP suggests a mechanism for ventricular tachyarrhythmias and SD, relevant to future risk stratification.

Analysis of risk stratification and prevention of sudden death in pediatric patients with hypertrophic cardiomyopathy: Dilemmas and clarity.

Hypertrophic cardiomyopathy (HCM) has been considered the most common cause of sudden death (SD) in the young. However, introduction of implantable cardioverter-defibrillators (ICDs) in HCM has proved highly effective and the mainstay of preventing SD in children, adolescents, and adults by terminating malignant ventricular tachyarrhythmias. Nevertheless, ICD decision making is generally regarded as more difficult in pediatrics, and the strategy for selecting ICD patients from this population remains without consensus. Prospective studies in HCM children and adolescents have shown the American Heart Association/American College of Cardiology traditional major risk marker strategy to be reliable with >90% sensitivity in selecting patients for SD prevention. International data in >2000 young HCM patients assembled over 20 years who were stratified by major risk markers showed ICDs effectively prevented SD in 20%. Alternatively, novel quantitative risk scoring initiatives provide 5-year risk estimates that are potentially useful as adjunctive tools to facilitate discussion of prophylactic ICD risks vs benefit but are as yet unsupported by prospective outcome studies. Risk scoring strategies are characterized by reasonable discriminatory statistical power (C-statistic 0.69-0.76) for identifying patients with SD events but with relatively low sensitivity, albeit with specificity comparable with the risk marker strategy. While some reticence for obligating healthy-appearing young patients to lifelong device implants is understandable, underutilization of the ICD in high-risk children and adolescents can represent a lost opportunity for fulfilling the long-standing aspiration of SD prevention. This review provides a critical assessment of the current strengths and weaknesses of SD risk stratification strategies in young HCM patients in an effort to clarify clinical decision making in this challenging subpopulation.

Clinical Significance of Postoperative Atrial Fibrillation in Hypertrophic Cardiomyopathy Patients Undergoing Septal Myectomy.

BACKGROUND: The optimal management of hypertrophic cardiomyopathy (HCM) patients with postoperative atrial fibrillation (POAF) after surgical myectomy remains unknown. We sought to investigate the association between POAF and atrial fibrillation (AF) or cardioembolic events during follow-up to bridge this gap. METHODS: Patients undergoing surgical myectomy at 2 HCM referral centres in North America from 2002 to 2020 were included in this study. Patients with preoperative AF were excluded. POAF was defined as any episode of AF within 30 days after surgery. RESULTS: Of 1176 patients, 375 (31.9%) had POAF. Age (adjusted hazard ratio [HR] 1.05, 95% confidence interval [CI] 1.03-1.06; P < 0.001), premyectomy left atrial diameter (LAD; adjusted HR 1.6, 95% CI 1.32-2.02; P < 0.001), and smoking (adjusted HR 1.60, 95% CI 1.17-2.20; P = 0.001) were associated with POAF on multivariable analysis. Of 934 patients with follow-up data, of duration 4.3 ± 4.1 years, AF was detected in 86 (9.2%). Only POAF (HR 4.20, 95% CI 2.44-7.23; P < 0.001), previous history of stroke (HR 4.81, 95% CI 1.63-14.17; P = 0.01), and postmyectomy LAD (HR 1.80, 95% CI 1.21-2.70; P = 0.004) were associated with AF incidence during follow-up. Cardioembolic events occurred in only 15 patients (1.6%). POAF was not associated with increased cardioembolic risk, with only 3 patients with POAF suffering such an event, all more than 4 years after surgery. CONCLUSIONS: POAF is common in HCM patients undergoing myectomy and is a predictor of AF during follow-up. Over long-term follow-up, cardioembolic events are uncommon. These findings suggest that routine long-term anticoagulation for all HCM patients with postmyectomy AF is not justified after the initial postoperative period.

Ventricular Septal Myectomy for Obstructive Hypertrophic Cardiomyopathy (Analysis Spanning 60 Years Of Practice): AJC Expert Panel.

Surgical myectomy remains the time-honored primary treatment for hypertrophic cardiomyopathy patients with drug refractory limiting symptoms due to LV outflow obstruction. Based on >50 years experience, surgery reliably reverses disabling heart failure by permanently abolishing mechanical outflow impedance and mitral regurgitation, with normalization of LV pressures and preserved systolic function. A consortium of 10 international currently active myectomy centers report about 11,000 operations, increasing significantly in number over the most recent 15 years. Performed in experienced multidisciplinary institutions, perioperative mortality for myectomy has declined to 0.6%, becoming one of the safest currently performed open-heart procedures. Extended myectomy relieves symptoms in >90% of patients by ≥ 1 NYHA functional class, returning most to normal daily activity, and also with a long-term survival benefit; concomitant Cox-Maze procedure can reduce the number of atrial fibrillation episodes. Surgery, preferably performed in high volume clinical environments, continues to flourish as a guideline-based and preferred high benefit: low treatment risk option for adults and children with drug refractory disabling symptoms from obstruction, despite prior challenges: higher operative mortality/skepticism in 1960s/1970s; dual-chamber pacing in 1990s, alcohol ablation in 2000s, and now introduction of novel negative inotropic drugs potentially useful for symptom management.

Survival Following Alcohol Septal Ablation or Septal Myectomy for Patients With Obstructive Hypertrophic Cardiomyopathy.

BACKGROUND: There is little information regarding long-term mortality comparing the 2 most common procedures for septal reduction for obstructive hypertrophic cardiomyopathy (HCM), alcohol septal ablation (ASA), and septal myectomy. OBJECTIVES: This study sought to compare the long-term mortality of patients with obstructive HCM following septal myectomy or ASA. METHODS: We evaluated outcomes of 3,859 patients who underwent ASA or septal myectomy in 3 specialized HCM centers. All-cause mortality was the primary endpoint of the study. RESULTS: In the study cohort, 585 (15.2%) patients underwent ASA, and 3,274 (84.8%) underwent septal myectomy. Patients undergoing ASA were significantly older (median age: 63.0 years [IQR: 52.7-72.8 years] vs 53.7 years [IQR: 44.9-62.8 years]; P < 0.001) and had smaller septal thickness (19.0 mm [IQR: 17.0-22.0 mm] vs 20.0 mm [IQR: 17.0-23.0 mm]; P = 0.007). Patients undergoing ASA also had more comorbidities, including renal failure, diabetes, hypertension, and coronary artery disease. There were 4 (0.7%) early deaths in the ASA group and 9 (0.3%) in the myectomy group. Over a median follow-up of 6.4 years (IQR: 3.6-10.2 years), the 10-year all-cause mortality rate was 26.1% in the ASA group and 8.2% in the myectomy group. After adjustment for age, sex, and comorbidities, the mortality remained greater in patients having septal reduction by ASA (HR: 1.68; 95% CI: 1.29-2.19; P < 0.001). CONCLUSIONS: In patients with obstructive hypertrophic cardiomyopathy, ASA is associated with increased long-term all-cause mortality compared with septal myectomy. This impact on survival is independent of other known factors but may be influenced by unmeasured confounding patient characteristics.

Management of Hypertrophic Cardiomyopathy: JACC State-of-the-Art Review.

Hypertrophic cardiomyopathy (HCM), a relatively common, globally distributed, and often inherited primary cardiac disease, has now transformed into a contemporary highly treatable condition with effective options that alter natural history along specific personalized adverse pathways at all ages. HCM patients with disease-related complications benefit from: matured risk stratification in which major markers reliably select patients for prophylactic defibrillators and prevention of arrhythmic sudden death; low risk to high benefit surgical myectomy (with percutaneous alcohol ablation a selective alternative) that reverses progressive heart failure caused by outflow obstruction; anticoagulation prophylaxis that prevents atrial fibrillation-related embolic stroke and ablation techniques that decrease the frequency of paroxysmal episodes; and occasionally, heart transplant for end-stage nonobstructive patients. Those innovations have substantially improved outcomes by significantly reducing morbidity and HCM-related mortality to 0.5%/y. Palliative pharmacological strategies with currently available negative inotropic drugs can control symptoms over the short-term in some patients, but generally do not alter long-term clinical course. Notably, a substantial proportion of HCM patients (largely those identified without outflow obstruction) experience a stable/benign course without major interventions. The expert panel has critically appraised all available data and presented management insights and recommendations with concise principles for clinical decision-making.

Is surgical myectomy challenged by emergence of novel drug therapy with mavacamten?

For 60 years, surgical myectomy has been the definitive treatment for symptomatic obstructive hypertrophic cardiomyopathy (HCM). Myectomy provides the opportunity to reverse heart failure symptoms in the vast majority of patient with low risk when performed in experienced centers and associated with extended longevity. More recently, a novel class of negative inotropic drug therapy with mavacamten has emerged offering expanded treatment options for obstructive HCM. In the recently completed phase III clinical trial, the EXPLORER-HCM about one-third of patients on mavacamten achieved the primary end-point of subjective symptomatic improvement and increased functional capacity assessed by peak VO2. Of note, outflow gradients persistent in 43% of patients on mavacamten and 50% with symptoms consistent with NYHA class II or greater. A subset of patients also experienced significant reversible systolic dysfunction. Therefore, it is timely to place into perspective the potential role of mavacamten in context of the established low risk: high benefit of surgical myectomy for treatment of heart failure.

Impact of comorbidities on atrial fibrillation and sudden cardiac death in hypertrophic cardiomyopathy.

BACKGROUND: The impact of comorbid disease states on the development of atrial and ventricular arrhythmias in patients with hypertrophic cardiomyopathy (HCM) remains unresolved. OBJECTIVE: Evaluate the association of comorbidities linked to arrhythmias in other cardiovascular diseases (e.g., obesity, systemic hypertension, diabetes, obstructive sleep apnea, renal disorders, tobacco, and alcohol use) to atrial fibrillation (AF) and sudden cardiac death (SCD) events in a large cohort of HCM patients. METHODS: A total  of 2269 patients, 54 ± 15 years of age, 1392 males, were evaluated at the Tufts HCM Institute between 2004 and 2018 and followed for an average of 4 ± 3 years for new-onset clinical AF and SCD events (appropriate defibrillation for ventricular tachyarrhythmias, resuscitated cardiac arrest, or SCD). RESULTS: One or more comorbidity was present in 75% of HCM patients, including 50% with ≥2 comorbidities, most commonly obesity (body mass index [BMI] ≥ 30 kg/m2 ) in 43%. New-onset atrial fibrillation developed in 11% of our cohort (2.6%/year). On univariate analysis, obesity was associated with a 1.7-fold increased risk for AF (p = .03) with 12% of obese patients developing AF (3.3%/year) as compared to 7% of patients with BMI < 25 kg/m2 (1.6%/year; p = .006). On multivariate analysis, age and LA transverse dimension emerged as the only variables predictive of AF. Comorbidities, including obesity, were not independently associated with AF development (p > .10 for each). SCD events occurred in 3.3% of patients (0.8%/year) and neither obesity nor other comorbidities were associated with increased risk for SCD (p > .10 for each). CONCLUSIONS: In adult HCM patients comorbidities do not appear to impact AF or SCD risk. Therefore, for most patients with HCM, adverse disease related events of AF and SCD appear to be primarily driven by underlying left ventricular and atrial myopathy as opposed to comorbidities.

Outcomes Over Follow-up ≥10 Years After Surgical Myectomy for Symptomatic Obstructive Hypertrophic Cardiomyopathy.

For over 50 years, surgical septal myectomy has been the preferred treatment for drug-refractory heart failure symptoms in obstructive hypertrophic cardiomyopathy (HCM). However, given the relatively youthful adult ages at which HCM surgery is usually performed, it is informative to evaluate longer-term results of myectomy after ≥10 years. We identified 139 consecutive obstructive HCM patients (50 ± 15 years of age; 55% men) who underwent surgical myectomy, 2003 to 2010 at Tufts HCM Center and followed 11.3 ± 2.7 years (range to 17). Operative mortality was low (0.6%) and left ventricular (LV) outflow gradients at rest were reduced from 56 ± 40 mm Hg preoperatively to 1 ± 7 mm Hg postoperatively, durable over the study period, with no patient requiring reoperation for the residual gradient. Over follow-up, 129 of 139 patients (93%) were alive ≥10 years after myectomy, including 17 patients ≥15 years. Of 118 patients with complete long-term clinical follow-up data, 109 (92%) experienced clinical improvement to New York Heart Association classes I or II. In 9 patients (8%) refractory class III/IV symptoms reoccurred 6.6 ± 3.9 years postoperatively, including 4 who ultimately underwent a heart transplant. After myectomy, there were 2 late HCM-related deaths, but none suddenly; notably 6 patients (12%) with prophylactic implantable cardioverter-defibrillators experienced appropriate therapy terminating ventricular tachycardia/ventricular fibrillation after myectomy. Survival following myectomy was 91% at 10 years (95% confidence interval: 85, 96%) not different from the age- and gender-matched general United States population (log-rank p = 0.64). In conclusion, myectomy provides permanent abolition of outflow gradients with reversal of heart failure and highly favorable long-term survival, representing a low-risk:high-benefit option when performed in experienced HCM centers. Myectomy did not protect absolutely against arrhythmic sudden death events, underscoring the importance of risk stratification in operative patients.

Cardiovascular Diseases That Have Emerged From the Darkness.

It is important for both the patient and physician communities to have timely access to information recognizing rapid progress in the diagnosis and treatment of familiar but relatively uncommon cardiovascular diseases. Patients with 3 cardiovascular diseases (ie, hypertrophic cardiomyopathy, pulmonary arterial hypertension, and transthyretin (TTR) cardiac amyloidosis (ATTR)]), once considered rare without effective management options and associated with malignant prognosis, have now benefited substantially from the development of a variety of innovative therapeutic strategies. In addition, in each case, enhanced diagnostic testing has expanded the patient population and allowed for more widespread administration of contemporary treatments. In hypertrophic cardiomyopathy, introduction of implantable defibrillators to prevent sudden death as well as high-benefit:low-risk septal reduction therapies to reverse heart failure have substantially reduced morbidity and disease-related mortality (to 0.5% per year). For pulmonary arterial hypertension, a disease once characterized by a particularly grim prognosis, prospective randomized drug trials with aggressive single (or combined) pharmacotherapy have measurably improved survival and quality of life for many patients. In cardiac amyloidosis, development of disease-specific drugs can for the first time reduce morbidity and mortality, prominently with breakthrough ATTR-protein-stabilizing tafamidis. In conclusion, in less common and visible cardiovascular diseases, it is crucial to recognize substantial progress and achievement, given that penetration of such information into clinical practice and the patient community can be inconsistent. Diseases such as hypertrophic cardiomyopathy, pulmonary arterial hypertension, and ATTR cardiac amyloidosis, once linked to a uniformly adverse prognosis, are now associated with the opportunity for patients to experience satisfactory quality of life and extended longevity.

LAMP2 Cardiomyopathy: Consequences of Impaired Autophagy in the Heart.

Background Human mutations in the X-linked lysosome-associated membrane protein-2 (LAMP2) gene can cause a multisystem Danon disease or a primary cardiomyopathy characterized by massive hypertrophy, conduction system abnormalities, and malignant ventricular arrhythmias. We introduced an in-frame LAMP2 gene exon 6 deletion mutation (denoted L2Δ6) causing human cardiomyopathy, into mouse LAMP2 gene, to elucidate its consequences on cardiomyocyte biology. This mutation results in in-frame deletion of 41 amino acids, compatible with presence of some defective LAMP2 protein. Methods and Results Left ventricular tissues from L2Δ6 and wild-type mice had equivalent amounts of LAMP2 RNA, but a significantly lower level of LAMP2 protein. By 20 weeks of age male mutant mice developed left ventricular hypertrophy which was followed by left ventricular dilatation and reduced systolic function. Cardiac electrophysiology and isolated cardiomyocyte studies demonstrated ventricular arrhythmia, conduction disturbances, abnormal calcium transients and increased sensitivity to catecholamines. Myocardial fibrosis was strikingly increased in 40-week-old L2Δ6 mice, recapitulating findings of human LAMP2 cardiomyopathy. Immunofluorescence and transmission electron microscopy identified mislocalization of lysosomes and accumulation of autophagosomes between sarcomeres, causing profound morphological changes disrupting the cellular ultrastructure. Transcription profile and protein expression analyses of L2Δ6 hearts showed significantly increased expression of genes encoding activators and protein components of autophagy, hypertrophy, and apoptosis. Conclusions We suggest that impaired autophagy results in cardiac hypertrophy and profound transcriptional reactions that impacted metabolism, calcium homeostasis, and cell survival. These responses define the molecular pathways that underlie the pathology and aberrant electrophysiology in cardiomyopathy of Danon disease.

Efficacy of Combined Cox-Maze IV and Ventricular Septal Myectomy for Treatment of Atrial Fibrillation in Patients With Obstructive Hypertrophic Cardiomyopathy.

Atrial fibrillation (AF) has important clinical consequences in hypertrophic cardiomyopathy (HC). Safety and efficacy of the Cox-Maze IV procedure (when combined with ventricular septal myectomy) in patients with obstructive HC and paroxysmal AF is largely unresolved. Records of 395 consecutive HC patients (age 55 ± 13 years) who underwent septal myectomy for heart failure symptoms between 2004 and 2015 were reviewed. Sixty-two patients also had concomitant complete biatrial Cox-Maze IV for a history of symptomatic paroxysmal AF (3.0 ± 3.6 episodes) combined with myectomy comprise the study cohort. Freedom from symptomatic AF recurrences after operation was assessed. Left ventricular outflow gradients were reduced from 81 ± 28 mm Hg preoperatively to 1.2 ± 6.8 mm Hg after operation. At most recent follow-up, 53 patients (85%) were asymptomatic or mildly symptomatic. Freedom from recurrent symptomatic AF after myectomy/Cox-Maze IV was: 85% (95% confidence interval [CI] 73, 92) at 1 year, 69% (95% CI 55, 79) at 3 years, and 64% (95% CI 48, 75) at 5 years, including 34 patients (54%) who have experienced no symptomatic AF episodes for up to 8.2 years following surgery. The only clinical predictor of recurrent AF over follow-up was preoperative transverse left atrial dimension ≥45 mm (p <0.01). In conclusion, biatrial Cox-Maze IV combined with septal myectomy is associated with favorable long-term freedom from symptomatic paroxysmal AF recurrence, as well as from obstructive heart failure symptoms. These data support myectomy/Cox-Maze as an effective management option for the subgroup of HC patients with symptomatic outflow obstruction and paroxysmal AF.

There is No Reason to Adopt ECG s and Abandon American Heart Association/American College of Cardiology History and Physical Screening for Detection of Cardiovascular Disease in the Young.

See Article Williams et al.

Surgical Approaches to Hypertrophic Obstructive Cardiomyopathy.

Left ventricular outflow tract obstruction secondary to hypertrophic obstructive cardiomyopathy remains a challenging entity facing clinicians. Despite the success of invasive therapies, some clinicians remain hesitant because of early results with unacceptable morbidity and mortality rates. However, current literature strongly suggests improved short- and long-term outcomes with extended septal myectomy and alcohol septal ablation compared with patients not undergoing such interventions. This review evaluates hypertrophic obstructive cardiomyopathy treatment with a focus on short- and long-term outcomes, perioperative complications, and major tenets of surgical intervention. The data reveal mortality rates approaching zero, and perioperative complications occur infrequently. Alcohol septal ablation and extended septal myectomy both consistently decrease left ventricular outlet tract pressure gradients and result in improved functional capacity with lower New York Heart Association class and should be recommended as treatment for patients with symptoms refractory to standard medical treatment.

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.

Results of surgical septal myectomy for obstructive hypertrophic cardiomyopathy: the Tufts experience.

BACKGROUND: For over 50 years, surgical septal myectomy has been the preferred treatment for drug-refractory heart failure symptoms in patients with obstructive hypertrophic cardiomyopathy (HCM). Over this time in the United States, the majority of myectomy operations have been performed in a small number of select referral centers. METHODS: We have taken the opportunity to report results from the relatively new Tufts HCM Center and surgical program, incorporated 13 years ago, during which 507 myectomies (52±14 years of age; 56% male) were performed by one cardiothoracic surgeon, Dr. Hassan Rastegar. RESULTS: Resting left ventricular (LV) outflow gradients were reduced from 56±42 mmHg preoperatively to 1.2±6.8 mmHg on most recent echocardiogram 2.0±2.5 years after surgery, and 94% of patients showed clinical improvement to NYHA functional class I or II. The first 200 myectomies were performed without mortality or major complications. Among all patients, 30-day mortality rate was 0.8%. Over follow-up of 3.2±2.8 years, 11 patients died (four due to HCM causes) with long-term survival after myectomy of 94% at 5 years (95% CI: 89-96%) and 91% at 10 years (95% CI: 84-95%), which did not differ from the age- and gender-matched general U.S. population (log-rank P=0.9). CONCLUSIONS: This experience demonstrates that, with the appropriate support, new HCM surgical programs can provide patients successful relief of outflow obstruction, extended longevity and restored of quality of life.

Alcohol septal ablation: in which patients and why?

At present, surgical septal myectomy is regarded as the "gold standard" treatment for most patients with obstructive hypertrophic cardiomyopathy (HCM) and drug-refractory symptoms. However, the best results are obtained by those surgeons who have extensive experience with this operation at a small number of referral centers. In the mid-1990s, percutaneous alcohol septal ablation was introduced as an alternative to myectomy to reduce LV outflow gradient and heart failure symptoms in patients with obstructive HCM. However, certain features of alcohol ablation limit its applicability to carefully selected patients. Because this procedure involves the injection of 1-4 mL of 96% ethanol into a septal perforator of the left anterior coronary artery to produce a myocardial infarction (with septal thinning, outflow tract widening and gradient reduction), alcohol ablation is limited by the size and distribution of the septal perforator branches. In addition, rich blood supply from other septal branches not occluded by the balloon and from the posterior descending coronary artery may restrict myocardial ischemia to portions of the septum that do not contribute to outflow obstruction. Septal hypertrophy may be either mild or particularly marked, and abnormalities of mitral valve apparatus may also play a major role in outflow obstruction. When such features are present, alcohol-induced septal thinning is unlikely to significantly reduce the gradient. In addition, persisting uncertainties regarding the risk for ventricular tachyarrhythmias after alcohol ablation suggest this procedure should be limited to patients of advanced age, patients at unacceptable operative risk due to comorbidities, or those with strong aversion to surgery. Further progress in the treatment for patients with obstructive HCM and severe refractory symptoms will come from assuring proper patient selection for alcohol septal ablation, as well as increasing the number of surgeons and centers experienced in performing septal myectomy.

Fabry Disease in Families With Hypertrophic Cardiomyopathy: Clinical Manifestations in the Classic and Later-Onset Phenotypes.

BACKGROUND: The screening of Icelandic patients clinically diagnosed with hypertrophic cardiomyopathy resulted in identification of 8 individuals from 2 families with X-linked Fabry disease (FD) caused by GLA(α-galactosidase A gene) mutations encoding p.D322E (family A) or p.I232T (family B). METHODS AND RESULTS: Familial screening of at-risk relatives identified mutations in 16 family A members (8 men and 8 heterozygotes) and 25 family B members (10 men and 15 heterozygotes). Clinical assessments, α-galactosidase A (α-GalA) activities, glycosphingolipid substrate levels, and in vitro mutation expression were used to categorize p.D322E as a classic FD mutation and p.I232T as a later-onset FD mutation. In vitro expression revealed that p.D322E and p.I232T had α-GalA activities of 1.4% and 14.9% of the mean wild-type activity, respectively. Family A men had markedly decreased α-GalA activity and childhood-onset classic manifestations, except for angiokeratoma and cornea verticillata. Family B men had residual α-GalA activity and developed FD manifestations in adulthood. Despite these differences, all family A and family B men >30 years of age had left ventricular hypertrophy, which was mainly asymmetrical, and had similar late gadolinium enhancement patterns. Ischemic stroke and severe white matter lesions were more frequent among family A men, but neither family A nor family B men had overt renal disease. Family A and family B heterozygotes had less severe or no clinical manifestations. CONCLUSIONS: Men with classic or later-onset FD caused by GLA missense mutations developed prominent and similar cardiovascular disease at similar ages, despite markedly different α-GalA activities.