Structural abnormalities in hypertrophic cardiomyopathy beyond left ventricular hypertrophy by multimodality imaging evaluation.

BACKGROUND: Echocardiography- and cardiovascular magnetic resonance (CMR)-based studies have revealed a wide range of phenotypic manifestations in hypertrophic cardiomyopathy (HCM) apart from hypertrophy. This study sought to comprehensively describe a number of structural abnormalities in HCM beyond hypertrophy, by multimodality imaging. METHODS: A total of 100 HCM patients were prospectively enrolled, undergoing standard and contrast echocardiography, and CMR. Morphological characteristics involving mitral valve leaflets (MVL), subvalvular apparatus, and left ventricular cavity and wall were investigated. Seventy healthy volunteers served as control population. RESULTS: As assessed by echo, MVLs were longer in HCM patients than in controls (anterior method 1: 24[22,28] vs 19[18,20] mm, P < 0.01; anterior method 2: 27[24, 29] vs 21[19, 23] mm, P < 0.01; posterior: 15[12,19] vs 14[13,15] mm, P < 0.01). Abnormal chordal attachment to anterior MVL, anterior papillary muscle displacement, and accessory apical-basal muscle bundle were present in 42 (42%), 61 (61%), and 35 (35%) patients, respectively (P values vs controls <0.01); direct papillary muscle insertion into MVL and hypertrabeculation were found in two and five patients, respectively. Contrast echocardiography (n = 94) detected myocardial crypts in 15 patients (16%). Overall, 83% of HCM subjects had at least one of these phenotypic manifestations. Echocardiography and CMR agreement for MVL length was poor, while for structural characteristics was moderate to substantial (Cohen's Kappa: 0.53-1.00). Except for posterior MVL length and hypertrabeculation, the phenotypic characteristics studied had acceptable reproducibility by echocardiography and CMR. CONCLUSIONS: Structural abnormalities in HCM beyond hypertrophy are significantly common. Multimodality imaging approach to these HCM facets by echocardiography and CMR is feasible and desirable.

Coronary-artery bypass surgery in patients with left ventricular dysfunction.

BACKGROUND: The role of coronary-artery bypass grafting (CABG) in the treatment of patients with coronary artery disease and heart failure has not been clearly established. METHODS: Between July 2002 and May 2007, a total of 1212 patients with an ejection fraction of 35% or less and coronary artery disease amenable to CABG were randomly assigned to medical therapy alone (602 patients) or medical therapy plus CABG (610 patients). The primary outcome was the rate of death from any cause. Major secondary outcomes included the rates of death from cardiovascular causes and of death from any cause or hospitalization for cardiovascular causes. RESULTS: The primary outcome occurred in 244 patients (41%) in the medical-therapy group and 218 (36%) in the CABG group (hazard ratio with CABG, 0.86; 95% confidence interval [CI], 0.72 to 1.04; P=0.12). A total of 201 patients (33%) in the medical-therapy group and 168 (28%) in the CABG group died from an adjudicated cardiovascular cause (hazard ratio with CABG, 0.81; 95% CI, 0.66 to 1.00; P=0.05). Death from any cause or hospitalization for cardiovascular causes occurred in 411 patients (68%) in the medical-therapy group and 351 (58%) in the CABG group (hazard ratio with CABG, 0.74; 95% CI, 0.64 to 0.85; P<0.001). By the end of the follow-up period (median, 56 months), 100 patients in the medical-therapy group (17%) underwent CABG, and 555 patients in the CABG group (91%) underwent CABG. CONCLUSIONS: In this randomized trial, there was no significant difference between medical therapy alone and medical therapy plus CABG with respect to the primary end point of death from any cause. Patients assigned to CABG, as compared with those assigned to medical therapy alone, had lower rates of death from cardiovascular causes and of death from any cause or hospitalization for cardiovascular causes. (Funded by the National Heart, Lung, and Blood Institute and Abbott Laboratories; STICH ClinicalTrials.gov number, NCT00023595.).

Identification of a novel de novo deletion in RAF1 associated with biventricular hypertrophy in Noonan syndrome.

Biventricular hypertrophy (BVH) is a disease state characterized by the thickening of the ventricle walls. The differential diagnosis of BVH with other congenital and familial diseases in which increased ventricle wall thickness is a prominent clinical feature is fundamental due to its therapeutic and prognostic value, mainly during infancy. We describe a 2-month-old infant presenting BVH. Using exome sequencing, we identified a novel de novo 3-bp deletion in the RAF1 gene that is located in the binding active site for the 14-3-3 peptide. Based on docking calculations, we demonstrate that this novel mutation impairs protein/target binding, thus constitutively activating Ras signaling, which is a dysregulation associated with Noonan syndrome. Finally, our study underlines the importance of molecular modeling to understand the roles of novel mutations in pathogenesis.

Influence of baseline left ventricular function on the clinical outcome of surgical ventricular reconstruction in patients with ischaemic cardiomyopathy.

AIMS: The Surgical Treatment for Ischemic Heart Failure (STICH) trial demonstrated no overall benefit when surgical ventricular reconstruction (SVR) was added to coronary artery bypass grafting (CABG) in patients with ischaemic cardiomyopathy. The present analysis was to determine whether, based on baseline left ventricular (LV) function parameters, any subgroups could be identified that benefited from SVR. METHODS AND RESULTS: Among the 1000 patients enrolled, Core Lab measures of baseline LV function with adequate quality were obtained in 710 patients using echocardiography, in 352 using cardiovascular magnetic resonance, and in 344 using radionuclide imaging. The relationship between LV end-systolic volume index (ESVI), end-diastolic volume index, ejection fraction (EF), regional wall motion abnormalities, and outcome were first assessed only by echocardiographic measures, and then by 13 algorithms using a different hierarchy of imaging modalities and their quality. The median ESVI and EF were 78.0 (range: 22.8-283.8) mL/m2 and 28.0%, respectively. Hazard ratios comparing the randomized arms by subgroups of LVESVI and LVEF measured by echocardiography found that patients with smaller ventricles (LVESVI <60 mL/m2) and better LVEF (≥33%) may have benefitted by SVR, while those with larger ventricles (LVESVI >90 mL/m(2)) and lower LVEF (≤25%) did worse with SVR. Algorithms using all three imaging modalities found a weaker relationship between LV global function and the effects of SVR. The extent of regional wall motion abnormality did not influence the effects of SVR. CONCLUSIONS: Subgroup analyses of the STICH trial suggest that patients with less dilated LV and better LVEF may benefit from SVR, while those with larger LV and poorer LVEF may do worse. Clinical Trial Registration #: NCT00023595.

Colchicine for prevention of postpericardiotomy syndrome and postoperative atrial fibrillation: the COPPS-2 randomized clinical trial.

IMPORTANCE: Postpericardiotomy syndrome, postoperative atrial fibrillation (AF), and postoperative effusions may be responsible for increased morbidity and health care costs after cardiac surgery. Postoperative use of colchicine prevented these complications in a single trial. OBJECTIVE: To determine the efficacy and safety of perioperative use of oral colchicine in reducing postpericardiotomy syndrome, postoperative AF, and postoperative pericardial or pleural effusions. DESIGN, SETTING, AND PARTICIPANTS: Investigator-initiated, double-blind, placebo-controlled, randomized clinical trial among 360 consecutive candidates for cardiac surgery enrolled in 11 Italian centers between March 2012 and March 2014. At enrollment, mean age of the trial participants was 67.5 years (SD, 10.6 years), 69% were men, and 36% had planned valvular surgery. Main exclusion criteria were absence of sinus rhythm at enrollment, cardiac transplantation, and contraindications to colchicine. INTERVENTIONS: Patients were randomized to receive placebo (n=180) or colchicine (0.5 mg twice daily in patients ≥70 kg or 0.5 mg once daily in patients <70 kg; n=180) starting between 48 and 72 hours before surgery and continued for 1 month after surgery. MAIN OUTCOMES AND MEASURES: Occurrence of postpericardiotomy syndrome within 3 months; main secondary study end points were postoperative AF and pericardial or pleural effusion. RESULTS: The primary end point of postpericardiotomy syndrome occurred in 35 patients (19.4%) assigned to colchicine and in 53 (29.4%) assigned to placebo (absolute difference, 10.0%; 95% CI, 1.1%-18.7%; number needed to treat = 10). There were no significant differences between the colchicine and placebo groups for the secondary end points of postoperative AF (colchicine, 61 patients [33.9%]; placebo, 75 patients [41.7%]; absolute difference, 7.8%; 95% CI, -2.2% to 17.6%) or postoperative pericardial/pleural effusion (colchicine, 103 patients [57.2%]; placebo, 106 patients [58.9%]; absolute difference, 1.7%; 95% CI, -8.5% to 11.7%), although there was a reduction in postoperative AF in the prespecified on-treatment analysis (placebo, 61/148 patients [41.2%]; colchicine, 38/141 patients [27.0%]; absolute difference, 14.2%; 95% CI, 3.3%-24.7%). Adverse events occurred in 21 patients (11.7%) in the placebo group vs 36 (20.0%) in the colchicine group (absolute difference, 8.3%; 95% CI; 0.76%-15.9%; number needed to harm = 12), but discontinuation rates were similar. No serious adverse events were observed. CONCLUSIONS AND RELEVANCE: Among patients undergoing cardiac surgery, perioperative use of colchicine compared with placebo reduced the incidence of postpericardiotomy syndrome but not of postoperative AF or postoperative pericardial/pleural effusion. The increased risk of gastrointestinal adverse effects reduced the potential benefits of colchicine in this setting. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01552187.

Rationale and design of the COlchicine for Prevention of the Post-pericardiotomy Syndrome and Post-operative Atrial Fibrillation (COPPS-2 trial): a randomized, placebo-controlled, multicenter study on the use of colchicine for the primary prevention of the postpericardiotomy syndrome, postoperative effusions, and postoperative atrial fibrillation.

BACKGROUND: The efficacy and safety of colchicine for the primary prevention of the postpericardiotomy syndrome (PPS), postoperative effusions, and postoperative atrial fibrillation (POAF) remain uncertain. Although preliminary data from a single trial of colchicine given for 1 month postoperatively (COPPS trial) were promising, the results have not been confirmed in a large, multicenter trial. Moreover, in the COPPS trial, colchicine was given 3 days postoperatively. METHODS: The COPPS-2 study is a multicenter, double-blind, placebo-controlled randomized trial. Forty-eight to 72 hours before planned cardiac surgery, 360 patients, 180 in each treatment arm, will be randomized to receive placebo or colchicine without a loading dose (0.5 mg twice a day for 1 month in patients weighing ≥70 kg and 0.5 mg once for patients weighing <70 kg or intolerant to the highest dose). The primary efficacy end point is the incidence of PPS, postoperative effusions, and POAF at 3 months after surgery. Secondary end points are the incidence of cardiac tamponade or need for pericardiocentesis or thoracentesis, PPS recurrence, disease-related admissions, stroke, and overall mortality. CONCLUSIONS: The COPPS-2 trial will evaluate the use of colchicine for the primary prevention of PPS, postoperative effusions, and POAF, potentially providing stronger evidence to support the use of preoperative colchicine without a loading dose to prevent several postoperative complications. ClinicalTrials.gov Identifier: NCT01552187.

A contemporary European experience with surgical septal myectomy in hypertrophic cardiomyopathy.

AIMS: The recent American College of Cardiology and American Heart Association Guidelines on hypertrophic cardiomyopathy (HCM) have confirmed surgical myectomy as the gold standard for non-pharmacological treatment of obstructive HCM. However, during the last 15 years, an extensive use of alcohol septal ablation has led to the virtual extinction of myectomy programmes in several European countries. Therefore, many HCM candidates for myectomy in Europe cannot be offered the option of this procedure. The purpose of our study is to report the difficulties and results in developing a myectomy programme for HCM in a centre without previous experience with this procedure. METHODS AND RESULTS: The clinical course is reported of 124 consecutive patients with obstructive HCM and heart failure symptoms who underwent myectomy at a single European centre between 1996 and 2010. The median follow-up was 20.3 months (inter-quartile range: 3.9-40.6 months). No patients were lost to follow-up. A cumulative incidence of HCM-related death after myectomy was 0.8, 3.3, and 11.2% at 1, 5, and 10 years, respectively, including one operative death (procedural mortality 0.8%). The left ventricular (LV) outflow gradient decreased from 95 ± 36 mmHg before surgery to 12 ± 6 mmHg at most recent evaluation (P < 0.001), with none of the patients having a significant residual LV outflow gradient. Of the 97 patients in New York Heart Association functional class III-IV before surgery, 93 (96%) were in class I-II at most recent evaluation (P < 0.001). CONCLUSION: Our results show that the development of a myectomy programme at a centre without previous experience with this procedure is feasible and can lead to highly favourable clinical results.

Impact of secondary mitral valve chordal cutting on valve geometry in obstructive hypertrophic cardiomyopathy with marked septal hypertrophy.

AIMS: In patients with obstructive hypertrophic cardiomyopathy (HCM) and mild septal thickness undergoing myectomy, resecting fibrotic anterior mitral leaflet (AML) secondary chordae moves the mitral valve (MV) away from the outflow tract and ejection flow, reducing the need for a deep septal excision. Aim of the present study was to assess whether chordal resection has similarly favourable effects in patients with important hypertrophy, who represent the majority of patients with obstructive HCM. METHODS AND RESULTS: The MV position in the ventricular cavity, assessed from echocardiography as AML-annulus ratio, was compared before and after chordal resection in 150 consecutive HCM patients with important (≥20 mm) and 62 with mild (≤19 mm) septal thickness undergoing myectomy. Preoperatively, MV position was displaced towards the septum to a similar extent in both groups. Postoperatively, AML-annulus ratio increased of an equal degree in both groups, from 0.43 ± 0.05 to 0.55 ± 0.06 (P < 0.001) a 28% increase, and from 0.43 ± 0.06 to 0.55 ± 0.06 (P < 0.001) a 26% increase, respectively, indicating a similar MV shift away from the outflow tract. When AML-annulus ratio was compared in the study cohort and 124 normal subjects, MV position was within normal range in <4% of patients preoperatively and normalized in >50% postoperatively. CONCLUSIONS: In obstructive HCM, displacement of the MV apparatus into the outflow tract interferes with the ejection flow. Resection of fibrotic secondary chordae moves the MV apparatus away from the outflow tract and enlarges the outflow area independently of septal thickness, facilitating septal myectomy by reducing the need for a deep muscular excision.

Colchicine reduces postoperative atrial fibrillation: results of the Colchicine for the Prevention of the Postpericardiotomy Syndrome (COPPS) atrial fibrillation substudy.

BACKGROUND: Inflammation and pericarditis may be contributing factors for postoperative atrial fibrillation (POAF), and both are potentially affected by antiinflammatory drugs and colchicine, which has been shown to be safe and efficacious for the prevention of pericarditis and the postpericardiotomy syndrome (PPS). The aim of the Colchicine for the Prevention of the Post-Pericardiotomy Syndrome (COPPS) POAF substudy was to test the efficacy and safety of colchicine for the prevention of POAF after cardiac surgery. METHODS AND RESULTS: The COPPS POAF substudy included 336 patients (mean age, 65.7±12.3 years; 69% male) of the COPPS trial, a multicenter, double-blind, randomized trial. Substudy patients were in sinus rhythm before starting the intervention (placebo/colchicine 1.0 mg twice daily starting on postoperative day 3 followed by a maintenance dose of 0.5 mg twice daily for 1 month in patients ≥70 kg, halved doses for patients <70 kg or intolerant to the highest dose). The substudy primary end point was the incidence of POAF on intervention at 1 month. Despite well-balanced baseline characteristics, patients on colchicine had a reduced incidence of POAF (12.0% versus 22.0%, respectively; P=0.021; relative risk reduction, 45%; number needed to treat, 11) with a shorter in-hospital stay (9.4±3.7 versus 10.3±4.3 days; P=0.040) and rehabilitation stay (12.1±6.1 versus 13.9±6.5 days; P=0.009). Side effects were similar in the study groups. CONCLUSION: Colchicine seems safe and efficacious in the reduction of POAF with the potentiality of halving the complication and reducing the hospital stay.

Fish oil and postoperative atrial fibrillation: the Omega-3 Fatty Acids for Prevention of Post-operative Atrial Fibrillation (OPERA) randomized trial.

CONTEXT: Postoperative atrial fibrillation or flutter (AF) is one of the most common complications of cardiac surgery and significantly increases morbidity and health care utilization. A few small trials have evaluated whether long-chain n-3-polyunsaturated fatty acids (PUFAs) reduce postoperative AF, with mixed results. OBJECTIVE: To determine whether perioperative n-3-PUFA supplementation reduces postoperative AF. DESIGN, SETTING, AND PATIENTS: The Omega-3 Fatty Acids for Prevention of Post-operative Atrial Fibrillation (OPERA) double-blind, placebo-controlled, randomized clinical trial. A total of 1516 patients scheduled for cardiac surgery in 28 centers in the United States, Italy, and Argentina were enrolled between August 2010 and June 2012. Inclusion criteria were broad; the main exclusions were regular use of fish oil or absence of sinus rhythm at enrollment. INTERVENTION: Patients were randomized to receive fish oil (1-g capsules containing ≥840 mg n-3-PUFAs as ethyl esters) or placebo, with preoperative loading of 10 g over 3 to 5 days (or 8 g over 2 days) followed postoperatively by 2 g/d until hospital discharge or postoperative day 10, whichever came first. MAIN OUTCOME MEASURE: Occurrence of postoperative AF lasting longer than 30 seconds. Secondary end points were postoperative AF lasting longer than 1 hour, resulting in symptoms, or treated with cardioversion; postoperative AF excluding atrial flutter; time to first postoperative AF; number of AF episodes per patient; hospital utilization; and major adverse cardiovascular events, 30-day mortality, bleeding, and other adverse events. RESULTS: At enrollment, mean age was 64 (SD, 13) years; 72.2% of patients were men, and 51.8% had planned valvular surgery. The primary end point occurred in 233 (30.7%) patients assigned to placebo and 227 (30.0%) assigned to n-3-PUFAs (odds ratio, 0.96 [95% CI, 0.77-1.20]; P = .74). None of the secondary end points were significantly different between the placebo and fish oil groups, including postoperative AF that was sustained, symptomatic, or treated (231 [30.5%] vs 224 [29.6%], P = .70) or number of postoperative AF episodes per patient (1 episode: 156 [20.6%] vs 157 [20.7%]; 2 episodes: 59 [7.8%] vs 49 [6.5%]; ≥3 episodes: 18 [2.4%] vs 21 [2.8%]) (P = .73). Supplementation with n-3-PUFAs was generally well tolerated, with no evidence for increased risk of bleeding or serious adverse events. CONCLUSION: In this large multinational trial among patients undergoing cardiac surgery, perioperative supplementation with n-3-PUFAs, compared with placebo, did not reduce the risk of postoperative AF. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00970489.

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.

The ω-3 Fatty Acids for Prevention of Post-Operative Atrial Fibrillation trial--rationale and design.

Postoperative atrial fibrillation/flutter (PoAF) commonly complicates cardiac surgery, occurring in 25% to 60% of patients. Postoperative atrial fibrillation/flutter is associated with significant morbidity, higher long-term mortality, and increased health care costs. Novel preventive therapies are clearly needed. In experiments and short-term trials, seafood-derived long-chain ω-3 polyunsaturated fatty acids (PUFAs) influence several risk factors that might reduce risk of PoAF. A few small and generally underpowered trials have evaluated effects of ω-3-PUFAs supplementation on PoAF with mixed results. The OPERA trial is an appropriately powered, investigator-initiated, randomized, double-blind, placebo-controlled, multinational trial to determine whether perioperative oral ω-3-PUFAs reduces occurrence of PoAF in patients undergoing cardiac surgery. Additional aims include evaluation of resource use, biologic pathways and mechanisms, postoperative cognitive decline, and safety. Broad inclusion criteria encompass a "real-world" population of outpatients and inpatients scheduled for cardiac surgery. Treatment comprises a total preoperative loading dose of 8 to 10 g of ω-3-PUFAs or placebo divided over 2 to 5 days, followed by 2 g/d until hospital discharge or postoperative day 10, whichever comes first. Based on anticipated 30% event rate in controls, total enrollment of 1,516 patients (758 per treatment arm) will provide 90% power to detect 25% reduction in PoAF. The OPERA trial will provide invaluable evidence to inform biologic pathways; proof of concept that ω-3-PUFAs influence cardiac arrhythmias; and potential regulatory standards and clinical use of this simple, inexpensive, and low-risk intervention to prevent PoAF.

Colchicine prevents early postoperative pericardial and pleural effusions.

BACKGROUND: No preventive pharmacologic strategies have been proven efficacious for the prevention of postoperative effusions after cardiac surgery. Colchicine is safe and efficacious for the prevention of pericarditis. On this basis, we realized a substudy of the COPPS trial to assess the efficacy and safety of colchicine for the prevention of postoperative pericardial and pleural effusions. METHODS: The COPPS is a multicenter, double-blind, randomized trial, where 360 consecutive patients (mean age 65.7 ± 12.3 years, 66% men), 180 in each treatment arm, were randomized on the third postoperative day to receive placebo or colchicine for 1 month (1.0 mg twice daily for the first day, followed by a maintenance dose of 0.5 mg twice daily in patients ≥70 kg, and halved doses for patients <70 kg). The incidence of postoperative effusions was evaluated in each study group. RESULTS: Despite similar baseline features, colchicine significantly reduced the incidence of postoperative pericardial (12.8% vs 22.8%, P = .019, relative risk reduction 43.9%, no. of patients needed to treat 10) and pleural effusions (12.2% vs 25.6%, P = .002, relative risk reduction 52.3%, no. of patients needed to treat 8). The rate of side effects (only gastrointestinal intolerance) and drug withdrawal was similar in the study groups with a trend toward an increased rate of both events for colchicine. In multivariable analysis, female gender (hazard ratio 1.76, 95% CI 1.03-3.03, P = .040) and pleura incision (hazard ratio 2.58, 95% CI 1.53-4.53, P < .001) were risk factors for postoperative effusions. CONCLUSIONS: Colchicine is safe and efficacious for the primary prevention of postoperative effusions after cardiac surgery.

COlchicine for the Prevention of the Post-pericardiotomy Syndrome (COPPS): a multicentre, randomized, double-blind, placebo-controlled trial.

AIMS: No drug has been proven efficacious to prevent the post-pericardiotomy syndrome (PPS), but colchicine seems safe and effective for the treatment and prevention of pericarditis. The aim of the COlchicine for the Prevention of the Post-pericardiotomy Syndrome (COPPS) trial is to test the efficacy and safety of colchicine for the primary prevention of the PPS. METHODS AND RESULTS: The COPPS study is a multicentre, double-blind, randomized trial. On the third post-operative day, 360 patients (mean age 65.7 ± 12.3 years, 66% males), 180 in each treatment arm, were randomized to receive placebo or colchicine (1.0 mg twice daily for the first day followed by a maintenance dose of 0.5 mg twice daily for 1 month in patients ≥70 kg, and halved doses for patients <70 kg or intolerant to the highest dose). The primary efficacy endpoint was the incidence of PPS at 12 months. Secondary endpoint was the combined rate of disease-related hospitalization, cardiac tamponade, constrictive pericarditis, and relapses. Baseline characteristics were well balanced between the study groups. Colchicine significantly reduced the incidence of the PPS at 12 months compared with placebo (respectively, 8.9 vs. 21.1%; P = 0.002; number needed to treat = 8). Colchicine also reduced the secondary endpoint (respectively, 0.6 vs. 5.0%; P = 0.024). The rate of side effects (mainly related to gastrointestinal intolerance) was similar in the colchicine and placebo groups (respectively, 8.9 vs. 5.0%; P = 0.212). CONCLUSION: Colchicine is safe and efficacious in the prevention of the PPS and its related complications and may halve the risk of developing the syndrome following cardiac surgery. ClinicalTrials.gov number, NCT00128427.

Evidence of evolution towards left midventricular obstruction in severe Anderson-Fabry cardiomyopathy.

AIMS: In Fabry cardiomyopathy, left ventricular outflow tract obstruction mimicking hypertrophic cardiomyopathy is a very rare finding, with few cases reported and successfully treated with cardiac surgery. In our population of patients with Fabry disease and severe left ventricular hypertrophy (LVH) at the time of diagnosis, we observed an evolution towards a midventricular obstructive phenotype. METHODS AND RESULTS: We present a case series of three classically affected Fabry male patients with significant diagnostic delay and severe cardiac involvement (maximal wall thickness >20 mm) at first evaluation. All patients developed midventricular obstructive form over time despite prompt initiation and optimal compliance to enzyme replacement therapy. The extension and distribution of the LVH, involving the papillary muscles, was the main mechanism of obstruction, unlike the asymmetric septal basal hypertrophy and the mitral valve abnormalities commonly seen as substrate of left ventricular outflow tract obstruction in hypertrophic cardiomyopathy. CONCLUSIONS: Fabry cardiomyopathy can evolve over time towards a midventricular obstructive form due to massive LVH in classically affected men with significant diagnostic delay and severe LVH before enzyme replacement therapy initiation. This newly described cardiac phenotype could represent an adverse outcome of the disease.

Not Only Diagnostic Yield: Whole-Exome Sequencing in Infantile Cardiomyopathies Impacts on Clinical and Family Management.

Whole-exome sequencing (WES) is a powerful and comprehensive tool for the genetic diagnosis of rare diseases, but few reports describe its timely application and clinical impact on infantile cardiomyopathies (CM). We conducted a retrospective analysis of patients with infantile CMs who had trio (proband and parents)-WES to determine whether results contributed to clinical management in urgent and non-urgent settings. Twenty-nine out of 42 enrolled patients (69.0%) received a definitive molecular diagnosis. The mean time-to-diagnosis was 9.7 days in urgent settings, and 17 out of 24 patients (70.8%) obtained an etiological classification. In non-urgent settings, the mean time-to-diagnosis was 225 days, and 12 out of 18 patients (66.7%) had a molecular diagnosis. In 37 out of 42 patients (88.1%), the genetic findings contributed to clinical management, including heart transplantation, palliative care, or medical treatment, independent of the patient's critical condition. All 29 patients and families with a definitive diagnosis received specific counseling about recurrence risk, and in seven (24.1%) cases, the result facilitated diagnosis in parents or siblings. In conclusion, genetic diagnosis significantly contributes to patients' clinical and family management, and trio-WES should be performed promptly to be an essential part of care in infantile cardiomyopathy, maximizing its clinical utility.

Surgical Single Stage Treatment for Obstructive Hypertrophic Cardiomyopathy and Aortic Arch Aneurysm.

Coexistence of obstructive hypertrophic cardiomyopathy and severe aortic pathology is extremely rare; nonetheless, the association between these two diseases is fascinating. Here we present a unique case report of a patient with obstructive hypertrophic cardiomyopathy and aortic arch aneurysm treated by a single surgical procedure.

Congenital Muscular Mitral-Aortic Discontinuity Identified in Patients With Obstructive Hypertrophic Cardiomyopathy.

BACKGROUND: The mitral valve is often structurally abnormal in hypertrophic cardiomyopathy (HCM). However, the mechanisms responsible for these abnormalities remain controversial. In 2016 we identified, at myectomy, muscular mitral-aortic discontinuity in 5 young patients with obstructive HCM. OBJECTIVES: This study sought to confirm our preliminary findings and assess the prevalence of muscular mitral-aortic discontinuity in obstructive HCM. METHODS: At our center, from January 2017 to April 2018, the area between the anterior mitral leaflet and aortic valve was inspected at myectomy in 106 consecutive patients with HCM. RESULTS: Muscular mitral-aortic discontinuity was identified in 28 (26%) patients and was significantly more common in younger than older patients (age 39 ± 13 years vs. 58 ± 11 years; p < 0.001). Muscular discontinuity was present in each of 6 patients aged <30 years but only 1 (2.7%) of 37 aged ≥60 years. Pathogenic sarcomere mutations were identified in 22 (79%) of 28 patients with and 24 (31%) of 78 without discontinuity (p < 0.001) and were associated with discontinuity independently of age (p = 0.021). Discontinuity mean length was 7.3 mm and was inversely related to age (p = 0.022). At echocardiography, the anterior mitral leaflet was longer in patients with than those without discontinuity (34 ± 4 mm vs. 29 ± 5 mm; p < 0.001). CONCLUSIONS: We report, for the first time, muscular mitral-aortic discontinuity in HCM. At myectomy, a long muscular discontinuity displaced the anterior mitral leaflet toward the apex in most young patients, was significantly associated with sarcomere mutations independent of age, and was extremely uncommon in older patients. These findings suggest that a long muscular mitral-aortic discontinuity could predispose to the development of outflow obstruction in young patients with sarcomere mutations.

Multidisciplinary evaluation and management of obstructive hypertrophic cardiomyopathy in 2020: Towards the HCM Heart Team.

Patients with hypertrophic cardiomyopathy (HCM) exhibit a variable phenotype with ventricular hypertrophy as the cardinal manifestation and left ventricular (LV) outflow tract obstruction (LVOTO) as a key pathophysiologic determinant. Patients with severe LVOTO usually present with exertional dyspnea, exertional syncope, and heart failure symptoms, while successful relief of LVOTO by pharmacological or invasive interventions leads to a dramatic improvement in clinical status. Proper management of obstructive HCM remains challenging and poses numerous clinical dilemmas. Since the development of surgical myectomy over half a century ago, progress in the management of LVOTO in HCM has paralleled technological advances in genetic testing, cardiac imaging, arrhythmic prophylaxis, cardiac surgery and interventional cardiology. These changes have been incorporated in dedicated scientific guidelines on both sides of the Atlantic. However, either the 2011 American guidelines or the 2014 European guidelines remain largely based on expert consensus for lack of recommendations with level of evidence A regarding any of the treatment options commonly employed in HCM. Consequently, management of obstructive HCM patients remains largely subjective and dependent on clinical judgment, local expertise, and patient preference. Following the trend that has emerged for other cardiac diseases amenable to invasive interventions, adequate evaluation and management of obstruction in HCM today requires a multidisciplinary team capable of optimizing referral, choosing the best available options, minimizing complications and ensuring state-of-the-art results. The concept of an HCM Heart Team is coming of age. This review aims to provide an update of available pharmacologic and invasive options for the management of LVOTO in HCM, either in adulthood or in childhood, highlighting areas for multidisciplinary integration and future development.