Role of Genetics in Diagnosis and Management of Hypertrophic Cardiomyopathy: A Glimpse into the Future.

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiomyopathy. It follows an autosomal dominant inheritance pattern in most cases, with incomplete penetrance and heterogeneity. It is familial in 60% of cases and most of these are caused by pathogenic variants in the core sarcomeric genes (MYH7, MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1). Genetic testing using targeted disease-specific panels that utilize next-generation sequencing (NGS) and include sarcomeric genes with the strongest evidence of association and syndrome-associated genes is highly recommended for every HCM patient to confirm the diagnosis, identify the molecular etiology, and guide screening and management. The yield of genetic testing for a disease-causing variant is 30% in sporadic cases and up to 60% in familial cases and in younger patients with typical asymmetrical septal hypertrophy. Genetic testing remains challenging in the interpretation of results and classification of variants. Therefore, in 2015 the American College of Medical Genetics and Genomics (ACMG) established guidelines to classify and interpret the variants with an emphasis on the necessity of periodic reassessment of variant classification as genetic knowledge rapidly expands. The current guidelines recommend focused cascade genetic testing regardless of age in phenotype-negative first-degree relatives if a variant with decisive evidence of pathogenicity has been identified in the proband. Genetic test results in family members guide longitudinal clinical surveillance. At present, there is emerging evidence for genetic test application in risk stratification and management but its implementation into clinical practice needs further study. Promising fields such as gene therapy and implementation of artificial intelligence in the diagnosis of HCM are emerging and paving the way for more effective screening and management, but many challenges and obstacles need to be overcome before establishing the practical implications of these new methods.

Using Augmented Mean Arterial Pressure to Identify High Mortality Risk Patients With Moderate Aortic Stenosis.

OBJECTIVE: To study the usefulness of a novel echocardiographic marker, augmented mean arterial pressure (AugMAP = [(mean aortic valve gradient + systolic blood pressure) + (2 × diastolic blood pressure)] / 3), in identifying high-risk patients with moderate aortic stenosis (AS). PATIENTS AND METHODS: Adults with moderate AS (aortic valve area, 1.0-1.5 cm2) at Mayo Clinic sites from January 1, 2010, through December 31, 2020, were identified. Baseline demographic, echocardiographic, and all-cause mortality data were retrieved. Patients were grouped into higher and lower AugMAP groups using a cutoff value of 80 mm Hg for analysis. Kaplan-Meier and Cox regression models were used to assess the performance of AugMAP. RESULTS: A total of 4563 patients with moderate AS were included (mean ± SD age, 73.7±12.5 years; 60.5% men). Median follow-up was 2.5 years; 36.0% of patients died. The mean ± SD left ventricular ejection fraction (LVEF) was 60.1%±11.4%, and the mean ± SD AugMAP was 99.1±13.1 mm Hg. Patients in the lower AugMAP group, with either preserved or reduced LVEF, had significantly worse survival performance (all P<.001). Multivariate Cox regression showed that AugMAP (hazard ratio, 0.962; 95% CI, 0.942 to 0.981 per 5-mm Hg increase; P<.001) and AugMAP less than 80 mm Hg (hazard ratio, 1.477; 95% CI, 1.241 to 1.756; P<.001) were independently associated with all-cause mortality. CONCLUSION: AugMAP is a simple and effective echocardiographic marker to identify high-risk patients with moderate AS independent of LVEF. It can potentially be used in the candidate selection process if moderate AS becomes indicated for aortic valve intervention in the future.

Transcatheter Aortic Valve Replacement Prognostication with Augmented Mean Arterial Pressure.

BACKGROUND: Post-transcatheter aortic valve replacement (TAVR) patient outcome is an important research topic. To accurately assess post-TAVR mortality, we examined a family of new echo parameters (augmented systolic blood pressure (AugSBP) and arterial mean pressure (AugMAP)) derived from blood pressure and aortic valve gradients. METHODS: Patients in the Mayo Clinic National Cardiovascular Diseases Registry-TAVR database who underwent TAVR between 1 January 2012 and 30 June 2017 were identified to retrieve baseline clinical, echocardiographic and mortality data. AugSBP, AugMAP and valvulo-arterial impedance (Zva) (Zva) were evaluated using Cox regression. Receiver operating characteristic curve analysis and the c-index were used to assess the model performance against the Society of Thoracic Surgeons (STS) risk score. RESULTS: The final cohort contained 974 patients with a mean age of 81.4 ± 8.3 years old, and 56.6% were male. The mean STS risk score was 8.2 ± 5.2. The median follow-up duration was 354 days, and the one-year all-cause mortality rate was 14.2%. Both univariate and multivariate Cox regression showed that AugSBP and AugMAP parameters were independent predictors for intermediate-term post-TAVR mortality (all p < 0.0001). AugMAP1 < 102.5 mmHg was associated with a 3-fold-increased risk of all-cause mortality 1-year post-TAVR (hazard ratio 3.0, 95%confidence interval 2.0-4.5, p < 0.0001). A univariate model of AugMAP1 surpassed the STS score model in predicting intermediate-term post-TAVR mortality (area under the curve: 0.700 vs. 0.587, p = 0.005; c-index: 0.681 vs. 0.585, p = 0.001). CONCLUSIONS: Augmented mean arterial pressure provides clinicians with a simple but effective approach to quickly identify patients at risk and potentially improve post-TAVR prognosis.

Natural history and clinical significance of isolated complete left bundle branch block without associated structural heart disease.

OBJECTIVE: Left bundle branch block (LBBB), which is associated with underlying cardiac disease, is believed to play a role in the pathogenesis of cardiomyopathy through delays in interventricular conduction, leading to dyssynchrony. However, this has not been established in previous studies. It is unclear whether LBBB indicates clinically advanced cardiac disease or is an independent factor responsible for increased mortality and the development of heart failure. We investigated the natural history of isolated LBBB without any associated structural heart disease in order to determine its clinical significance. METHODS: We performed a retrospective chart review on consecutive patients who fulfilled the 12-lead electrocardiographic (ECG) criteria for complete LBBB and had a normal echocardiogram with no evidence of structural heart disease and left or right ventricular systolic dysfunction within three months of the initial ECG between January 1, 2000 and December 31, 2009. We excluded patients with documented coronary artery disease (CAD) at any time, any structural heart disease, or cardiac devices. We evaluated the primary endpoints of mortality and incidence of cardiomyopathy, as well as any heart failure hospitalizations over a 1- and 10-year period. RESULTS: We identified 2522 eligible patients. The mean follow-up duration was 8.4±3.2 years. The one-year mortality rate was 7.8%, with a 10-year mortality rate of 22.0%. The incidence of cardiomyopathy over one year was 3.2% and over 10 years was 9.1%. There was no significant difference in QRS duration between patients who were alive and those that were deceased at 10 years (141+/-18 vs. 141+/-17 ms; p=0.951) and patients with and without cardiomyopathy at 10 years (142±17 vs. 141±17 ms; p=0.532). CONCLUSION: Isolated LBBB occurring without structural heart disease, ventricular dysfunction, or CAD is associated with a low mortality rate and incidence of cardiomyopathy.

Long-Term Clinical Outcomes of Underdosed Direct Oral Anticoagulants in Patients with Atrial Fibrillation and Atrial Flutter.

BACKGROUND: Although direct oral anticoagulants (DOACs) have been shown to be effective at reducing the risk of stroke in patients with atrial fibrillation/flutter (AF), they are sometimes underdosed off-label to mitigate their associated higher bleeding risk. We sought to evaluate frequency and clinical outcomes of inappropriate underdosing of DOACS in patients with AF. METHODS: We conducted a study of subjects with AF who had a clinical indication for stroke prophylaxis (with a congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke or transient ischemic attack, vascular disease, age 65 to 47 years, sex category [CHA2DS2-VASc] of 2 or greater) and were prescribed 1 of the 4 clinically approved DOACs (apixaban, rivaroxaban, dabigatran, or edoxaban). We compared all-cause mortality, composite of stroke and systemic embolism, composite of myocardial infarction (MI), acute coronary syndromes (ACS), and coronary revascularization, and major bleeding between patients appropriately dosed and inappropriately underdosed. RESULTS: A total of 8125 patients met inclusion criteria, with a mean follow up of 2.2 ± 2 years. Of those, 1724 patients (21.2%) were inappropriately dosed. After adjusting for baseline variables, there was no difference in all-cause mortality, risk of stroke or systemic embolism, International Society on Thrombosis and Haemostasis (ISTH) major bleeding, or composite of myocardial infarction, acute coronary syndromes, or coronary revascularization between patients appropriately dosed and inappropriately underdosed. In subgroup analysis, only apixaban demonstrated an increased incidence all-cause mortality (hazard ratio [HR] 1.24, 95% confidence interval [CI] 1.03-1.49) with inappropriate underdosing. There was no difference in the remaining clinical outcomes noted on subgroup analysis. CONCLUSION: Underdosing of DOACs did not minimize risk of bleeding, systemic embolization or all-cause mortality in patients with AF. Inappropriate underdosing with apixaban in particular was associated with increased all-cause mortality.

Primary Malignant Pericardial Mesothelioma: A Clinical Case Series Illustrating the Necessity of a Multidisciplinary Approach.

Primary malignant pericardial mesothelioma is a rare cardiac neoplasm. The authors evaluated risk factors, clinical presentation, and outcomes by reviewing all biopsy-confirmed cases at one institution. The use of multimodality imaging, detailed hemodynamic assessment for the presence of an effusive-constrictive profile, and cytology evaluation can support the diagnosis. (Level of Difficulty: Advanced.).

Risk of death in long-term follow-up of patients with apical hypertrophic cardiomyopathy.

Apical hypertrophic cardiomyopathy (HC) has been considered a "benign" form of HC, with limited data on long-term outcome. We compared apical HC patients with a non-HC, age- and gender-matched Minnesota white population to identify outcomes and prognostic factors. Between 1976 and 2006, 193 patients (62% men) with apical HC were seen at our clinic. Their most recent echocardiographic examinations were reviewed. Mean ± SD age at first presentation was 58 ± 17 years. A family history of HC or sudden cardiac death (SCD) was reported by 43 patients (22%); coronary artery disease was known in 22 (11%). An apical pouch was present in 29 patients, including an apical aneurysm in 6 and apical dilatation with hypokinesis in 23. Median follow-up (187 patients [97%]) was 78 months (range, 1-350). Death from all causes occurred in 55 patients (29%; 33 women) at a mean age of 72 years (range, 20-92). During follow-up, more women had heart failure (p = 0.001), atrial fibrillation (p = 0.009), or died (p <0.001) than men. Survival was worse than expected (p = 0.001); the observed versus expected 20-year survival was 47% versus 60%. SCD, resuscitated cardiac arrest, and/or defibrillator discharge was observed in 11 patients (6%) during follow-up. Multivariate predictors of decreased survival were higher age at baseline (p <0.001), female gender (p <0.001), and atrial fibrillation at baseline (p = 0.06). In conclusion, apical HC in this population was associated with increased mortality, especially in women. Because apical HC is less benign than previously suspected, careful longitudinal care is warranted.

Intraoperative echocardiography in valvular heart disease: an evidence-based appraisal.

Intraoperative (IO) transesophageal echocardiography (TEE) is widely used for assessing the results of valvular heart disease (VHD) surgery. Epiaortic ultrasonography (EAU) has been recommended for prevention of perioperative strokes. To what extent does high-quality evidence justify the widespread use of these imaging modalities? In March 2009, we searched MEDLINE (PubMed and OVID interfaces) and EMBASE for studies published in English using database-specific controlled vocabulary describing the concepts of IOTEE, cardiac surgery, VHD, and EAU. We found no randomized trials or studies with control groups assessing the impact of IOTEE in VHD surgery. Pooled analysis of 8 observational studies including 15,540 patients showed an average incidence of 11% for prebypass surgical changes and 4% for second pump runs, suggesting that patients undergoing VHD surgery may benefit significantly from IOTEE, particularly from postcardiopulmonary bypass IOTEE in aortic repair and mitral repair and replacement, but less so in isolated aortic replacement. Further available indirect evidence was satisfactory in the test accuracy and surgical quality control aspects, with low complication rates for IOTEE. The data supporting EAU included 12,687 patients in 2 prospective randomized studies and 4 nonrandomized, controlled studies, producing inconsistent outcome-related results. Despite low-quality scientific evidence supporting IOTEE in VHD surgery, we conclude that indirect evidence supporting its use is satisfactory and suggests that IOTEE may offer considerable benefit in valvular repairs and mitral replacements. The value of IOTEE in isolated aortic valve replacement remains less clear. Evidence supporting EAU is scientifically more robust but conflicting. These findings have important clinical policy and research implications.

Perioperative cardiovascular assessment of patients undergoing noncardiac surgery.

Preoperative assessment of the cardiac patient before noncardiac surgery is common in the clinical practice of the medical consultant, anesthesiologist, and surgeon. Currently, most noncardiac surgical procedures are performed for patients of advanced age, and the number of such surgeries is likely to increase with the aging of the population. These same patients have an increased prevalence of cardiovascular disease, especially ischemic heart disease, which is the primary cause of perioperative morbidity and mortality associated with noncardiac surgery. Since 1996, 3 American College of Cardiology/American Heart Association guideline documents have been published, each reflecting the available literature, with recommendations for the preoperative cardiovascular evaluation and treatment of the patient undergoing noncardiac surgery. Our review describes the 2007 American College of Cardiology/American Heart Association guidelines, the most recent revision, focusing on a newly recommended 5-step algorithmic approach to managing this clinical problem, particularly for the patient with known or suspected coronary heart disease. Continued emphasis should be given to preoperative clinical risk stratification, with noninvasive testing reserved for those patients in whom a substantial change in medical management would be anticipated based on results of testing. Pharmacologic therapy holds more promise than coronary revascularization for the reduction of major adverse perioperative cardiac events that might complicate noncardiac surgery.

Real-time three-dimensional transesophageal echocardiography in the intraoperative assessment of mitral valve disease.

BACKGROUND: The aims of this study were to evaluate the feasibility of real-time 3-dimensional (3D) transesophageal echocardiography in the intraoperative assessment of mitral valve (MV) pathology and to compare this novel technique with 2-dimensional (2D) transesophageal echocardiography. METHODS: Forty-two consecutive patients undergoing MV repair for mitral regurgitation (MR) were studied prospectively. Intraoperative 2D and 3D transesophageal echocardiographic (TEE) examinations were performed using a recently introduced TEE probe that provides real-time 3D imaging. Expert echocardiographers blinded to 2D TEE findings assessed the etiology of MR on 3D transesophageal echocardiography. Similarly, experts blinded to 3D TEE findings assessed 2D TEE findings. Both were compared with the anatomic findings reported by the surgeon. RESULTS: At the time of surgical inspection, ischemic MR was identified in 12% of patients, complex bileaflet myxomatous disease in 31%, and specific scallop disease in 55%. Three-dimensional TEE image acquisition was performed in a short period of time (60 +/- 18 seconds) and was feasible in all patients, with optimal (36%) or good (33%) imaging quality in the majority of cases. Three-dimensional TEE imaging was superior to 2D TEE imaging in the diagnosis of P1, A2, A3, and bileaflet disease (P < .05). CONCLUSIONS: Real-time 3D transesophageal echocardiography is a feasible method for identifying specific MV pathology in the setting of complex disease and can be expeditiously used in the intraoperative evaluation of patients undergoing MV repair.

Thromboembolic complications after surgical correction of mitral regurgitation incidence, predictors, and clinical implications.

OBJECTIVES: We sought to define thromboembolic risk after surgery for mitral regurgitation (MR), particularly ischemic stroke (IS) compared with the general population. BACKGROUND: Guidelines recommend surgery in asymptomatic patients with MR, but IS risks are unknown. METHODS: In 1,344 patients (age 65 +/- 12 years) consecutively operated for MR (procedures: 897 mitral valve repair [MRep] and 447 valve replacement: 231 mechanical mitral valve replacement [MVRm], 216 biological mitral valve replacement [MVRb]), thromboembolic complications, particularly IS (diagnosed by neurologists), during follow-up were assessed early (<30 days), midterm (30 to 180 days), and long-term (>or=180 days). RESULTS: Ischemic stroke occurred in 130 patients: 1.9 +/- 0.4% and 2.7 +/- 0.5% at 30 days and 180 days, respectively, and 8.1 +/- 0.8% at 5 years. We found that IS rates were lowest after MRep versus MVRb and MVRm (6.1 +/- 0.9% vs. 8 +/- 2.1%, and 16.1 +/- 2.7% at 5 years, respectively, p < 0.001). Comparison with population-expected IS showed high risk at <30 days (risk ratio 41, 95% confidence interval 26 to 60, p < 0.001 but p > 0.10 between procedures) and moderate risk at >30 days (risk ratio 1.7 overall; 1.3 for MRep; 0.98 for MVRb; 4.8 for MVRm). Beyond 180 days, IS risk declined further and was similar to the population for MRep (relative risk 1.2) and for MVRb (relative risk 0.9). Bleeding risk >30 days was lowest in MRep versus MVRb and MVRm (10-year risk 7 +/- 1%, 14 +/- 4%, and 16 +/- 3%, respectively). CONCLUSIONS: Thromboembolic complications after MR surgery are a reason for both concern and encouragement. The risk of IS is notable early, irrespective of procedure, but in the long term it is not greater than in the population after MRep and MVRb. Preference for MRep should be emphasized, and trials aiming at preventing IS should be conducted to reduce thromboembolic and hemorrhagic risk after surgery for MR.