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.

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.

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.

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.).

ACC/AHA 2006 guideline update on perioperative cardiovascular evaluation for noncardiac surgery: focused update on perioperative beta-blocker therapy--a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2002 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery).

The American College of Cardiology/American Heart Association (ACC/AHA) Task Force on Practice Guidelines makes every effort to avoid any actual, potential, or perceived conflict of interest that might arise as a result of an industry relationship or personal interest of the writing committee. Specifically, all members of the writing committee, as well as peer reviewers of the document, were asked to provide disclosure statements of all such relationships that might be perceived as real or potential conflicts of interest. These statements are reviewed by the parent task force, reported orally to all members of the writing committee at each meeting, and updated and reviewed by the writing committee as changes occur. Please see Appendix 1 for author relationships with industry and Appendix 2 for peer reviewer relationships with industry. These guidelines attempt to define practices that meet the needs of most patients in most circumstances. These guideline recommendations reflect a consensus of expert opinion after a thorough review of the available, current scientific evidence and are intended to improve patient care. If these guidelines are used as the basis for regulatory/payer decisions, the ultimate goal is quality of care and serving the patient's best interests. The ultimate judgment regarding care of a particular patient must be made by the healthcare provider and patient in light of all the circumstances presented by that patient.

Safety of exercise stress testing in patients with abnormal concentrations of serum potassium.

The objective of this study was to determine the safety of performing exercise stress testing in patients with abnormal serum potassium concentrations. Data were reviewed from 9,084 patients (mean age 63 +/- 12 years) referred for exercise echocardiography who had serum potassium measured <48 hours before the test were reviewed, and the occurrence of arrhythmias during stress testing was determined. Of 10,272 studies, 9,067 (88%) were in patients with normokalemia and 1,205 (12%) were in patients with abnormal serum potassium concentrations: 309 (26%) with hypokalemia (mean 3.4 +/- 0.16 mmol/L) and 896 (74%) with hyperkalemia (mean 5.1 +/- 0.19 mmol/L). Ventricular and supraventricular ectopy were common during exercise. Only 1 patient (potassium 4.9 mmol/L) had sustained ventricular tachycardia; all other episodes were nonsustained. Although ventricular and supraventricular ectopy are common during exercise testing, life-threatening arrhythmias are not. Exercise testing is generally safe despite mild to moderate hypokalemia or hyperkalemia.

Association of obesity with left ventricular remodeling and diastolic dysfunction in patients without coronary artery disease.

Obese patients frequently complain of dyspnea. Deconditioning and altered left ventricular (LV) systolic or diastolic function with elevated filling pressures may contribute to dyspnea. This study analyzed 4,281 patients who underwent diagnostic coronary angiography from January 1, 1995, to December 31, 2000. No patients had coronary artery stenoses >50% of the luminal diameter, and all underwent echocardiography within the same 6-year period. The association between body mass index (BMI) and LV structure and systolic and diastolic function was examined. All analyses controlled for age and gender, with the effect size for BMI expressed using a standardized coefficient (SC). A higher BMI was associated with greater LV mass (SC 0.18, p <0.001), wall thickness (SC 0.17, p <0.001), and end-diastolic diameter (SC 0.07, p <0.001). Stroke volume increased with a higher BMI (SC 0.12, p = 0.001), but there was no association between BMI and the ejection fraction (SC 0.003, p = 0.81). Hemodynamic data from invasive studies showed an association between a higher BMI and increased LV end-diastolic pressure (mean 17 mm Hg for BMI <25 kg/m(2) vs 24 mm Hg for BMI >or=40 kg/m(2); SC 0.18, p <0.001), which persisted after controlling for end-diastolic volume (SC 0.22, p <0.001). Obesity was associated with ventricular remodeling, which may normalize wall stress while increasing stroke volume to match metabolic demand. Obesity was not associated with decreased systolic function. However, obesity was associated with increased LV end-diastolic pressure, which suggests an association between obesity and diastolic dysfunction. In conclusion, ventricular remodeling, LV diastolic dysfunction, and elevated filling pressures may contribute to the prevalence of heart failure in obese patients.

Consecutive 1127 therapeutic echocardiographically guided pericardiocenteses: clinical profile, practice patterns, and outcomes spanning 21 years.

OBJECTIVES: To evaluate consecutive therapeutic echocardiographically (echo)-guided pericardiocenteses performed at Mayo Clinic, Rochester, Minn, from 1979 to 2000 and to determine whether patient profiles, practice patterns, and outcomes have changed over time. PATIENTS AND METHODS: Consecutive echo-guided pericardiocenteses performed between February 1, 1979, and January 31, 2000, for treatment of clinically significant pericardial effusions were identified in the Mayo Clinic Echocardiographic-guided Pericardiocentesis Registry. The medical records of these patients were examined, and a follow-up survey was conducted. Clinical profiles, echocardiographic findings, procedural details, and outcomes were determined for 3 periods: February 1, 1979, through January 31, 1986; February 1, 1986, through January 31, 1993; and February 1, 1993, through January 31, 2000. RESULTS: During the 21-year study period, 1127 therapeutic echo-guided pericardiocenteses were performed in 977 patients. The mean +/- SD age at pericardiocentesis increased from 49+/-14 years in period 1 to 57+/-14 years in period 3. In recent years, cardiothoracic surgery replaced malignancy as the leading cause of an effusion requiring pericardiocentesis and together with malignancy and perforation from catheter-based procedures accounted for nearly 70% of all pericardiocenteses performed. The procedural success rate was 97% overall, with a total complication rate of 4.7% (major, 1.2%; minor, 3.5%). These rates did not change significantly over time. The use of a pericardial catheter for extended drainage increased from 23% in period 1 to 75% in period 3 (P<.001), whereas rates of effusion recurrence and pericardial surgery decreased significantly (P<.001). CONCLUSIONS: The profile of patients presenting with clinically significant pericardial effusion has changed over time. Increasing numbers of older patients and those who have undergone cardiothoracic surgery or catheter-based procedures develop effusions that can be rapidly, safely, and effectively managed with echo-guided pericardiocentesis. Extended drainage with use of a pericardial catheter has become standard practice, and concomitantly, recurrence rates and need for surgical management have decreased considerably.

Outcomes of patients with reduced exercise capacity at time of exercise echocardiography.

OBJECTIVE: To characterize the prognostic implications of exercise echocardiography in patients who have reduced exercise capacity at the time of testing. PATIENTS AND METHODS: We examined the outcomes of 941 patients at the Mayo Clinic in Rochester, Minn, between January 1, 1990, and December 31, 1995, who had reduced exercise capacity on exercise echocardiography (women, <5 metabolic equivalents; men, <7 metabolic equivalents) and evaluated the potential association between clinical, electrocardiographic, and echocardiographic variables and outcomes for patients with normal vs abnormal exercise echocardiograms. We used variables of independent prognostic value to estimate cardiac risk. RESULTS: For patients with normal exercise echocardiograms (n=282), the rate of cardiac death or nonfatal myocardial infarction was 09% per person-year of follow-up, and previous coronary revascularization was the only predictor of the time to cardiac event. For patients with abnormal exercise echocardiograms (n=659), the cardiac event rate was 4.4%. Independent predictors of outcome were exercise left ventricular (LV) ejection fraction (risk ratio, 1.44 per 10% decrement; 95% confidence interval, 1.2-1.7; P<.001) and an increase or no change in LV end-systolic size in response to exercise (risk ratio, 2.22; 95% confidence interval, 1.2-4.1; P=.01). CONCLUSION: Exercise echocardiographic findings have important prognostic implications for patients who have reduced exercise capacity on testing. Echocardiographic descriptors of LV systolic function and dysfunction obtained immediately after exercise can be used to stratify cardiac risk of patients who do not achieve a level of exercise ordinarily considered to be of "diagnostic" value.

Cardiac amyloidosis presenting with elevations of cardiac troponin I and angina pectoris.

We present the case of a 43-year-old male who was initially evaluated for angina pectoris and dyspnea. His CK, CK-MB, and cTnI were all elevated following a blood transfusion and he underwent coronary arteriography, which demonstrated no luminal obstructions. After several months, he was transferred to Mayo Clinic where diagnoses of fulminant cardiac amyloidosis and systemic multiple myeloma were established. The cTnI remained elevated despite normalization of the CK and CK-MB. Despite aggressive treatment, the patient died. Postmortem analysis demonstrated amyloid cardiac deposition including involvement of the coronary microvasculature. Electron microscopy revealed myocyte compression injury from amyloid infiltration. We believe this is the first report of elevated troponin I in a patient with cardiac amyloidosis. The electron microscopy in our case confirms cardiac damage as the mechanism for cTnI elevation. This observation strengthens our knowledge about the specificity of cTnI for the detection of cardiac injury.