Hepatic steatosis and advanced hepatic fibrosis are independent predictors of long-term mortality in acute myocardial infarction.

AIM: To examine the prevalence and prognosis of hepatic steatosis and fibrosis in post-acute myocardial infarction (AMI) patients. METHODS: Patients presenting with AMI to a tertiary hospital were examined from 2014 to 2021. Hepatic steatosis and advanced hepatic fibrosis were determined using the Hepatic Steatosis Index and fibrosis-4 index, respectively. The primary outcome was all-cause mortality. Cox regression models identified determinants of mortality after adjustments and Kaplan-Meier curves were constructed for all-cause mortality, stratified by hepatic steatosis and advanced fibrosis. RESULTS: Of 5765 patients included, 24.8% had hepatic steatosis, of whom 41.7% were diagnosed with advanced fibrosis. The median follow-up duration was 2.7 years. Patients with hepatic steatosis tended to be younger, female, with elevated body mass index and an increased metabolic burden of diabetes, hypertension and hyperlipidaemia. Patients with hepatic steatosis (24.6% vs. 20.9% mortality, P < .001) and advanced fibrosis (45.6% vs. 32.9% mortality, P < .001) had higher all-cause mortality rates compared with their respective counterparts. Hepatic steatosis (adjusted hazard ratio 1.364, 95% CI 1.145-1.625, P = .001) was associated with all-cause mortality after adjustment for confounders. Survival curves showed excess mortality in patients with hepatic steatosis compared with those without (P = .002). CONCLUSIONS: Hepatic steatosis and advanced fibrosis have a substantial prevalence among patients with AMI. Both are associated with mortality, with an incrementally higher risk when advanced fibrosis ensues. Hepatic steatosis and fibrosis could help risk stratification of AMI patients beyond conventional risk factors.

Outcomes of culture-negative vs. culture-positive infective endocarditis: the ESC-EORP EURO-ENDO registry.

AIM: Fatality of infective endocarditis (IE) is high worldwide, and its diagnosis remains a challenge. The objective of the present study was to compare the clinical characteristics and outcomes of patients with culture-positive (CPIE) vs. culture-negative IE (CNIE). METHODS AND RESULTS: This was an ancillary analysis of the ESC-EORP EURO-ENDO registry. Overall, 3113 patients who were diagnosed with IE during the study period were included in the present study. Of these, 2590 (83.2%) had CPIE, whereas 523 (16.8%) had CNIE. As many as 1488 (48.1%) patients underwent cardiac surgery during the index hospitalization, 1259 (48.8%) with CPIE and 229 (44.5%) with CNIE. The CNIE was a predictor of 1-year mortality [hazard ratio (HR) 1.28, 95% confidence interval (CI) 1.04-1.56], whereas surgery was significantly associated with survival (HR 0.49, 95% CI 0.41-0.58). The 1-year mortality was significantly higher in CNIE than CPIE patients in the medical subgroup, but it was not significantly different in CNIE vs. CPIE patients who underwent surgery. CONCLUSION: The present analysis of the EURO-ENDO registry confirms a higher long-term mortality in patients with CNIE compared with patients with CPIE. This difference was present in patients receiving medical therapy alone and not in those who underwent surgery, with surgery being associated with reduced mortality. Additional efforts are required both to improve the aetiological diagnosis of IE and identify CNIE cases early before progressive disease potentially contraindicates surgery.

Effects of initial invasive vs. initial conservative treatment strategies on recurrent and total cardiovascular events in the ISCHEMIA trial.

AIMS: The International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial prespecified an analysis to determine whether accounting for recurrent cardiovascular events in addition to first events modified understanding of the treatment effects. METHODS AND RESULTS: Patients with stable coronary artery disease (CAD) and moderate or severe ischaemia on stress testing were randomized to either initial invasive (INV) or initial conservative (CON) management. The primary outcome was a composite of cardiovascular death, myocardial infarction (MI), and hospitalization for unstable angina, heart failure, or cardiac arrest. The Ghosh-Lin method was used to estimate mean cumulative incidence of total events with death as a competing risk. The 5179 ISCHEMIA patients experienced 670 index events (318 INV, 352 CON) and 203 recurrent events (102 INV, 101 CON). A single primary event was observed in 9.8% of INV and 10.8% of CON patients while ≥2 primary events were observed in 2.5% and 2.8%, respectively. Patients with recurrent events were older; had more frequent hypertension, diabetes, prior MI, or cerebrovascular disease; and had more multivessel CAD. The average number of primary endpoint events per 100 patients over 4 years was 18.2 in INV [95% confidence interval (CI) 15.8-20.9] and 19.7 in CON (95% CI 17.5-22.2), difference -1.5 (95% CI -5.0 to 2.0, P = 0.398). Comparable results were obtained when all-cause death was substituted for cardiovascular death and when stroke was added as an event. CONCLUSIONS: In stable CAD patients with moderate or severe myocardial ischaemia enrolled in ISCHEMIA, an initial INV treatment strategy did not prevent either net recurrent events or net total events more effectively than an initial CON strategy. CLINICAL TRIAL REGISTRATION: ISCHEMIA ClinicalTrials.gov number, NCT01471522, https://clinicaltrials.gov/ct2/show/NCT01471522.

Association Between Calcium Supplementation and the Risk of Cardiovascular Disease and Stroke: A Systematic Review and Meta-Analysis.

BACKGROUND: Some observational studies and randomised controlled trials (RCTs) have reported an association between calcium supplementation and increased risk of cardiovascular disease. Previous meta-analyses on the topic, based on data from RCTs and observational studies, have contradictory findings. This meta-analysis was conducted to determine the difference in associated risks of calcium supplementation with cardiovascular disease and stroke in RCTs. METHODS: Relevant studies published from database inception to 6 August 2021 were sourced from PubMed, Embase, Scopus, and the Cochrane Central Register of Controlled Trials. Any RCTs focusing on the relationship between calcium supplementation and incidence of cardiovascular disease or stroke were included. Articles were screened independently by two authors, according to the PICO criteria, with disagreements resolved by a third author. RESULTS: Twelve RCTs were included in the meta-analysis. Calcium supplementation was not associated with myocardial infarction, total stroke, heart failure admission, and all-cause/cardiovascular mortality. Subgroup analysis focusing on calcium monotherapy/calcium co-therapy with vitamin D, female sex, follow-up duration, and geographical region did not affect the findings. CONCLUSION: Calcium supplementation was not associated with myocardial infarction, total stroke, heart failure admission, and cardiovascular/all-cause mortality. Further studies are required to examine and understand these associations.

Natural History of Patients With Ischemia and No Obstructive Coronary Artery Disease: The CIAO-ISCHEMIA Study.

BACKGROUND: Ischemia with no obstructive coronary artery disease (INOCA) is common and has an adverse prognosis. We set out to describe the natural history of symptoms and ischemia in INOCA. METHODS: CIAO-ISCHEMIA (Changes in Ischemia and Angina over One Year in ISCHEMIA Trial Screen Failures With INOCA) was an international cohort study conducted from 2014 to 2019 involving angina assessments (Seattle Angina Questionnaire) and stress echocardiograms 1 year apart. This was an ancillary study that included patients with a history of angina who were not randomly assigned in the ISCHEMIA trial. Stress-induced wall motion abnormalities were determined by an echocardiographic core laboratory blinded to symptoms, coronary artery disease status, and test timing. Medical therapy was at the discretion of treating physicians. The primary outcome was the correlation between the changes in the Seattle Angina Questionnaire angina frequency score and changes in echocardiographic ischemia. We also analyzed predictors of 1-year changes in both angina and ischemia, and we compared CIAO participants with ISCHEMIA participants with obstructive coronary artery disease who had stress echocardiography before enrollment, as CIAO participants did. RESULTS: INOCA participants in CIAO were more often female (66% of 208 versus 26% of 865 ISCHEMIA participants with obstructive coronary artery disease, P<0.001), but the magnitude of ischemia was similar (median 4 ischemic segments [interquartile range, 3-5] both groups). Ischemia and angina were not significantly correlated at enrollment in CIAO (P=0.46) or ISCHEMIA stress echocardiography participants (P=0.35). At 1 year, the stress echocardiogram was normal in half of CIAO participants, and 23% had moderate or severe ischemia (≥3 ischemic segments). Angina improved in 43% and worsened in 14%. Change in ischemia over 1 year was not significantly correlated with change in angina (ρ=0.029). CONCLUSIONS: Improvement in ischemia and angina were common in INOCA but not correlated. Our INOCA cohort had a degree of inducible wall motion abnormalities similar to concurrently enrolled ISCHEMIA participants with obstructive coronary artery disease. Our results highlight the complex nature of INOCA pathophysiology and the multifactorial nature of angina. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02347215.

Predictors of outcome in the ISCHEMIA-CKD trial: Anatomy versus ischemia.

BACKGROUND: The ISCHEMIA-CKD (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches-Chronic Kidney Disease) trial found no advantage to an invasive strategy compared to conservative management in reducing all-cause death or myocardial infarction (D/MI). However, the prognostic influence of angiographic coronary artery disease (CAD) burden and ischemia severity remains unknown in this population. We compared the relative impact of CAD extent and severity of myocardial ischemia on D/MI in patients with advanced chronic kidney disease (CKD). METHODS: Participants randomized to invasive management with available data on coronary angiography and stress testing were included. Extent of CAD was defined by the number of major epicardial vessels with ≥50% diameter stenosis by quantitative coronary angiography. Ischemia severity was assessed by site investigators as moderate or severe using trial definitions. The primary endpoint was D/MI. RESULTS: Of the 388 participants, 307 (79.1%) had complete coronary angiography and stress testing data. D/MI occurred in 104/307 participants (33.9%). Extent of CAD was associated with an increased risk of D/MI (P < .001), while ischemia severity was not (P = .249). These relationships persisted following multivariable adjustment. Using 0-vessel disease (VD) as reference, the adjusted hazard ratio (HR) for 1VD was 1.86, 95% confidence interval (CI) 0.94 to 3.68, P = .073; 2VD: HR 2.13, 95% CI 1.10 to 4.12, P = .025; 3VD: HR 4.00, 95% CI 2.06 to 7.76, P < .001. Using moderate ischemia as the reference, the HR for severe ischemia was 0.84, 95% CI 0.54 to 1.30, P = .427. CONCLUSION: Among ISCHEMIA-CKD participants randomized to the invasive strategy, extent of CAD predicted D/MI whereas severity of ischemia did not.

Effects of Glucagon-Like Peptide-1 Receptor Agonist (GLP-1RA) on Cardiac Structure and Function: A Systematic Review and Meta-Analysis of Randomized-Controlled Trials.

PURPOSE: Recent trials suggest glucagon-like peptide-1 receptor agonists (GLP-1RAs) may have a cardioprotective role by reducing major adverse cardiac events, stroke mortality and heart failure-related hospitalisations. We examined whether and how GLP-1RAs affect cardiac function in cardiovascular and metabolic diseases including type 2 diabetes, heart failure and post-myocardial infarction. METHODS: In this PRISMA-adherent systematic review and meta-analysis, three databases were searched from inception to July 2021 and registered on PROSPERO (CRD42021259661). RESULTS: 20 reports of 19 randomized placebo-controlled trials including 2062 participants were meta-analyzed. Among type 2 diabetes patients, GLP-1RA resulted in improved systolic function measured by circumferential strain (mean difference [MD]= -5.48; 95% CI: -10.47 to -0.49; P= 0.03; I2= 89%) and diastolic dysfunction measured by E / A (MD= -0.15; 95% CI: -0.25 to -0.05; P= 0.003; I2= 0%). For post-myocardial infarction patients, GLP-1RA reduced infarct size (g) (MD= -5.36; 95% CI: -10.68 to -0.04; P= 0.05; I2= 78%). Liraglutide, but not exenatide, demonstrated improved systolic function, by increasing left ventricular ejection fraction (MD= 4.89; 95% CI: 3.62 to 6.16; P< 0.00001; I2= 0%) and reducing left ventricular end-systolic volume (MD= -4.15; 95% CI: -7.49 to -0.81; P = 0.01; I2= 0%). Among heart failure patients, no significant changes were noted. CONCLUSION: GLP-1RA drugs may improve systolic and diastolic function in type 2 diabetes and reduce infarct size post-acute myocardial infarction with no demonstrable effect on cardiac function in heart failure. Tailored recommendations for the use of GLP-1RAs for cardioprotection should be considered for each patient's condition.

A systematic review and meta-analysis of non-vitamin K antagonist oral anticoagulants vs vitamin K antagonists after transcatheter aortic valve replacement in patients with atrial fibrillation.

PURPOSE: Transcatheter aortic valve replacement (TAVR) is increasingly carried out in patients with aortic valvular conditions. Atrial fibrillation (AF) is a common comorbidity among patients undergoing TAVR. Despite this, there remains a paucity of data and established guidelines regarding anticoagulation use post-TAVR in patients with AF. METHODS: Four databases were searched from inception until 12 October 2021. A title and abstract sieve, full-text review and data extraction were conducted by independent authors, and articles including patients without AF were excluded. The Review Manager (Version 5.4) was utilised in data analysis. RESULTS: A total of 25,199 post-TAVR patients with AF were included from seven articles, with 9764 patients on non-vitamin K antagonist oral anticoagulants (NOAC) and 15,435 patients on vitamin K antagonists (VKA). In this analysis, there was a significantly lower risk of all-cause mortality at 1 year (RR: 0.75, CI: 0.58-0.97, p = 0.04, I2 = 56%), and bleeding at 1 year (RR: 0.73, CI: 0.68-0.79, p = < 0.00001, I2 = 0%), between patients on NOAC and VKA. There were no detectable differences between patients on NOAC and VKA for all-cause mortality at 2 years, stroke within 30 days, stroke within 1 year, ischaemic stroke at 1 year and life-threatening bleeding at 30 days. CONCLUSION: While the results of this analysis reveal NOAC as a potential alternate treatment modality to VKA in post-TAVR patients with AF, further research is needed to determine the full safety and efficacy profile of NOAC (PROSPERO: CRD42021283548).

One-year outcomes of patients with ST-segment elevation myocardial infarction during the COVID-19 pandemic.

The pandemic has led to adverse short-term outcomes for patients with ST-segment elevation myocardial infarction (STEMI). It is unknown if this translates to poorer long-term outcomes. In Singapore, the escalation of the outbreak response on February 7, 2020 demanded adaptation of STEMI care to stringent infection control measures. A total of 321 patients presenting with STEMI and undergoing primary percutaneous coronary intervention at a tertiary hospital were enrolled and followed up over 1-year. They were allocated into three groups based on admission date-(1) Before outbreak response (BOR): December 1, 2019-February 6, 2020, (2) During outbreak response (DOR): February 7-March 31, 2020, and (3) control group: November 1-December 31, 2018. The incidence of cardiac-related mortality, cardiac-related readmissions, and recurrent coronary events were examined. Although in-hospital outcomes were worse in BOR and DOR groups compared to the control group, there were no differences in the 1-year cardiac-related mortality (BOR 8.7%, DOR 7.1%, control 4.8%, p = 0.563), cardiac-related readmissions (BOR 15.1%, DOR 11.6%, control 12.0%, p = 0.693), and recurrent coronary events (BOR 3.2%, DOR 1.8%, control 1.2%, p = 0.596). There were higher rates of additional PCI during the index admission in DOR, compared to BOR and control groups (p = 0.027). While patients admitted for STEMI during the pandemic may have poorer in-hospital outcomes, their long-term outcomes remain comparable to the pre-pandemic era.

Long-Term Prognosis of Acute Myocardial Infarction Associated With Metabolic Health and Obesity Status.

OBJECTIVE: Emerging evidence supports the favorable cardiovascular health in nonobese subjects with healthy metabolism. However, little is known regarding the prognosis across the range of metabolic phenotypes once cardiovascular disease is established. We examined the prognosis of patients with acute myocardial infarction (AMI) stratified according to metabolic health and obesity status. METHODS: This is a retrospective study on consecutive patients with AMI admitted to a tertiary hospital between 2014 and 2021. Patients were allocated into the following 4 groups based on metabolic and obesity profile: (1) metabolically healthy obese (MHO), (2) metabolically healthy nonobese (MHNO), (3) metabolically unhealthy obese (MUO), and (4) metabolically unhealthy nonobese (MUNO). Metabolic health was defined in accordance to the Biobank Standardisation and Harmonisation for Research Excellence in the European Union Healthy Obese Project. The primary outcome was all-cause mortality. The Cox regression analysis examined the independent association between mortality and metabolic phenotypes, adjusting for age, sex, AMI type, chronic kidney disease, smoking status, and left ventricular ejection fraction. RESULTS: Of 9958 patients, the majority (68.5%) were MUNO, followed by MUO (25.1%), MHNO (5.6%), and MHO (0.8%). MHO had the lowest mortality (7.4%), followed by MHNO (9.7%), MUO (19.2%), and MUNO (22.6%) (P < .001). Compared with MHNO, MUO (hazard ratio [HR], 1.737; 95% confidence interval [CI], 1.282-2.355; P < .001) and MUNO (HR, 1.482; 95% CI, 1.108-1.981; P = .008) had a significantly higher mortality risk but not MHO (HR, 1.390; 95% CI, 0.594-3.251; P = .447), after adjusting for confounders. The Kaplan-Meier curves showed favorable survival in the metabolically healthy and obesity groups, with the highest overall survival in the MHO, followed by MHNO, MUO, and MUNO (P < .001). CONCLUSION: Metabolically healthy and obese patients with AMI have favorable prognosis compared with metabolically unhealthy and nonobese patients. It is equally important to prioritize intensive metabolic risk factor management to weight reduction in the early phase after AMI.

Clinical and echocardiographic characteristics associated with the development of infective endocarditis in patients with significant mitral stenosis.

BACKGROUND: Infective endocarditis (IE) confers significant mortality and morbidity in patients with underlying mitral stenosis (MS), with both diseased native valves and after valvular procedures. PURPOSE: We examined the clinical and echocardiographic parameters in association with the development of IE on patients with significant MS. METHODS: A total of 478 consecutive patients with index echocardiographic diagnosis of significant mitral stenosis (mitral valve area <1.5 cm2 ) were included. Patients were grouped into those with or without IE on at least 5 years of follow-up. Baseline clinical, echocardiographic profile and clinical outcomes were compared. RESULTS: IE was observed in 4.4% (n = 21) of the cohort. These patients were younger (45.3 ± 14.6 vs. 53.2 ± 15.5 years, p = 0.022) at the time of MS diagnosis. NT-proBNP was higher in patients who developed IE (13529 ± 12230 vs. 4381 ± 5875 pg/ml, p < 0.001), with larger left atrial diameter (54.4 ± 10.1 vs. 49.9 ± 9.5 mm, p = 0.040) and elevated pulmonary artery systolic pressure (PASP, 62.3 ± 17.2 vs. 47.2 ± 16.5 mmHg, p = 0.026). There was no significant difference in terms of MS severity, other concomitant valvulopathies, or etiology (rheumatic or degenerative) of MS. Patients who smoked had higher incidence of IE (33.3% vs. 14.2%, log-rank 7.27, p = 0.007). After adjusting for age, valve procedure and PASP, patients who smoked remained at elevated risk of IE (adjusted hazards ratio 2.99, 95% confidence interval 1.18-7.56, p = 0.021). CONCLUSION: IE occurs in a proportion of patients with MS. Smoking, younger age of diagnosis of MS as well as dilated left atria with elevated PASP may be associated with an elevated risk of this complication.

Severe Functional Tricuspid Valve Regurgitation: Predictors of Mortality After Initial Diagnosis.

BACKGROUND: Severe functional tricuspid regurgitation (fTR) is associated with adverse clinical outcomes and remains under-treated. There is recent interest in this disease due to emerging tricuspid valve therapies. However, the timing and selection of patients who may benefit from treatment is uncertain. Risk factors associated with mortality after diagnosis of severe fTR may help guide treatment. AIM: We studied patients with severe fTR to assess predictors of mortality. METHODS: We retrospectively identified consecutive patients who had severe fTR diagnosed on transthoracic echocardiography in a single academic tertiary hospital. These were categorised into atrial fibrillation (AF)- and non-AF-related groups. Patient characteristics and echocardiographic parameters were collected. We then analysed the collected parameters on their impact on occurrence of mortality and also on the time to mortality. RESULTS: A total of 635 patients with severe fTR were studied (41.6 % male, mean age of 68.6±15.4 yrs). There were 130 (20.5%) in the AF-related group and 505 (79.5%) in the non-AF related-group. Median follow-up duration was 774 days, during which 154 (24.3%) deaths occurred within the first year. Older age on diagnosis, reduced left ventricular ejection fraction (LVEF) (<50%), high pulmonary systolic pressure (PASP) (>50 mmHg) and a prior history of heart failure admissions were associated with occurrence of mortality. Older age on diagnosis, reduced LVEF, and high PASP were also found to be associated with time to mortality. CONCLUSIONS: For patients diagnosed with severe fTR, advanced age on diagnosis, prior heart failure admission, LVEF <50%, and PASP >50 mmHg are associated with mortality. These factors could form the basis of future studies that determine the timing and decision to intervene in patients with severe fTR.

Low Relative Valve Load is Associated With Paradoxical Low-Flow Aortic Stenosis Despite Preserved Left Ventricular Ejection Fraction and Adverse Clinical Outcomes.

BACKGROUND: Paradoxical low-flow (LF) severe aortic stenosis (AS) despite preserved left ventricular (LV) ejection fraction (LVEF) has been shown to be distinct from normal-flow (NF) AS, with a poorer prognosis. Relative valve load (RVL) is a novel echocardiographic haemodynamic index based on the ratio of transaortic mean pressure gradient to the global valvulo-arterial impedance (Zva) in order to estimate the contribution of the valvular afterload to the global LV load. We aimed to determine the usefulness of RVL in LF AS versus NF AS. METHOD: A total of 450 consecutive patients with medically managed severe AS (aortic valve area <1.0 cm2) with preserved LVEF (>50%) were studied. Patients were divided into LF (stroke volume index <35 mL/m2) or NF, and high RVL or low RVL. Baseline clinical and echocardiographic profiles, as well as clinical outcomes, were compared. RESULTS: There were 149 (33.1%) patients with LF. Despite higher global impedance in LF (Zva 6.3±2.4 vs 3.9±0.9 mmHg/mL/m2; p<0.001) compared with NF, the RVL in LF AS was significantly lower (5.4±2.7 vs 9.8±5.1 mL/m2; p<0.001). On multivariable analysis, low RVL (≤7.51) remained independently associated with poor clinical outcomes on Cox regression (hazard ratio, 1.31; 95% confidence interval, 1.03-1.68), with 53.2% sensitivity and 70.3% specificity. This was comparable to other prognostic indices in AS. Kaplan-Meier curves demonstrated that low RVL was associated with increased mortality. CONCLUSIONS: Increased systemic arterial afterload may be important in the pathophysiology of LF AS. Low RVL was an independent predictor of poor clinical outcomes in medically managed severe AS. There may be a greater role in the attenuation of systemic arterial afterload in AS to improve outcomes.

Inter-Ethnic Differences in Valvular Dysfunction, Aortopathy, and Progression of Disease of an Asian Bicuspid Aortic Valve Population.

BACKGROUND: There are differences in bicuspid aortic valve (BAV) characteristics between Asian and European populations, but little is known about the inter-ethnic differences in bicuspid valve function and aortic root dimensions within the diverse Asian population. METHODS: From 1992-2017, 562 patients with index echocardiographic diagnosis of BAV in a tertiary health care institution in Singapore were analysed according to their ethnic groups: Chinese, Malay, Indian, and Eurasian. Study outcomes included BAV complications (infective endocarditis, aortic dissection) and clinical outcomes (aortic valve surgery, aortic root surgery, all-cause mortality). Total events were defined as composite outcome of all BAV complications and outcomes. Aortic dimensions and aortic dilatation rates were also studied. RESULTS: There were 379 (67.5%) Chinese, 79 (14.0%) Malay, 73 (13.0%) Indian, and 31 (5.5%) Eurasian patients. Type 1 BAV (58.5%) was the most prevalent BAV morphology, with moderate-to-severe aortic stenosis (AS) (36.8%) being the most common complication in the overall population. There was a higher prevalence of type 0 BAV in Chinese and Indian groups, and type 1 BAV with fusion of left-right coronary cusp in Eurasian and Malay groups (p=0.082). There was no difference in significant AS among groups. The highest prevalence of moderate-to-severe aortic regurgitation was observed amongst the Eurasian group, followed by Chinese, Indian, and Malay groups (p=0.033). The Chinese group had the largest mean indexed diameters of the aortic root. Multivariable linear regression demonstrated that only the Chinese had significantly larger indexed diameters in the aortic annulus, sinotubular junction (STJ), and ascending aorta (AA), relative to the Eurasian group, after adjusting for age, sex, smoking, hypertension, hyperlipidaemia, diabetes, and aortic regurgitation. On follow-up echocardiography, there was a trend towards the highest dilatation rates of sinus of Valsalva and STJ amongst Indian, and AA amongst Malay groups. Kaplan-Meier curves showed the highest incidence of total events amongst Chinese, followed by Malay, Indian and Eurasian (log-rank=9.691; p=0.021) patients. CONCLUSION: There were differences in BAV morphology, valve dysfunction, aortopathy, and prognosis within the Asian population. Chinese patients had one of the highest prevalence of significant aortic regurgitation, with the largest aortic dimensions and worst outcomes compared with other Asian ethnicities. Closer surveillance is warranted in BAV patients within the Asian population.

Plasma Clearance of B-Type Natriuretic Peptide (BNP) before and after Bariatric Surgery for Morbid Obesity.

BACKGROUND: Obese patients have lower plasma concentrations of the cardiac natriuretic peptides (NPs) than their age- and sex-matched counterparts. This may reflect lower production and/or increased peptide clearance. It is unclear whether NP bioactivity is affected by obesity. METHODS: We studied the effects of obesity on B-type natriuretic peptide (BNP) clearance and bioactivity by comparing results from standardized intravenous infusions of BNP administered 2 weeks before and 6 months after bariatric surgery in 12 consecutive patients with morbid obesity (body mass index, BMI > 35 kg/m2). Anthropometric, clinical, neurohormonal, renal, and echocardiographic variables were obtained pre- and postsurgery. Pre- vs postsurgery calculated intrainfusion peptide clearances were compared. RESULTS: BMI (44.3 ± 5.0 vs 33.9 ± 5.2 kg/m2, P < 0.001) and waist circumference (130.3 ± 11.9 vs 107.5 ± 14.7 cm, P < 0.001) decreased substantially after bariatric surgery. Calculated plasma clearance of BNP was reduced (approximately 30%) after surgery. Though not controlled for, sodium intake was presumably lower after bariatric surgery. Despite this, preinfusion endogenous plasma NP concentrations did not significantly differ between pre- and postsurgery studies. The ratio of plasma N-terminal (NT)-proBNP to 24 h urine sodium excretion was higher postsurgery (P = 0.046; with similar nonsignificant findings for BNP, atrial NP (ANP) and NT-proANP), indicating increased circulating NPs for a given sodium status. Mean plasma NP concentrations for given calculated end-systolic wall stress and cardiac filling pressures (as assessed by echocardiographic E/e') rose slightly, but not significantly postsurgery. Second messenger, hemodynamic, renal, and neurohormonal responses to BNP were not altered between studies. CONCLUSION: Obesity is associated with increased clearance, but preserved bioactivity, of BNP.

An Asian Perspective on Gender Differences in Clinical Outcomes and Echocardiographic Profiles of Patients With Medically Managed Severe Aortic Stenosis.

BACKGROUND: Gender differences in valvular heart disease are increasingly recognised. A prior study has suggested better surgical outcomes in women with symptomatic aortic stenosis (AS). We investigate gender differences in medically managed severe AS. METHOD: We studied 347 patients with severe AS (aortic valve area index <0.6 cm2/m2) in terms of baseline clinical background, echocardiographic characteristics, and clinical outcomes. Appropriate univariate and multivariate models were employed, while Kaplan-Meier curves were constructed to compare mortality outcomes. RESULTS: In total, 205 (59%) patients were women. Despite higher incidences of hypertension (75.6% vs 47.3%) and diabetes mellitus (46.5% vs 29.5%) in women, women had improved survival (Kaplan-Meier log-rank = 6.24, p = 0.012). After adjusting for age (hazard ratio [HR], 1.034; 95% confidence interval [CI], 1.014-1.054), hypertension (HR, 1.469; 95% CI, 0.807-2.673), diabetes (HR, 1.219; 95% CI, 0.693-2.145), and indexed aortic valve area (HR 0.145, 95% CI 0.031-0.684) on multivariate analyses, female gender remained independently associated with lower mortality (HR, 0.561; 95%, CI 0.332-0.947). Women tended to have smaller body surface area (BSA), left ventricular (LV) internal diastolic diameter, and smaller LV outflow tract diameter but were similar to men in terms of LV ejection fraction, AS severity, and patterns of LV remodelling. CONCLUSIONS: Women appeared to have better outcomes compared to men in medically managed severe AS. These gender differences warrant further study and may affect prognosis, follow-up, and timing of valve surgery.

Exclusion of alternative exon 33 of CaV1.2 calcium channels in heart is proarrhythmogenic.

Alternative splicing changes the CaV1.2 calcium channel electrophysiological property, but the in vivo significance of such altered channel function is lacking. Structure-function studies of heterologously expressed CaV1.2 channels could not recapitulate channel function in the native milieu of the cardiomyocyte. To address this gap in knowledge, we investigated the role of alternative exon 33 of the CaV1.2 calcium channel in heart function. Exclusion of exon 33 in CaV1.2 channels has been reported to shift the activation potential -10.4 mV to the hyperpolarized direction, and increased expression of CaV1.2Δ33 channels was observed in rat myocardial infarcted hearts. However, how a change in CaV1.2 channel electrophysiological property, due to alternative splicing, might affect cardiac function in vivo is unknown. To address these questions, we generated mCacna1c exon 33-/--null mice. These mice contained CaV1.2Δ33 channels with a gain-of-function that included conduction of larger currents that reflects a shift in voltage dependence and a modest increase in single-channel open probability. This altered channel property underscored the development of ventricular arrhythmia, which is reflected in significantly more deaths of exon 33-/- mice from ß-adrenergic stimulation. In vivo telemetric recordings also confirmed increased frequencies in premature ventricular contractions, tachycardia, and lengthened QT interval. Taken together, the significant decrease or absence of exon 33-containing CaV1.2 channels is potentially proarrhythmic in the heart. Of clinical relevance, human ischemic and dilated cardiomyopathy hearts showed increased inclusion of exon 33. However, the possible role that inclusion of exon 33 in CaV1.2 channels may play in the pathogenesis of human heart failure remains unclear.

Differences in Clinical and Echocardiographic Profiles and Outcomes of Patients With Atrial Fibrillation Versus Sinus Rhythm in Medically Managed Severe Aortic Stenosis and Preserved Left Ventricular Ejection Fraction.

BACKGROUND: Atrial fibrillation (AF) results in the loss of atrial booster pump function and portends poorer outcome in aortic valve stenosis (AS). However, its characteristics and impact on medically managed AS remained under-recognised. We compared these patients with AF to sinus rhythm (SR). METHOD: In total, 347 consecutive patients with medically managed severe AS (aortic valve area <1 cm2) and preserved left ventricular ejection fraction (>50%) were studied, in terms of echocardiographic characteristics and clinical outcomes. Appropriate univariate and multivariate models were used, while Kaplan-Meier curves and Cox regression models were constructed to compare clinical outcomes (mortality, admissions for congestive cardiac failure, and stroke). RESULTS: Ninety (90) (25.9%) patients had AF. Patients with AF had lower body mass index (BMI 18.5±10.4 vs 23.8±6.2 g/m2; p<0.001), larger left ventricular mass index (LVMI 127.9±39.0 vs 116.7±36.5; p=0.017), and left atrial volume index (53.2±20.0 vs 31.0±9.2 mL/m2; p=0.004). Atrial fibrillation was associated with higher mortality (52.2% vs 37.4%; Kaplan-Meier log-rank 7.18; p=0.007), admissions for congestive cardiac failure (log-rank 6.42; p=0.011), and poorer composite outcomes (log-rank 6.29; p=0.012). The incidence of stroke in both groups were similar on follow-up (log-rank 0.08; p=0.776). After adjusting for age, BMI, LVMI, and left atrial volume index on Cox regression, AF remained independently associated with poorer composite clinical outcomes (hazard ratio, 1.66; 95% confidence interval 1.07-2.58). CONCLUSIONS: Atrial fibrillation remained an important comorbidity affecting a quarter of patients with medically managed severe AS. It was independently associated with poorer clinical outcomes and may thus aid in prognostication and management.

Assessment of left atrial appendage function by transthoracic pulsed Doppler echocardiography: Comparing against transesophageal interrogation and predicting echocardiographic risk factors for stroke.

AIMS: Transesophageal echocardiographic (TEE) findings of left atrial appendage (LAA) thrombus, spontaneous echo contrast (SEC), and LAA dysfunction are established risk factors of cardioembolic stroke. The semi-invasive nature of TEE limits its utility as a routine risk stratification tool. We aim to correlate TEE and transthoracic echocardiography (TTE) pulsed Doppler measurements of LAA flow velocities and use TTE measurements to predict TEE findings. METHODS AND RESULTS: We prospectively measured pulsed Doppler LAA flow velocities in 103 consecutive patients on TEE and TTE. There was a strong correlation between TEE and TTE LAA emptying velocity (LAA E) (r = .88, P < .001) and a moderate correlation between LAA filling velocities (r = .50, P < .001). TTE LAA E predicted the presence of thrombus or SEC independent of atrial fibrillation (AF). To predict the presence of thrombus or SEC, the optimal TTE LAA E cutoff was ≤30 cm/s in all patients (75% sensitive, 90% specific) and ≤31 cm/s in AF patients (80% sensitive, 79% specific). To predict LAA dysfunction (TEE E ≤ 20 cm/s), the optimal TTE LAA E cutoff was ≤27 cm/s (100% sensitive, 89% specific in all patients and 100% sensitive, 74% specific in AF patients). CONCLUSIONS: TTE assessment of LAA function is feasible and correlates well with the more invasive TEE method. It predicts the presence of thrombus, SEC, and LAA dysfunction on TEE. TTE LAA assessment has incremental value in thromboembolic risk stratification and should be utilized more frequently.

Predicting changes in flow category in patients with severe aortic stenosis and preserved left ventricular ejection fraction on medical therapy.

BACKGROUND/OBJECTIVES: Controversy surrounds the prognosis and management of patients with paradoxical low-flow severe aortic stenosis (AS) with preserved left ventricular ejection fraction (LVEF). It was not certain if patients in a particular flow category remained in the same category as disease progressed. We investigated whether there were switches in categories and if so, their predictors. METHODS: Consecutive subjects (n = 203) with isolated severe AS and paired echocardiography (>180 days apart) were studied. They were divided into 4 groups, based on their flow categories and if they progressed on subsequent echocardiography to switch or remain in the same flow category. Univariate analyses of clinical and echocardiographic parameters identified predictors of these changes in flow category. RESULTS: One hundred eighteen were normal flow (SVI ≥ 35 mL/m2 ), while 85 were low flow on index echocardiography. In the patients with normal flow, 33% switched to low flow. This was associated with higher valvuloarterial impedance (Zva, P < .001) and lower systemic arterial compliance (SAC, P < .001) compared to index echocardiography, and predicted by higher initial Zva (optimized cutoff >4.77 mm Hg/mL/m2 , AUC = 0.81 [95% CI:0.75-0.87, P < .001]). In patients with low flow, 25% switched to normal flow, which was associated with lower Zva and higher SAC and the switch was predicted by a higher initial mean transaortic pressure gradient. CONCLUSIONS: A significant number of patients switched flow categories in severe AS with preserved LVEF on subsequent echocardiography. Changes in flow were reflected by respective changes in Zva and SAC. Identifying echocardiographic predictors of a switch in category may guide prognostication and management of such patients.