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Background: Echocardiographic indexes of aortic stenosis may not comprehensively reflect disease morbidity. Plasma proteomic profiling may add prognostic value in these patients., Methods and Results: Proximity extension assays (Olink) of 183 circulating cardiovascular and inflammatory proteins were performed in a prospective follow-up study of 122 asymptomatic/minimally symptomatic patients (mean±SD age, 69.1±10.9 years; 61% men) with moderate to severe aortic stenosis and preserved left ventricular ejection fraction. Protein signatures of higher-risk echocardiographic subgroups were determined. Associations of proteins with the primary composite outcome (heart failure hospitalization, progression to New York Heart Association class III-IV, or all-cause mortality) were evaluated using competing risk analyses, with aortic valve replacement being the competing risk. Network analysis unveiled mutually exclusive communities of proteins and echocardiographic parameters, connected only through NT-proBNP (N-terminal pro-B-type natriuretic peptide). Members of the tumor necrosis factor receptor superfamily (TNFRSF1A, TNFRSF1B, and TNFRSF14), and trefoil factor-3 were major hub proteins among the circulating biomarkers. Left ventricular global longitudinal strain >-15% was associated with higher levels of proteins, primarily of inflammation and immune regulation, whereas aortic valve area <1 cm 2 , E/e' >15, and left atrial reservoir strain <20% were associated with higher levels of NT-proBNP. Of 14 proteins associated with the primary end point, phospholipase-C, C-X-C motif chemokine-9, and interleukin-10 receptor subunit β demonstrated the highest hazard ratios after adjusting for clinical factors ( q <0.05)., Conclusions: Plasma proteins involved in inflammation and immune regulation were differentially expressed in patients with aortic stenosis with reduced left ventricular global longitudinal strain, and associated with adverse clinical outcomes. Their incorporation into aortic stenosis risk stratification warrants further assessment.

Background: The role of left atrial (LA) strain as an imaging biomarker in aortic stenosis is not well established. The aim of this study was to investigate the prognostic performance of phasic LA strain in relation to clinical and echocardiographic variables and N-terminal pro-B-type natriuretic peptide in asymptomatic and minimally symptomatic patients with moderate to severe aortic stenosis and left ventricular ejection fraction > 50%., Methods: LA reservoir strain (LASr), LA conduit strain (LAScd), and LA contractile strain (LASct) were measured using speckle-tracking echocardiography. The primary outcome was a composite of all-cause mortality, heart failure hospitalization, progression to New York Heart Association functional class III or IV, acute coronary syndrome, or syncope. Secondary outcomes 1 and 2 comprised the same end points but excluded acute coronary syndrome and additionally syncope, respectively. The prognostic performance of phasic LA strain cutoffs was evaluated in competing risk analyses, aortic valve replacement being the competing risk., Results: Among 173 patients (mean age, 69 ± 11 years; mean peak transaortic velocity, 4.0 ± 0.8 m/sec), median LASr, LAScd, and LASct were 27% (interquartile range [IQR], 22%-32%), 12% (IQR, 8%-15%), and 16% (IQR, 13%-18%), respectively. Over a median of 2.7 years (IQR, 1.4-4.6 years), the primary outcome and secondary outcomes 1 and 2 occurred in 66 (38%), 62 (36%), and 59 (34%) patients, respectively. LASr < 20%, LAScd < 6%, and LASct < 12% were identified as optimal cutoffs of the primary outcome. In competing risk analyses, progressing from echocardiographic to echocardiographic-clinical and combined models incorporating N-terminal pro-B-type natriuretic peptide, LA strain parameters outperformed other key echocardiographic variables and significantly predicted clinical outcomes. LASr < 20% was associated with the primary outcome and secondary outcome 1, LAScd < 6% with all clinical outcomes, and LASct < 12% with secondary outcome 2. LAScd < 6% had the highest specificity (95%) and positive predictive value (82%) for the primary outcome, and competing risk models incorporating LAScd < 6% had the best discriminative value., Conclusions: In well-compensated patients with moderate to severe aortic stenosis and preserved left ventricular ejection fractions, LA strain was superior to other echocardiographic indices and incremental to N-terminal pro-B-type natriuretic peptide for risk stratification. LAScd < 6%, LASr < 20%, and LASct < 12% identified patients at higher risk for adverse outcomes., (Copyright © 2022 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.)

Objective: We investigated the prognostic significance of selected known and novel circulating biomarkers in aortic stenosis (AS)., Methods: N-terminal pro-BNP (NT-proBNP), high-sensitivity troponin-T (hsTnT), growth differentiation factor-15 (GDF-15), suppression of tumorigenicity-2 (ST2), mid-regional proadrenomedullin (MR-proADM) and mid-regional proatrial natriuretic peptide (MR-proANP) were measured in patients with moderate to severe AS, New York Heart Association (NYHA) class I-II and left ventricular ejection fraction ≥50%, recruited consecutively across five centres from 2011 to 2018. Their ability to predict both primary (all-cause mortality, heart failure hospitalisation or progression to NYHA class III-IV) and secondary (additionally incorporating syncope and acute coronary syndrome) outcomes was determined by competing risk analyses., Results: Among 173 patients with AS (age 69±11 years, 55% male, peak transaortic velocity (Vmax) 4.0±0.8 m/s), the primary and secondary outcomes occurred in 59 (34%) and 66 (38%), respectively. With aortic valve replacement as a competing risk, the primary outcome was determined consistently by the comorbidity index and each selected biomarker except ST2 (p<0.05), independent of NYHA class, Vmax, LV-global longitudinal strain and serum creatinine. MR-proADM had the highest discriminative value for both primary (subdistribution HR (SHR) 11.3, 95% CI 3.9 to 32.7) and secondary outcomes (SHR 12.6, 95% CI 4.7 to 33.5). Prognostic assessment of dual-biomarker combinations identified MR-proADM plus either hsTnT or NT-proBNP as the best predictive model for both clinical outcomes. Paired biomarker models were not superior to those including MR-proADM as the sole circulating biomarker., Conclusion: MR-proADM most powerfully portended worse prognosis and should be further assessed as possibly the biomarker of choice for risk stratification in AS., Competing Interests: Competing interests: SHE reports personal fees from Medtronic, Edwards Lifesciences and Abbott Medical, outside the submitted work. ZPD reports personal/speaker fees from GE and Phillips, and non-financial support from Phillips, outside the submitted work. AMR reports grants from National Medical Research Council of Singapore during the conduct of the study, is a long-term collaborator with Roche Diagnostics, the provider of assays central to this submission, and received support in kind, grants, speaker’s honoraria and acted on advisory boards for Roche Diagnostics. LHHL reports grants from National Medical Research Council of Singapore during the conduct of the study., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims: Left ventricular ejection fraction is the conventional measure used to guide heart failure management, regardless of underlying etiology. Left ventricular global longitudinal strain (LV-GLS) by speckle tracking echocardiography (STE) is a more sensitive measure of intrinsic myocardial function. We aim to establish LV-GLS as a marker of replacement myocardial fibrosis on cardiovascular magnetic resonance (CMR) and validate the prognostic value of LV-GLS thresholds associated with fibrosis. Methods and results: LV-GLS thresholds of replacement fibrosis were established in the derivation cohort: 151 patients (57 ± 10 years; 58% males) with hypertension who underwent STE to measure LV-GLS and CMR. Prognostic value of the thresholds was validated in a separate outcome cohort: 261 patients with moderate-severe aortic stenosis (AS; 71 ± 12 years; 58% males; NYHA functional class I-II) and preserved LVEF ≥50%. Primary outcome was a composite of cardiovascular mortality, heart failure hospitalization, and myocardial infarction. In the derivation cohort, LV-GLS demonstrated good discrimination (c-statistics 0.74 [0.66-0.83]; P < 0.001) and calibration (Hosmer-Lemeshow χ 2 = 6.37; P = 0.605) for replacement fibrosis. In the outcome cohort, 47 events occurred over 16 [3.3, 42.2] months. Patients with LV-GLS > -15.0% (corresponding to 95% specificity to rule-in myocardial fibrosis) had the worst outcomes compared to patients with LV-GLS < -21.0% (corresponding to 95% sensitivity to rule-out myocardial fibrosis) and those between -21.0 and -15.0% (log-rank P < 0.001). LV-GLS offered independent prognostic value over clinical variables, AS severity and echocardiographic LV mass and E/e'. Conclusion: LV-GLS thresholds associated with replacement myocardial fibrosis is a novel approach to risk-stratify patients with AS and preserved LVEF., Competing Interests: The department of Cardiology at Leiden University receives unrestricted research grants from Abbott Vascular, Bayer, Biotronik, BIoventrix, Boston Scientific, Edwards Lifesciences, GE Healthcare, Ionis and Medtronic. VD received speaker fees from Abbott Vascular, Edwards Lifesciences, GE Healthcare, MSD, Medtronic and Novartis. JJB received speaker fees from Abbott Vascular. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Le, Huang, Singh, Toh, Ewe, Tang, Loo, Bryant, Ang, Tay, Soo, Yip, Oon, Gong, Lunaria, Yong, Lee, Yeo, Chai, Goh, Ling, Ong, Richards, Delgado, Bax, Ding, Ling and Chin.)

Context: Coconut oil is rich in medium-chain fatty acids and has been claimed to have numerous health benefits., Objective: This review aimed to examine the evidence surrounding coconut oil consumption and its impact on cardiovascular health., Data Sources: A systematic literature search of the PubMed, Embase, the Cochrane Library, and CINAHL databases, up to May 2019, was performed., Data Extraction: Study characteristics including study design, population, intervention, comparator, outcome, and source of funding were summarized., Data Analysis: Meta-analyses included 12 studies to provide estimates of effects. Subgroup analyses were performed to account for any differences in the study-level characteristics. When compared with plant oils and animal oils, coconut oil was found to significantly increase high-density lipoprotein cholesterol (HDL-C) by 0.57 mg/dL (95%CI, 0.40-0.74 mg/dL; I2 = 6.7%) and 0.33 mg/dL (0.01-0.65 mg/dL; I2 = 0%), respectively. Coconut oil significantly raised low-density lipoprotein cholesterol (LDL-C) by 0.26 mg/dL (0.09-0.43 mg/dL; I2 = 59.7%) compared with plant oils and lowered LDL-C (-0.37 mg/dL; -0.69 to -0.05 mg/dL; I2 = 48.1%) compared with animal oils. No significant effects on triglyceride were observed. Better lipid profiles were demonstrated with the virgin form of coconut oil., Conclusion: Compared with animal oils, coconut oil demonstrated a better lipid profile n comparison with plant oils, coconut oil significantly increased HDL-C and LDL-C., (© The Author(s) 2019. Published by Oxford University Press on behalf of the International Life Sciences Institute. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Myxomatous mitral valve prolapse (MMVP) and fibroelastic deficiency (FED) are two common variants of degenerative mitral valve disease (DMVD), which is a leading cause of mitral regurgitation worldwide. While pathohistological studies have revealed differences in extracellular matrix content in MMVP and FED, the molecular mechanisms underlying these two disease entities remain to be elucidated. By using surgically removed valvular specimens from MMVP and FED patients that were categorized on the basis of echocardiographic, clinical and operative findings, a cluster of microRNAs that expressed differentially were identified. The expressions of has-miR-500, -3174, -17, -1193, -646, -1273e, -4298, -203, -505, and -939 showed significant differences between MMVP and FED after applying Bonferroni correction (p < 0.002174). The possible involvement of microRNAs in the pathogenesis of DMVD were further suggested by the presences of in silico predicted target sites on a number of genes reported to be involved in extracellular matrix homeostasis and marker genes for cellular composition of mitral valves, including decorin (DCN), aggrecan (ACAN), fibromodulin (FMOD), α actin 2 (ACTA2), extracellular matrix protein 2 (ECM2), desmin (DES), endothelial cell specific molecule 1 (ESM1), and platelet/ endothelial cell adhesion molecule 1 (PECAM1), as well as inverse correlations of selected microRNA and mRNA expression in MMVP and FED groups. Our results provide evidence that distinct molecular mechanisms underlie MMVP and FED. Moreover, the microRNAs identified may be targets for the future development of diagnostic biomarkers and therapeutics.

Background: Statins have been shown to be beneficial in primary and secondary prevention settings; however, their role in the elderly remains a clinical conundrum, given that age-related factors could alter the risk-benefit ratio of statin treatment. This study aimed to critically evaluate the efficacy and safety of statins for primary prevention of cardiovascular disease (CVD) in the elderly., Methods: We systematically reviewed randomized controlled trials comparing any statins with placebo or usual care for primary prevention of CVD in subjects aged ≥65 years. Relative risks (RRs) using a random effects model were calculated and sensitivity analyses were performed to assess the robustness of findings., Results: Eight studies (n = 25,952) were included in the meta-analysis. Statins significantly reduced the risks of composite major adverse cardiovascular events (RR 0.82, 95% CI 0.74-0.92), nonfatal myocardial infarction [MI] (0.75, 0.59-0.94) and total MI (0.74, 0.61-0.90). Treatment effects of statins were statistically insignificant in fatal MI (0.43, 0.09-2.01), stroke (fatal: 0.76, 0.24-2.45; nonfatal: 0.76, 0.53-1.11; total: 0.85, 0.68-1.06) and all-cause mortality (0.96, 0.88-1.04). Significant differences were not observed in myalgia (0.88, 0.69-1.13), elevation of hepatic transaminases (0.98, 0.71-1.34), new-onset diabetes (1.07, 0.77-1.48), serious adverse events (1.00, 0.97-1.04) and discontinuation due to adverse events (1.10, 0.85-1.42). The occurrence of myopathy, rhabdomyolysis and cognitive impairment was largely unreported in the included trials., Conclusions: From a risk-benefit perspective, there is a role of statins for the primary prevention of major adverse cardiovascular events in elderly patients. Further studies are needed to ascertain the benefits of statins on fatal MI, stroke and all-cause mortality.

Purpose: This study aimed to evaluate the cost-effectiveness of statins for primary prevention of stroke and myocardial infarction (MI) in the elderly in Singapore., Methods: A Markov model was developed to investigate the lifetime costs, quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs) of statin treatment in those aged 65 years and older without a history of stroke or MI from the perspective of Singapore's healthcare system, using elderly-specific clinical data and local costs from hospital databases. A lifetime horizon was used and all costs and health outcomes were discounted at 3% annually., Results: In the base-case analysis, statin treatment prevented an additional four strokes and eight MIs among 1,000 "healthy" elderly individuals compared with no treatment. Statin treatment resulted in a QALY gain of 0.26 and additional costs of SGD 11,314 per person, yielding an ICER of SGD 43,925 (USD 33,495) per QALY gained. The results were sensitive to statin effectiveness, particularly statins' effect on all-cause mortality, and cost of statin medication. Probabilistic sensitivity analysis demonstrated that the probability of statin treatment being cost-effective was 72% at a willingness-to-pay threshold of SGD 65,000 (USD 49,546) per QALY gained. Shortening the time horizon from lifetime to 10 years (simulating limited life expectancy) considerably increased the ICER to SGD 291,313 (USD 167,171) per QALY. Female gender and younger age were also associated with higher ICERs owing to a lower baseline risk of cardiovascular disease (CVD) and higher costs to manage events in these subgroups., Conclusions: Statin treatment for the primary prevention of CVD in the elderly was cost-effective. However, treatment warrants re-evaluation when the prognosis of the individual is considered less than ten years; other goals may take precedence over CVD prevention.

Aims: The aim of the study was to measure rest and stress myocardial blood flow (MBF) values prospectively in a low-risk population with 128-slice dual-source computed tomography (CT) and to compare MBF/coronary flow reserve (CFR) values to that of a second population with a documented coronary artery disease (CAD)., Methods and Results: This study evaluates resting and hyperaemic MBF in 35 low-risk individuals identified by the modified Framingham Risk score and a calcium score of <100. The patients were scanned using 80 kV and quantitative blood flow values were generated using complete time-attenuation curves. Global resting and hyperaemic MBF was 74.08 ± 16.30 and 135.24 ± 28.89 mL/100 g/min, respectively, with CFR of 1.86 ± 0.38. Resting MBF was 76.98 ± 25.68, 66.98 ± 19.66, 81.34 ± 21.40, and 63.35 ± 16.35 mL/100 g/min in anterior, septal, lateral, and inferior walls, respectively, and corresponding hyperaemic MBF was 133.25 ± 29.80, 123.47 ± 31.03, 148.60 ± 32.69, and 124.21 ± 31.54 mL/100 g/min, respectively. In the population with CAD, global resting and hyperaemic MBF were 82.29 ± 16.87 and 81.98 ± 18.54 mL/100 g/min and 107.95 ± 25.25 and 106.93 ± 32.91 mL/100 g/min in the group with ischaemia only and infarction only, respectively, with corresponding CFR of 1.33 ± 0.27 and 1.33 ± 0.46, respectively (statistically different from the low-risk population). Radiation dose for CT myocardial perfusion imaging (CTMPI) was 6.72 ± 2.71 and 6.19 ± 2.19 mSv for stress and rest scans, respectively. This was 30% lower than a radiation dose in the scanning historical cohort at 100 kV. There was no significant difference in the signal-to-noise ratio and contrast-to-noise ratio between low-risk cohort and historical cohort scanned at 80 and 100 kV, respectively., Conclusions: Baseline, hyperaemic MBF and CFR values in a low-risk cohort can be evaluated with dynamic myocardial perfusion imaging using 80 kV., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.)

Background: Intact left atrial booster pump function helps maintain cardiac compensation in patients with aortic valve stenosis (AS). Because late diastolic mitral annular (A') velocity reflects left atrial systolic function, we hypothesized that A' velocity correlates with plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) level and clinical outcome in AS., Methods: We prospectively enrolled 53 consecutive patients (median age 74 years) with variable degrees of AS, in sinus rhythm, and left ventricular ejection fraction greater than 50%. Indices of valvular stenosis, left ventricular diastolic dysfunction, and mitral annular motion were correlated with plasma NT-proBNP and a composite clinical end point comprising cardiac death and symptom-driven aortic valve replacement., Results: Tissue Doppler echocardiographic parameters, including early diastolic (E') velocity and A' velocity and ratio of early diastolic transmitral (E) to E' velocity (E/E') at the annular septum correlated better with NT-proBNP levels than body surface area-indexed aortic valve area. Eighteen patients had the composite end point, which was univariately predicted by body surface area-indexed aortic valve area, NT-proBNP, and all tissue Doppler echocardiographic indices. This outcome was most strongly predicted by the combination of septal A' velocity and E/E' ratio in bivariate Cox modeling. Septal annular A' velocity less than 9.6 cm/s was associated with significantly reduced event-free survival (Kaplan Meier log rank = 27.3, P < .0001) and predicted the end point with a sensitivity, specificity, and accuracy of 94%, 80%, and 85%, respectively., Conclusions: In patients with AS and normal ejection fraction, annular tissue Doppler echocardiographic indices may better reflect the physiologic consequences of afterload burden on the left ventricle than body surface area-indexed aortic valve area. Lower A' velocity is a predictor of cardiac death and need for valve surgery, suggesting an important role for compensatory left atrial booster pump function.

A 30-year-old male presented with acute pericarditis and a moderate pericardial effusion. His condition deteriorated suddenly with a marked elevation in blood pressure. The hypertension was erroneously correlated with a low probability of cardiac tamponade, leading to a delay in performing an echocardiogram. The echocardiogram subsequently showed features of cardiac tamponade. Severe elevation of blood pressure in a patient with cardiac tamponade is a rare and under-recognized disorder. This condition is discussed here.

This report describes the case of a man who presented with fever, weight loss, and Streptococcus mitis septicemia. He was found to have congenital bilateral coronary artery fistula, a rare condition. There was no evidence of vegetation on the heart valves on transthoracic or transesophageal echocardiography. Instead, transesophageal echocardiography showed vegetation within the coronary sinus near its entrance into the right atrium. Coronary angiography confirmed the presence of a left circumflex artery to coronary sinus fistula and a right coronary artery to coronary sinus fistula. To the authors' knowledge this combination of findings has never been reported before.

Introduction: Hyperhomocysteinaemia is an emerging risk factor for coronary artery disease (CAD) and most studies done to date are in Caucasian populations. We aimed to determine whether hyperhomocysteinaemia is a risk factor for acute myocardial infarction (AMI) in a Southeast Asian population comprising different ethnic groups and relate it to the traditional risk factors and plasma vitamin B12 and folate levels., Materials and Methods: This was a case-control study comprising 168 AMI patients and 141 controls with a median age of 55 years (range, 27 to 77 years), living in Singapore. Homocysteine was measured by fluorescence polarisation immunoassay and vitamin B12 and folate were measured by electrochemiluminescence immunoassay. Logistic regression analysis was use to test the association of homocysteine, vitamin B12 and folate with the occurrence of AMI. The study was approved by the Tan Tock Seng Ethics Committee., Results: We found that the odds of having AMI was higher for subjects with hypertension, smoking habit, lower plasma folate and vitamin B12 levels and non-Chinese ethnic group. On the other hand, plasma homocysteine level was not significantly associated with AMI. The baseline levels of plasma total homocysteine in both AMI patients and controls were higher than other studies (median values between 12 and 14 umol/L)., Conclusion: In our population, plasma total homocysteine levels were not associated with AMI but low plasma levels of folate and vitamin B12 were independently associated.

Non-diabetic males, particularly those with very low levels of high density lipoprotein (HDL) type cholesterol and high levels of very low density type lipoprotein (VLDL), are associated with insulin resistance and decreased insulin sensitivity. The evidence that elevation of HDL cholesterol and diminution of triglycerides with drugs, with improvement in insulin sensitivity is still lacking. In the treatment of the dyslipidaemic syndromes with hypolipidaemic drugs, the associated metabolic abnormality of insulin resistance/sensitivity has to be addressed. We investigated the degree of decreased insulin sensitivity in 23 patients with low HDL and/or raised triglycerides by measuring the fasting, first and second hour insulin levels during an oral glucose tolerance test (OGTT) and repeated the measurements after a 6-month course of fenofibrate. The insulin levels were correlated with the OGTT, blood pressure, total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides measured before and at the end of the trial. The serum insulin at the second hour of the OGTT fell from 100.79 +/- 42.79 mU/l to 54.56 +/- 25.43 mU/l (P < 0.0005) even though there was no change in the blood glucose level at this point. Our study shows that fenofibrate (Lipanthyl) 300 mg daily significantly raises the pretreatment low HDL cholesterol (from 0.64 +/- 0.1 mmol/l to 0.99 +/- 0.2 mmol/l) as well as lowers the triglyceride level (from 2.17 +/- 1.1 mmol/l to 1.43 +/- 0.64 mmol/l) in patients with low HDL/dyslipidaemic syndrome. The data also support the conclusion that treatment with fenofibrate increases insulin sensitivity as measured by the corresponding insulin levels of the OGTT in the study subjects who presented with very low HDL cholesterol level. There was also a decrease in blood pressure readings in our study subjects. Throughout the trial, there was no significant change in body weight or exercise level in the subjects studied.