Circulating isomiRs May Be Superior Biomarkers Compared to Their Corresponding miRNAs: A Pilot Biomarker Study of Using isomiR-Ome to Detect Coronary Calcium-Based Cardiovascular Risk in Patients with NAFLD.

Circulating miRNAs are increasingly being considered as biomarkers in various medical contexts, but the value of analyzing isomiRs (isoforms of canonical miRNA sequences) has not frequently been assessed. Here we hypothesize that an in-depth analysis of the full circulating miRNA landscape could identify specific isomiRs that are stronger biomarkers, compared to their corresponding miRNA, for identifying increased CV risk in patients with non-alcoholic fatty liver disease (NAFLD)-a clinical unmet need. Plasma miRNAs were sequenced with next-generation sequencing (NGS). Liver fat content was measured with magnetic-resonance spectrometry (MRS); CV risk was determined, beyond using traditional biomarkers, by a CT-based measurement of coronary artery calcium (CAC) score and the calculation of a CAC score-based CV-risk percentile (CAC-CV%). This pilot study included n = 13 patients, age > 45 years, with an MRS-measured liver fat content of ≥5% (wt/wt), and free of overt CVD. NGS identified 1103 miRNAs and 404,022 different isomiRs, of which 280 (25%) and 1418 (0.35%), respectively, passed an abundance threshold. Eighteen (sixteen/two) circulating miRNAs correlated positively/negatively, respectively, with CAC-CV%, nine of which also significantly discriminated between high/low CV risk through ROC-AUC analysis. IsomiR-ome analyses uncovered 67 isomiRs highly correlated (R ≥ 0.55) with CAC-CV%. Specific isomiRs of miRNAs 101-3p, 144-3p, 421, and 484 exhibited stronger associations with CAC-CV% compared to their corresponding miRNA. Additionally, while miRNAs 140-3p, 223-3p, 30e-5p, and 342-3p did not correlate with CAC-CV%, specific isomiRs with altered seed sequences exhibited a strong correlation with coronary atherosclerosis burden. Their predicted isomiRs-specific targets were uniquely enriched (compared to their canonical miRNA sequence) in CV Disease (CVD)-related pathways. Two of the isomiRs exhibited discriminative ROC-AUC, and another two showed a correlation with reverse cholesterol transport from cholesterol-loaded macrophages to ApoB-depleted plasma. In summary, we propose a pipeline for exploring circulating isomiR-ome as an approach to uncover novel and strong CVD biomarkers.

Post-COVID-19 Peripartum Cardiomyopathy: Experience from a Large Tertiary Referral Center.

BACKGROUND: Peripartum cardiomyopathy (PPCM) is a rare but potentially devastating complication of pregnancy. Although the pathophysiology of PPCM is not fully understood, there are known risk factors for developing PPCM, which are maternal and gestation related. In the first wave of the coronavirus disease 2019 (COVID-19) pandemic, we witnessed an elevated incidence of PPCM among COVID-19 survivors. OBJECTIVES: To present a single-center case series of three patients diagnosed with peripartum cardiomyopathy after recovered from COVID-19 during the index pregnancy. METHODS: In this single center case study, all patients diagnosed with PPCM at our institute during the examined time frame were included. Electronic medical records were studied. RESULTS: Three patients previously diagnosed with asymptomatic or mildly symptomatic COVID-19 disease during pregnancy presented with PPCM before or shortly after delivery. Patients underwent testing to rule out residual COVID-19 myocarditis, were treated pharmacologically and with wearable defibrillators as needed, and were examined in follow-up 1-9 months after delivery. CONCLUSIONS: Residual endothelial damage due to COVID-19 disease, even if originally mild in presentation, could predispose pregnant patients to PPCM and should be considered as a risk factor when assessing patients with new onset symptoms of heart failure. Further research is needed to confirm this hypothesis and fully determine the underlying pathophysiology. These preliminary findings warrant a high index of suspicion for PPCM in COVID-19 recoverers.

Effect of green-Mediterranean diet on intrahepatic fat: the DIRECT PLUS randomised controlled trial.

OBJECTIVE: To examine the effectiveness of green-Mediterranean (MED) diet, further restricted in red/processed meat, and enriched with green plants and polyphenols on non-alcoholic fatty liver disease (NAFLD), reflected by intrahepatic fat (IHF) loss. DESIGN: For the DIRECT-PLUS 18-month randomized clinical trial, we assigned 294 participants with abdominal obesity/dyslipidaemia into healthy dietary guidelines (HDG), MED and green-MED weight-loss diet groups, all accompanied by physical activity. Both isocaloric MED groups consumed 28 g/day walnuts (+440 mg/day polyphenols provided). The green-MED group further consumed green tea (3-4 cups/day) and Mankai (a Wolffia globosa aquatic plant strain; 100 g/day frozen cubes) green shake (+1240 mg/day total polyphenols provided). IHF% 18-month changes were quantified continuously by proton magnetic resonance spectroscopy (MRS). RESULTS: Participants (age=51 years; 88% men; body mass index=31.3 kg/m2; median IHF%=6.6%; mean=10.2%; 62% with NAFLD) had 89.8% 18-month retention-rate, and 78% had eligible follow-up MRS. Overall, NAFLD prevalence declined to: 54.8% (HDG), 47.9% (MED) and 31.5% (green-MED), p=0.012 between groups. Despite similar moderate weight-loss in both MED groups, green-MED group achieved almost double IHF% loss (-38.9% proportionally), as compared with MED (-19.6% proportionally; p=0.035 weight loss adjusted) and HDG (-12.2% proportionally; p<0.001). After 18 months, both MED groups had significantly higher total plasma polyphenol levels versus HDG, with higher detection of Naringenin and 2-5-dihydroxybenzoic-acid in green-MED. Greater IHF% loss was independently associated with increased Mankai and walnuts intake, decreased red/processed meat consumption, improved serum folate and adipokines/lipids biomarkers, changes in microbiome composition (beta-diversity) and specific bacteria (p<0.05 for all). CONCLUSION: The new suggested strategy of green-Mediterranean diet, amplified with green plant-based proteins/polyphenols as Mankai, green tea, and walnuts, and restricted in red/processed meat can double IHF loss than other healthy nutritional strategies and reduce NAFLD in half. TRIAL REGISTRATION NUMBER: NCT03020186.

Predictors of high-risk coronary artery disease in subjects with normal SPECT myocardial perfusion imaging.

BACKGROUND: While uncommon, normal stress SPECT myocardial perfusion imaging (MPI) can be seen in patients with high-risk coronary artery disease (CAD) by invasive coronary angiography (ICA).The predictors of high-risk CAD in patients with normal SPECT-MPI have not been described. METHODS: We studied 580 patients (age 64 ± 12 years, 49% men) without known CAD who underwent stress-gated SPECT-MPI [exercise (41%) or vasodilator (59%)] <2 months before ICA and had summed stress score (SSS) <4. High-risk CAD was defined as 3 vessels with ≥70% stenosis, 2 vessels with ≥70% stenosis including proximal left anterior descending, or left main with ≥50% stenosis. Obstructive non-high-risk CAD was defined by the presence of a ≥70% stenosis but without having other high-risk criteria. Tenfold cross-validated receiver operating characteristic (ROC) estimates were obtained to assess the predictors of high-risk CAD. RESULTS: Forty-two subjects (7.2%) had high-risk CAD and 168 (29.0%) had obstructive non-high-risk CAD. Variables associated with high-risk CAD were pretest probability of CAD ≥66% (Odds ratio [OR] 3.63, 95% CI 1.6-8.3, P = .002), SSS > 0 (OR 7.46, 95% CI 2.6-21.1, P < 0.001), and abnormal TID (OR 2.16, 95% CI 1.0-4.5, P = 0.044). When substituted for TID, EF change was also predictive of high-risk CAD (OR 0.93, 95% CI 0.9-1.0, P = 0.023). The prevalence of high-risk CAD increased as the number of these predictors increased. In a sub-analysis of patients in whom quantitative total perfusion deficit (TPD) was available, TPD > 0 was also a predictor of high-risk CAD (OR 6.01, 95% CI 1.5-22.2, P = 0.011). CONCLUSION: Several clinical, stress, and SPECT-MPI findings are associated high-risk CAD among patients with normal SPECT-MPI. Consideration of these factors may improve the overall assessment of the likelihood of high-risk CAD in patients undergoing stress SPECT-MPI.

Prediction of revascularization after myocardial perfusion SPECT by machine learning in a large population.

OBJECTIVE: We aimed to investigate if early revascularization in patients with suspected coronary artery disease can be effectively predicted by integrating clinical data and quantitative image features derived from perfusion SPECT (MPS) by machine learning (ML) approach. METHODS: 713 rest (201)Thallium/stress (99m)Technetium MPS studies with correlating invasive angiography with 372 revascularization events (275 PCI/97 CABG) within 90 days after MPS (91% within 30 days) were considered. Transient ischemic dilation, stress combined supine/prone total perfusion deficit (TPD), supine rest and stress TPD, exercise ejection fraction, and end-systolic volume, along with clinical parameters including patient gender, history of hypertension and diabetes mellitus, ST-depression on baseline ECG, ECG and clinical response during stress, and post-ECG probability by boosted ensemble ML algorithm (LogitBoost) to predict revascularization events. These features were selected using an automated feature selection algorithm from all available clinical and quantitative data (33 parameters). Tenfold cross-validation was utilized to train and test the prediction model. The prediction of revascularization by ML algorithm was compared to standalone measures of perfusion and visual analysis by two experienced readers utilizing all imaging, quantitative, and clinical data. RESULTS: The sensitivity of machine learning (ML) (73.6% ± 4.3%) for prediction of revascularization was similar to one reader (73.9% ± 4.6%) and standalone measures of perfusion (75.5% ± 4.5%). The specificity of ML (74.7% ± 4.2%) was also better than both expert readers (67.2% ± 4.9% and 66.0% ± 5.0%, P < .05), but was similar to ischemic TPD (68.3% ± 4.9%, P < .05). The receiver operator characteristics areas under curve for ML (0.81 ± 0.02) was similar to reader 1 (0.81 ± 0.02) but superior to reader 2 (0.72 ± 0.02, P < .01) and standalone measure of perfusion (0.77 ± 0.02, P < .01). CONCLUSION: ML approach is comparable or better than experienced readers in prediction of the early revascularization after MPS, and is significantly better than standalone measures of perfusion derived from MPS.

Two-position supine/prone myocardial perfusion SPECT (MPS) imaging improves visual inter-observer correlation and agreement.

OBJECTIVES: We aimed to compare the inter-observer agreement between two experienced readers using supine vs combined supine/prone myocardial perfusion SPECT (MPS) in a large population. METHODS: 1,181 consecutive patients without known coronary artery disease (CAD) undergoing rest (201)Tl/stress (99m)Tc-sestamibi MPS studies were evaluated. Visual reads were performed in two consecutive steps, with readers scoring the stress supine perfusion images during step 1 and rescoring the images using both supine/prone data during step 2. Visual summed stress scores (SSS) of two readers including regional scores in different vascular territories were compared. RESULTS: The specificity for both readers improved using combined supine/prone imaging (reader 1: 92% vs 86% [P = .0002], reader 2: 88% vs 72% [P < .0001]). The inter-observer correlation for SSS (0.90 vs 0.84, P < .0001) and inter-observer agreement for combined supine/prone reading (bias = 1.0, 95% confidence interval (CI) 0.9-1.2 vs bias = 3.1, 95% CI 2.8-3.4, P < .0001) were significantly better as compared to supine-only reading. The overall correlation between SSS scores for two readers improved with supine/prone imaging for both genders, as well as in the left anterior descending and right coronary territories. CONCLUSION: The inter-observer correlation and agreement significantly improve using two-position supine/prone vs supine-only imaging.

INO-8875, a highly selective A1 adenosine receptor agonist: evaluation of chronotropic, dromotropic, and hemodynamic effects in rats.

Selective pharmacological activation of the adenosine 1 receptor (A(1)R) is a promising new approach to achieve a potent block of atrioventricular (A-V)-nodal conduction without significant cardiovascular side effects. The purpose of the present study was to evaluate the cardiovascular profile of INO-8875, a highly selective A(1)R agonist, and to compare its properties with N-[3(R)-tetrahydrofuranyl]-6-aminopurine riboside (CVT-510), which has already been shown to induce negative dromotropic effects with minimal cardiovascular side effects in animals and in clinical studies. Dose-response experiments in the isolated hearts of rats were used to evaluate the functional selectivity of INO-8875 for the slowing of A-V-nodal conduction. Ventilated adult rats were used to study the effects of INO-8875, in vivo, on arterial blood pressure as well as on supraventricular electrophysiology. Ex vivo, INO-8875 (100 nM to 3 µM) progressively prolonged A-V-nodal conduction without reducing left ventricular function or coronary resistance. In vivo, INO-8875 up to a dose of 50 µg/kg did not reduce the carotid arterial blood pressure (n = 4). INO-8875 (1-50 µg/kg) and CVT-510 (20 and 50 µg/kg) both induced a dose-dependent decrease in heart rate and atrial refractoriness, as well as slowing of A-V-nodal conduction. However, compared with CVT-510, the activity of INO-8875 was more pronounced in A-V-nodal function. INO-8875 exhibited a greater duration of action, lasting up to 2.5 hours post dosing, whereas the effects of CVT-510 dissipated over 1 hour. INO-8875 demonstrates functional properties of a highly selective A(1)R agonist. INO-8875 exhibits an increased dromotropic effect and greater duration of action compared with CVT-510.

Quantification and characterisation of coronary artery plaque volume and adverse plaque features by coronary computed tomographic angiography: a direct comparison to intravascular ultrasound.

OBJECTIVE: We evaluated the performance of manual measures of coronary plaque volumes and atherosclerotic plaque features from coronary CT angiography (CTA), using intravascular ultrasound (IVUS) as the reference. METHODS: Thirty individual coronary plaques with suitable fiduciary markers were identified. Plaque volumes on coronary CTA were manually quantified by two observers and compared to IVUS plaque volumes as interpreted by an independent laboratory. The presence of adverse plaque characteristics-low attenuation plaque (LAP), positive remodelling (PR) and spotty calcification (SC)-on coronary CTA was evaluated and compared to IVUS. RESULTS: High correlation in plaque volumes was detected between observers (r = 0.94, P < 0.0001; 95 % limits of agreement <48.7 mm(3), bias 6.6 mm(3)). Excellent correlation (r = 0.95, P < 0.0001) was noted in plaque volume between independent observers and IVUS (95 % limits of agreement <40.6 mm(3), bias -4.4 mm(3)) and did not differ from IVUS (105.0 ± 56.7 vs. 109.4 ± 60.7 mm(3), P = 0.2). The frequency of LAP (10 % vs. 17 %), PR (7 % vs. 10 %) and SC (27 % vs. 33 %) was similar between coronary CTA and IVUS (all P = NS). CONCLUSIONS: Plaque volume on coronary CTA determined by manual methods demonstrates high correlation and modest agreement to IVUS. Further, coronary CTA demonstrates high accuracy for the identification of adverse plaque characteristics, including LAP, PR and SC. KEY POINTS: • Coronary CT angiography is a non-invasive test that enables coronary plaque assessment • Plaque quantification by coronary CT angiography correlates well with intravascular ultrasound findings • Coronary CT angiography can identify adverse plaque characteristics.

Improved accuracy of myocardial perfusion SPECT for detection of coronary artery disease by machine learning in a large population.

OBJECTIVE: We aimed to improve the diagnostic accuracy of myocardial perfusion SPECT (MPS) by integrating clinical data and quantitative image features with machine learning (ML) algorithms. METHODS: 1,181 rest (201)Tl/stress (99m)Tc-sestamibi dual-isotope MPS studies [713 consecutive cases with correlating invasive coronary angiography (ICA) and suspected coronary artery disease (CAD) and 468 with low likelihood (LLk) of CAD <5%] were considered. Cases with stenosis <70% by ICA and LLk of CAD were considered normal. Total stress perfusion deficit (TPD) for supine/prone data, stress/rest perfusion change, and transient ischemic dilatation were derived by automated perfusion quantification software and were combined with age, sex, and post-electrocardiogram CAD probability by a boosted ensemble ML algorithm (LogitBoost). The diagnostic accuracy of the model for prediction of obstructive CAD ≥70% was compared to standard prone/supine quantification and to visual analysis by two experienced readers utilizing all imaging, quantitative, and clinical data. Tenfold stratified cross-validation was performed. RESULTS: The diagnostic accuracy of ML (87.3% ± 2.1%) was similar to Expert 1 (86.0% ± 2.1%), but superior to combined supine/prone TPD (82.8% ± 2.2%) and Expert 2 (82.1% ± 2.2%) (P < .01). The receiver operator characteristic areas under curve for ML algorithm (0.94 ± 0.01) were higher than those for TPD and both visual readers (P < .001). The sensitivity of ML algorithm (78.9% ± 4.2%) was similar to TPD (75.6% ± 4.4%) and Expert 1 (76.3% ± 4.3%), but higher than that of Expert 2 (71.1% ± 4.6%), (P < .01). The specificity of ML algorithm (92.1% ± 2.2%) was similar to Expert 1 (91.4% ± 2.2%) and Expert 2 (88.3% ± 2.5%), but higher than TPD (86.8% ± 2.6%), (P < .01). CONCLUSION: ML significantly improves diagnostic performance of MPS by computational integration of quantitative perfusion and clinical data to the level rivaling expert analysis.

Downstream Imaging Studies Do Not Significantly Improve Outcome in Most Patients with Chest Pain Who Did Not Reach Their Target Heart Rate on a Stress ECHO Study.

Echocardiographic stress tests are often used to evaluate patients who complain of chest pain. However, some patients fail to reach the target heart rate required for the test to be conclusive (usually defined as 85% of the predicted maximal heart rate based on the patient's age) and are often sent for additional imaging tests, such as myocardial perfusion imaging (MPI) or cardiac computed tomography angiography (CTA). Few studies have evaluated the effectiveness of these additional tests in patients who present with chest pain but did not meet the heart rate requirements for a stress test. The primary objective of the study was to evaluate the efficacy of additional imaging tests for patients who experience chest pain during daily activities but are unable to reach the target heart rate currently required for an echocardiographic stress test. The study group included 415 consecutive patients who underwent a stress echocardiogram, did not achieve their target heart rate, and did not demonstrate abnormal changes during the test. The control group consisted of 415 consecutive patients who did reach their target heart rate and demonstrated no signs of ischemia. Demographic and clinical data, medication use, imaging test results (MPI, CTA, and/or coronary catheterization) and documented cardiac events that occurred during 1 year of follow-up were obtained from the electronic medical records. Of the 415 patients in the study group, 73 (17.6%) were referred to another imaging test within 12 months. Of these 73 patients, 59 underwent MPI and 14 underwent cardiac CTA. In 12 of these patients (16.4%) the test was considered to be abnormal, but only 7 patients (1.7%) subsequently underwent a percutaneous intervention (PCI). In the control group, 28 (6.7%) patients were referred for another imaging test. Of these 28 patients, 14 underwent MPI and 14 underwent cardiac CTA. None of these tests were found to be abnormal, but two patients (0.5%) underwent a PCI (p = 0.2 between groups). There were no deaths during the study period and no patients underwent bypass surgery. The majority of the patients who underwent PCI had additional clinical risk factors (diabetes, hypertension, and/or known coronary artery disease), had taken a beta blocker within 24 h prior to the test, and/or did not reach a heart rate above 78% of their target heart rate. Our study suggests that in most patients with chest pain who do not show ischemic changes on a stress echocardiogram, additional imaging studies can be safely deferred, even if the required target heart rate was not reached. However, in patients with diabetes and/or known coronary disease, those who took a beta blocker 24 h prior to the test, or those who did not achieve a heart rate above 78% of the current target heart rate, additional imaging studies should be considered.

The Association of Alanine Aminotransferase Levels With Myocardial Perfusion Imaging and Cardiovascular Morbidity.

INTRODUCTION: Studies suggest that non-alcoholic fatty liver disease (NAFLD) is associated with an independent risk of cardiovascular disease (CVD). We utilized a large cohort of patients undergoing myocardial perfusion imaging (MPI) with single photon emission computed tomography (SPECT) to determine the association between alanine aminotransferase (ALT) as a surrogate marker for presumed NAFLD, and the presence of myocardial ischemia and mortality. METHODS: We retrospectively assessed SPECT-MPI results and medical records of individuals evaluated between 1997 and 2008. We excluded patients with known non-NAFLD liver diseases, ALT values <17 or >340 U/L and absent liver tests. Elevated ALT cases were classified as presumed NAFLD. The primary endpoint was abnormal SPECT-MPI. Secondary endpoints included cardiac death, acute myocardial infarction and all-cause mortality. RESULTS: Of 26,034 patients who underwent SPECT-MPI, 11,324 met inclusion criteria. 1635 (14.4%) patients had elevated ALT. SPECT-MPI results did not differ significantly between subjects with elevated ALT and controls. Elevated ALT was associated with increased risk for the composite endpoint of cardiac death or acute myocardial infarction at 5-year follow-up (hazard ratio [HR] 1.3, 95% confidence interval [CI] 1.01-1.67) and in all-cause mortality (HR 1.27, CI 1.02-1.58) but only in patients with normal SPECT-MPI. CONCLUSIONS: The long-term mortality of patients with abnormal SPECT-MPI is not modulated by ALT, likely reflecting an already high risk and established CVD. However, patients with normal SPECT-MPI are at increased risk for a future cardiac event if they have an elevated ALT level, suggesting an important role for NAFLD in earlier stages of CVD.

Diet-induced Fasting Ghrelin Elevation Reflects the Recovery of Insulin Sensitivity and Visceral Adiposity Regression.

CONTEXT: Lower fasting ghrelin levels (FGL) are associated with obesity and metabolic syndrome. OBJECTIVE: We aimed to explore the dynamics of FGL during weight loss and its metabolic and adiposity-related manifestations beyond weight loss. METHODS: This was a secondary analysis of a clinical trial that randomized participants with abdominal obesity/dyslipidemia to 1 of 3 diets: healthy dietary guidelines (HDG), Mediterranean diet (MED), or green-MED diet, all combined with physical activity (PA). Both MED diets were similarly hypocaloric and included 28 g/day walnuts. The green-MED group further consumed green tea (3-4 cups/day) and a Wolffia globosa (Mankai) plant green shake. We measured FGL and quantified body fat depots by magnetic resonance imaging at baseline and after 18 months. RESULTS: Among 294 participants (body mass index = 31.3 kg/m2; FGL = 504 ± 208 pg/mL; retention rate = 89.8%), lower FGL was associated with unfavorable cardiometabolic parameters such as higher visceral adipose tissue (VAT), intrahepatic fat, leptin, and blood pressure (P < 0.05 for all; multivariate models). The ∆FGL18-month differed between men (+7.3 ± 26.6%) and women (-9.2% ± 21.3%; P = 0.001). After 18 months of moderate and similar weight loss among the MED groups, FGL increased by 1.3%, 5.4%, and 10.5% in HDG, MED, and green-MED groups, respectively (P = 0.03 for green-MED vs HDG); sex-stratified analysis revealed similar changes in men only. Among men, FGL18-month elevation was associated with favorable changes in insulin resistance profile and VAT regression, after adjusting for relative weight loss (HbA1c: r = -0.216; homeostatic model of insulin resistance: r = -0.154; HDL-c: r = 0.147; VAT: r = -0.221; P < 0.05 for all). Insulin resistance and VAT remained inversely related with FGL elevation beyond that explained by weight loss (residual regression analyses; P < 0.05). CONCLUSION: Diet-induced FGL elevation may reflect insulin sensitivity recovery and VAT regression beyond weight loss, specifically among men. Green-MED diet is associated with greater FGL elevation.

Loss of left ventricular rotation is a significant determinant of functional mitral regurgitation.

AIM: To evaluate insufficient rotational movement of the left ventricle (LV) as a potential novel mechanism for functional regurgitation of the mitral valve (FMR). METHODS AND RESULTS: We compared reference subjects and patients with LV dysfunction (LVD, ejection fraction EF < 50%) with and without FMR (regurgitant volume RVol>10 ml). Subjects without structural mitral valve pathology undergoing cardiac MRI were evaluated. Delayed enhancement, global LV remodeling parameters, systolic twist and torsion were measured (using manual and novel automated cardiac MRI tissue-tracking). The study included 117 subjects with mean ± SD age 50.4 ± 17.8 years, of which 30.8% were female. Compared to subjects with LVD without FMR (n = 31), those with FMR (n = 37) had similar clinical characteristics, diagnoses, delayed enhancement, EF, and longitudinal strain. Subjects with FMR had significantly larger left ventricles (EDVi:136.6 ± 41.8 vs 97.5 ± 26.2 ml/m, p < 0.0001) with wider separation between papillary muscles (21.1 ± 7.6 vs 17.2 ± 5.7 mm, p = 0.023). Notably, they had lower apical (p < 0.0001) but not basal rotation and lower peak systolic twist (3.1 ± 2.4° vs 5.5 ± 2.5°, p < 0.0001) and torsion (0.56 ± 0.38°/cm vs 0.88 ± 0.52°/cm, p = 0.004). In a multivariate model for RVol including age, gender, twist, LV end-diastolic volume, sphericity index and separation between papillary muscles, only gender, volume and twist were significant. Twist was the most powerful correlate (beta -2.23, CI -3.26 to -1.23 p < 0.001). In patients with FMR, peak systolic twist negatively correlates with RVol (r = -0.73, p < 0.0001). CONCLUSION: Reduced rotational systolic LV motion is significantly and independently associated with RVol among patients with FMR, suggesting a novel pathophysiological mechanism and a potential therapeutic target.

The effect of green Mediterranean diet on cardiometabolic risk; a randomised controlled trial.

BACKGROUND: A Mediterranean diet is favourable for cardiometabolic risk. OBJECTIVE: To examine the residual effect of a green Mediterranean diet, further enriched with green plant-based foods and lower meat intake, on cardiometabolic risk. METHODS: For the DIRECT-PLUS parallel, randomised clinical trial we assigned individuals with abdominal obesity/dyslipidaemia 1:1:1 into three diet groups: healthy dietary guidance (HDG), Mediterranean and green Mediterranean diet, all combined with physical activity. The Mediterranean diets were equally energy restricted and included 28 g/day walnuts. The green Mediterranean diet further included green tea (3-4 cups/day) and a Wolffia globosa (Mankai strain; 100 g/day frozen cubes) plant-based protein shake, which partially substituted animal protein. We examined the effect of the 6-month dietary induction weight loss phase on cardiometabolic state. RESULTS: Participants (n=294; age 51 years; body mass index 31.3 kg/m2; waist circumference 109.7 cm; 88% men; 10 year Framingham risk score 4.7%) had a 6-month retention rate of 98.3%. Both Mediterranean diets achieved similar weight loss ((green Mediterranean -6.2 kg; Mediterranean -5.4 kg) vs the HDG group -1.5 kg; p<0.001), but the green Mediterranean group had a greater reduction in waist circumference (-8.6 cm) than the Mediterranean (-6.8 cm; p=0.033) and HDG (-4.3 cm; p<0.001) groups. Stratification by gender showed that these differences were significant only among men. Within 6 months the green Mediterranean group achieved greater decrease in low-density lipoprotein cholesterol (LDL-C; green Mediterranean -6.1 mg/dL (-3.7%), -2.3 (-0.8%), HDG -0.2 mg/dL (+1.8%); p=0.012 between extreme groups), diastolic blood pressure (green Mediterranean -7.2 mm Hg, Mediterranean -5.2 mm Hg, HDG -3.4 mm Hg; p=0.005 between extreme groups), and homeostatic model assessment for insulin resistance (green Mediterranean -0.77, Mediterranean -0.46, HDG -0.27; p=0.020 between extreme groups). The LDL-C/high-density lipoprotein cholesterol (HDL-C) ratio decline was greater in the green Mediterranean group (-0.38) than in the Mediterranean (-0.21; p=0.021) and HDG (-0.14; p<0.001) groups. High-sensitivity C-reactive protein reduction was greater in the green Mediterranean group (-0.52 mg/L) than in the Mediterranean (-0.24 mg/L; p=0.023) and HDG (-0.15 mg/L; p=0.044) groups. The green Mediterranean group achieved a better improvement (-3.7% absolute risk reduction) in the 10-year Framingham Risk Score (Mediterranean-2.3%; p=0.073, HDG-1.4%; p<0.001). CONCLUSIONS: The green MED diet, supplemented with walnuts, green tea and Mankai and lower in meat/poultry, may amplify the beneficial cardiometabolic effects of Mediterranean diet. TRIAL REGISTRATION NUMBER: This study is registered under ClinicalTrials.gov Identifier no NCT03020186.

INO-8875, a Highly-Selective A1 Adenosine Receptor Agonist: Evaluation of Chronotropic, Dromotropic and Hemodynamic Effects in Rats.

Publication of this article is suspended until the authors can provide full identification and verification of the chemical structure of INO-8875.

Prevalence of left ventricular hypertrabeculation/noncompaction among patients with congenital dyserythropoietic anemia Type 1 (CDA1).

BACKGROUND: Congenital dyserythropoietic anemia type 1 (CDA1) is a rare autosomal recessive disease characterized by macrocytic anemia, ineffective erythropoiesis, and secondary hemochromatosis. Left-ventricular noncompaction (LVNC) is a cardiomyopathy that is commonly attributed to intrauterine arrest of normal compaction during the endomyocardial morphogenesis. LV hypertrabeculation/noncompaction (LVHT/NC) morphology, however, might exist in various hemoglobinopathies. Our primary objective was to determine whether the pattern of LVHT/NC is more prevalent among patients with CDA1, in comparison to subjects without CDA1, and to find potential risk factors for LVHT/NC among these patients. Our secondary objective was to evaluate the clinical implication of LVHT/NC. METHODS: We retrospectively assessed 32 CDA1 patients (median age 17.5, range 6-61) that underwent routine assessment of iron overload by cardiac magnetic resonance. Number and distribution of noncompacted LV segments were assessed in CDA1 patients and compared to 64 age- and gender-matched patients without CDA1. The ratio of noncompacted to compacted myocardium (NC/C ratio) in end-diastole was calculated for each of the three long-axis views. NC/C ratio > 2.3 was considered diagnostic for LVHT/NC. RESULTS: In multivariate analysis, the presence of CDA1 was independently associated with NC/C ratio > 2.3, a feature of LVHT/NC (adjusted OR = 11.46, 95%CI = 2.6-50.68, p = .001). CDA1 was strongly associated with increased number of myocardial segments exhibiting LVHT/NC pattern. Cardiac volumes and ejection fraction were preserved without clinical adverse events in long term follow-up. CONCLUSIONS: CDA1 patients have a higher prevalence of LVHT/NC than normal individuals, independent of myocardial iron overload and without effect on ejection fraction or clinical outcome.

Comparison of Accuracy of Left Atrial Area and Volume by Two-dimensional Trans-thoracic Echocardiography Versus Computed Tomography.

Left atrial (LA) size is prognostic of cardiovascular events and can be quantified as diameter, area, or volume. While LA area measurement by 2-dimensional (2D) echocardiography is performed by tracing LA borders in the apical 4-chamber view, LA volume is derived from a formula that is based on geometrical assumptions. We compared LA area and volume measurements obtained by trans-thoracic echocardiography (TTE) to those obtained using multi-detector computed tomography (MDCT). Sixty-four patients with MDCT and TTE performed within a 1-week period were included in the study. End-systolic LA area was planimetered from the 4-chamber view by TTE and MDCT. LA end-systolic volume was calculated using the biplane area-length (AL) method in both TTE and MDCT. Mean LA volume measurement using MDCT was significantly larger than TTE measurement (92 ± 31 mL vs 68 ± 27 mL, p <0.001). There was moderate correlation between MDCT and TTE in both LA area (0.74, p <0.0001), and volumetric measurements (0.77, p <0.0001). Bland-Altman agreement plots demonstrated a significantly lower bias and narrower 95% confidence intervals (CI) for the 2D area (bias: -5.5; 95% CI: -14.3 to 3.3) as compared with volumetric measurements (bias: -23.7; 95% CI: -64.9 to 17.5, p <0.0001). Contrary to current guidelines for chamber quantification, 2D TTE LA area has better agreement with MDCT than volumetric measurements by TTE. LA volumetric measurements are desirable; however, they are currently less reliable than the direct LA area tracing by 2D TTE and therefore represent a suboptimal and less reproducible method to determine LA size.

Correlation between atrial ZnT-1 expression and atrial fibrillation in humans: a pilot study.

BACKGROUND: Until recently, the membrane protein ZnT-1 was studied mainly in the context of zinc homeostasis. However, new findings indicate that it acts as an inhibitor of L-type calcium channels. We recently found that acute rapid pacing of the rat atria in vivo augments the expression of ZnT-1, while knockdown of ZnT-1 in culture can oppose the inhibition of L-type calcium channels following rapid pacing. This pilot study, the first to assess cardiac ZnT-1 in humans, was designed to look for possible correlation between the atrial expression of ZnT-1 and atrial fibrillation. METHODS: Right atrial appendage tissue was collected from 39 patients (27 with sinus rhythm and 12 with atrial fibrillation; 6-permanent, 6- paroxysmal or persistent) undergoing open-heart surgery. The expression of ZnT-1 was analyzed by Western blot utilizing beta-actin as an internal loading control and a standard rat heart sample (STD) for inter-blot comparison. RESULTS: Overall atrial fibrillation patients (n = 12) had median ZnT-1/beta-actin of 1.80 STD (inter-quartile range 1.26 to 2.85) versus 0.73 STD (0.24 to 1.64) in the sinus rhythm group (P = 0.002). No association was found between ZnT-1 level and most other clinical parameters tested. Multivariate analysis determined that atrial fibrillation and increased body mass index were the only independent variables clearly associated with higher ZnT-1 levels (Standardized coefficients Beta = 0.62, 0.31; P = 0.002, P = 0.04, respectively). CONCLUSIONS: This pilot study provides evidence for increased ZnT-1 expression in the atria of patients with atrial fibrillation.

FDG PET/CT of Cardiac Angiosarcoma With Pulmonary Metastases.

We present a case of an adolescent girl with a cardiac mass which was characterized as malignant on FDG PET/CT. In addition, FDG PET/CT revealed multiple hypermetabolic pulmonary lesions. The final diagnosis was primary cardiac angiosarcoma with pulmonary metastases, a rare malignancy especially in female patients at this age group. We emphasize the potential role of FDG PET/CT in patients with a cardiac neoplasm and present a literature review of FDG uptake in benign versus malignant cardiac tumors.