Endovascular Ablation of the Right Greater Splanchnic Nerve in Heart Failure With Preserved Ejection Fraction: Rationale, Design and Lead-in Phase Results of the REBALANCE-HF Trial.

OBJECTIVE: Splanchnic vasoconstriction augments transfer of blood volume from the abdomen into the thorax, which may increase filling pressures and hemodynamic congestion in patients with noncompliant hearts. Therapeutic interruption of splanchnic nerve activity holds promise to reduce hemodynamic congestion in patients with heart failure with preserved ejection fraction (HFpEF). Here we describe (1) the rationale and design of the first sham-controlled, randomized clinical trial of splanchnic nerve ablation for HFpEF and (2) the 12-month results of the lead-in (open-label) trial's participants. METHODS: REBALANCE-HF is a prospective, multicenter, randomized, double-blinded, sham-controlled clinical trial of endovascular, transcatheter, right-sided greater splanchnic nerve ablation for volume management (SAVM) in patients with HFpEF. The primary objectives are to evaluate the safety and efficacy of SAVM and identify responder characteristics to inform future studies. The trial consists of an open-label lead-in phase followed by the randomized, sham-controlled phase. The primary efficacy endpoint is the reduction in pulmonary capillary wedge pressure (PCWP) at 1-month follow-up compared to baseline during passive leg raise and 20W exercise. Secondary and exploratory endpoints include health status (Kansas City Cardiomyopathy Questionnaire), 6-minute walk test distance, New York Heart Association class, and NTproBNP levels at 3, 6 and 12 months. The primary safety endpoint is device- or procedure-related serious adverse events at the 1-month follow-up. RESULTS: The lead-in phase of the study, which enrolled 26 patients with HFpEF who underwent SAVM, demonstrated favorable safety outcomes and reduction in exercise PCWP at 1 month post-procedure and improvements in all secondary endpoints at 6 and 12 months of follow-up. The randomized phase of the trial (n = 44 SAVM; n = 46 sham) has completed enrollment, and follow-up is ongoing. CONCLUSION: REBALANCE-HF is the first sham-controlled randomized clinical trial of greater splanchnic nerve ablation in HFpEF. Initial 12-month open-label results are promising, and the results of the randomized portion of the trial will inform the design of a future pivotal clinical trial. SAVM may offer a promising therapeutic option for patients with HFpEF. TRIAL REGISTRATION: NCT04592445.

Atrial shunt device for heart failure with preserved and mildly reduced ejection fraction (REDUCE LAP-HF II): a randomised, multicentre, blinded, sham-controlled trial.

BACKGROUND: Placement of an interatrial shunt device reduces pulmonary capillary wedge pressure during exercise in patients with heart failure and preserved or mildly reduced ejection fraction. We aimed to investigate whether an interatrial shunt can reduce heart failure events or improve health status in these patients. METHODS: In this randomised, international, blinded, sham-controlled trial performed at 89 health-care centres, we included patients (aged ≥40 years) with symptomatic heart failure, an ejection fraction of at least 40%, and pulmonary capillary wedge pressure during exercise of at least 25 mm Hg while exceeding right atrial pressure by at least 5 mm Hg. Patients were randomly assigned (1:1) to receive either a shunt device or sham procedure. Patients and outcome assessors were masked to randomisation. The primary endpoint was a hierarchical composite of cardiovascular death or non-fatal ischemic stroke at 12 months, rate of total heart failure events up to 24 months, and change in Kansas City Cardiomyopathy Questionnaire overall summary score at 12 months. Pre-specified subgroup analyses were conducted for the heart failure event endpoint. Analysis of the primary endpoint, all other efficacy endpoints, and safety endpoints was conducted in the modified intention-to-treat population, defined as all patients randomly allocated to receive treatment, excluding those found to be ineligible after randomisation and therefore not treated. This study is registered with ClinicalTrials.gov, NCT03088033. FINDINGS: Between May 25, 2017, and July 24, 2020, 1072 participants were enrolled, of whom 626 were randomly assigned to either the atrial shunt device (n=314) or sham procedure (n=312). There were no differences between groups in the primary composite endpoint (win ratio 1·0 [95% CI 0·8-1·2]; p=0·85) or in the individual components of the primary endpoint. The prespecified subgroups demonstrating a differential effect of atrial shunt device treatment on heart failure events were pulmonary artery systolic pressure at 20W of exercise (pinteraction=0·002 [>70 mm Hg associated with worse outcomes]), right atrial volume index (pinteraction=0·012 [≥29·7 mL/m2, worse outcomes]), and sex (pinteraction=0·02 [men, worse outcomes]). There were no differences in the composite safety endpoint between the two groups (n=116 [38%] for shunt device vs n=97 [31%] for sham procedure; p=0·11). INTERPRETATION: Placement of an atrial shunt device did not reduce the total rate of heart failure events or improve health status in the overall population of patients with heart failure and ejection fraction of greater than or equal to 40%. FUNDING: Corvia Medical.

Dapagliflozin for heart failure according to body mass index: the DELIVER trial.

AIMS: Obesity is common and associated with unique phenotypic features in heart failure with preserved ejection fraction (HFpEF). Therefore, understanding the efficacy and safety of new therapies in HFpEF patients with obesity is important. The effects of dapagliflozin were examined according to body mass index (BMI) among patients in the Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure trial. METHODS AND RESULTS: Body mass index was analysed by World Health Organization (WHO) categories and as a continuous variable using restricted cubic splines. Body mass index ranged from 15.2 to 50 kg/m2 with a mean value of 29.8 (standard deviation ± 6.1) kg/m2. The proportions, by WHO category, were: normal weight 1343 (21.5%); overweight 2073 (33.1%); Class I obesity 1574 (25.2%); Class II obesity 798 (12.8%); and Class III obesity 415 (6.6%). Compared with placebo, dapagliflozin reduced the risk of the primary outcome to a similar extent across these categories: hazard ratio (95% confidence interval): 0.89 (0.69-1.15), 0.87 (0.70-1.08), 0.74 (0.58-0.93), 0.78 (0.57-1.08), and 0.72 (0.47-1.08), respectively (P-interaction = 0.82). The placebo-corrected change in Kansas City Cardiomyopathy Questionnaire total symptom score with dapagliflozin at 8 months was: 0.9 (-1.1, 2.8), 2.5 (0.8, 4.1), 1.9 (-0.1, 3.8), 2.7 (-0.5, 5.8), and 8.6 (4.0, 13.2) points, respectively (P-interaction = 0.03). The placebo-corrected change in weight at 12 months was: -0.88 (-1.28, -0.47), -0.65 (-1.04, -0.26), -1.42 (-1.89, -0.94), -1.17 (-1.94, -0.40), and -2.50 (-4.4, -0.64) kg (P-interaction = 0.002). CONCLUSIONS: Obesity is common in patients with HFpEF and is associated with higher rates of heart failure hospitalization and worse health status. Treatment with dapagliflozin improves cardiovascular outcomes across the spectrum of BMI, leads to greater symptom improvement in patients with obesity, compared with those without, and has the additional benefit of causing modest weight loss.

Predictive Value of Cardiac CTA, Cardiac MRI, and Transthoracic Echocardiography for Cardioembolic Stroke Recurrence.

BACKGROUND. Transthoracic echocardiography (TTE) is the standard of care for initial evaluation of patients with suspected cardioembolic stroke. Although TTE is useful for assessing certain sources of cardiac emboli, its diagnostic capability is limited in the detection of other sources, including left atrial thrombus and aortic plaques. OBJECTIVE. The purpose of this article was to investigate sensitivity, specificity, and predictive value of cardiac CTA (CCTA), cardiac MRI (CMRI), and TTE for recurrence in patients with suspected cardioembolic stroke. METHODS. We retrospectively included 151 patients with suspected cardioembolic stroke who underwent TTE and either CMRI (n = 75) or CCTA (n = 76) between January 2013 and May 2017. We evaluated for the presence of left atrial thrombus, left ventricular thrombus, vulnerable aortic plaque, cardiac tumors, and valvular vegetation as causes of cardioembolic stroke. The end point was stroke recurrence. Sensitivity, specificity, PPV, and NPV for recurrent stroke were calculated; the diagnostic accuracy of CMRI, CCTA, and TTE was compared between and within groups using AUC. RESULTS. Twelve and 14 recurrent strokes occurred in the CCTA and CMRI groups, respectively. Sensitivity, specificity, PPV, and NPV were 33.3%, 93.7%, 50.0%, and 88.2% for CCTA; 14.3%, 80.3%, 14.3%, and 80.3% for CMRI; 14.3%, 83.6%, 16.7%, and 80.9% for TTE in the CMRI group; and 8.3%, 93.7%, 20.0%, and 84.5% for TTE in the CCTA group. Accuracy was not different (p > .05) between CCTA (AUC = 0.63; 95% CI, 0.49-0.77), CMRI (0.53; 95% CI, 0.42-0.63), TTE in the CMRI group (0.51; 95% CI, 0.40-0.61), and TTE in the CCTA group (0.51; 95% CI, 0.42-0.59). In the CCTA group, atrial and ventricular thrombus were detected by CCTA in three patients and TTE in one patient; in the CMRI group, thrombus was detected by CMRI in one patient and TTE in two patients. CONCLUSION. CCTA, CMRI, and TTE showed comparably high specificity and NPV for cardioembolic stroke recurrence. CCTA and CMRI may be valid alternatives to TTE. CCTA may be preferred given potentially better detection of atrial and ventricular thrombus. CLINICAL IMPACT. CCTA and CMRI have similar clinical performance as TTE for predicting cardioembolic stroke recurrence. This observation may be especially important when TTE provides equivocal findings.

Catheter ablation of atrial fibrillation in patients with cor triatriatum sinister; case series and review of literature.

INTRODUCTION: Cor triatriatum sinister (CTS) is a rare congenital heart defect characterized by fibromuscular septation of the left atrium associated with atrial fibrillation (AF). The incidence of hemodynamically insignificant CTS in the AF ablation population and effect on ablation success are not known. Furthermore, little is known about the potential effect of CTS on arrhythmogenic substrate. OBJECTIVE: We define the incidence of hemodynamically insignificant CTS in patients undergoing AF ablation with RF and cryoballoon ablation, the technical challenges created by the left atrial partitioning, and the potentially arrhythmogenic effects of the membrane. We also review the literature of CA in patients with CTS. METHODS: First-time AF ablation cases at our institution over a 10-year period were screened to identify patients with CTS. Retrospective review was performed to obtain clinical characteristics and ablation data. RESULTS: Of the 3953 consecutive patients undergoing initial AF ablation during the study period, four patients (0.10%) had CTS. Ablation was successful acutely in all patients. One patient had recurrent AF and required repeat ablation for a single procedure success rate of 75% and multi-procedure success rate of 100%. The CTS membrane was associated with low voltage zones in the two patients in whom it was measured and with substrate for macro-reentrant atrial tachycardia in one of these patients. CONCLUSION: The incidence of hemodynamically insignificant CTS in patients undergoing CA for AF is very low, but does not serve as a significant barrier to successful ablation as long as directed access to the superoposterior chamber is obtained.

Weight and Metabolic Outcomes 12 Years after Gastric Bypass.

BACKGROUND: Few long-term or controlled studies of bariatric surgery have been conducted to date. We report the 12-year follow-up results of an observational, prospective study of Roux-en-Y gastric bypass that was conducted in the United States. METHODS: A total of 1156 patients with severe obesity comprised three groups: 418 patients who sought and underwent Roux-en-Y gastric bypass (surgery group), 417 patients who sought but did not undergo surgery (primarily for insurance reasons) (nonsurgery group 1), and 321 patients who did not seek surgery (nonsurgery group 2). We performed clinical examinations at baseline and at 2 years, 6 years, and 12 years to ascertain the presence of type 2 diabetes, hypertension, and dyslipidemia. RESULTS: The follow-up rate exceeded 90% at 12 years. The adjusted mean change from baseline in body weight in the surgery group was -45.0 kg (95% confidence interval [CI], -47.2 to -42.9; mean percent change, -35.0) at 2 years, -36.3 kg (95% CI, -39.0 to -33.5; mean percent change, -28.0) at 6 years, and -35.0 kg (95% CI, -38.4 to -31.7; mean percent change, -26.9) at 12 years; the mean change at 12 years in nonsurgery group 1 was -2.9 kg (95% CI, -6.9 to 1.0; mean percent change, -2.0), and the mean change at 12 years in nonsurgery group 2 was 0 kg (95% CI, -3.5 to 3.5; mean percent change, -0.9). Among the patients in the surgery group who had type 2 diabetes at baseline, type 2 diabetes remitted in 66 of 88 patients (75%) at 2 years, in 54 of 87 patients (62%) at 6 years, and in 43 of 84 patients (51%) at 12 years. The odds ratio for the incidence of type 2 diabetes at 12 years was 0.08 (95% CI, 0.03 to 0.24) for the surgery group versus nonsurgery group 1 and 0.09 (95% CI, 0.03 to 0.29) for the surgery group versus nonsurgery group 2 (P<0.001 for both comparisons). The surgery group had higher remission rates and lower incidence rates of hypertension and dyslipidemia than did nonsurgery group 1 (P<0.05 for all comparisons). CONCLUSIONS: This study showed long-term durability of weight loss and effective remission and prevention of type 2 diabetes, hypertension, and dyslipidemia after Roux-en-Y gastric bypass. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others.).

Exercise effects on arterial stiffness and heart health in children with excess weight: The SMART RCT.

INTRODUCTION: Childhood obesity and inactivity are associated with cardiovascular risk. Evidence is limited for exercise effects on arterial health in children. METHODS: One hundred and seventy-five inactive children with overweight or obesity (8-11 years, ≥85th percentile BMI, 61% female, 87% Black, 73% with obesity) were randomized to an 8-month daily after-school aerobic exercise program (40 min/day, n = 90) or a sedentary control condition (n = 85). Carotid-femoral pulse wave velocity (PWV, primary outcome, arterial stiffness), fitness, adiposity, blood pressure (BP), glucose, insulin resistance, lipids, and C-reactive protein were measured at baseline and posttest (8 months). Adiposity, fitness, and BP were measured again at follow-up, 8-12 months later. Intent-to-treat analyses were conducted using mixed models. RESULTS: The study had 89% retention, with attendance of 59% in exercise and 64% in the control condition, and vigorous exercise participation (average heart rate 161 ± 7 beats/min). Compared with controls, the exercise group had twice the improvement in fitness (VÈ®2 peak, 2.7 (95% CI 1.8, 3.6) vs. 1.3 (0.4, 2.3) mL/kg/min) and adiposity (-1.8 (-2.4, -1.1) vs. -0.8 (-1.5, -0.1)%), each p = 0.04, and a large improvement in HDL-cholesterol (0.13 (0.075, 0.186) vs. -0.028 (-0.083, 0.023) mmol/L, p < 0.0001). There was no group × time effect on other outcomes at 8 months, or on any outcomes at follow-up. The change in PWV at 8 months correlated with changes in insulin and insulin resistance (both r = 0.32), diastolic BP (r = 0.24), BMI (r = 0.22), and adiposity (r = 0.18). CONCLUSIONS: Eight months of aerobic exercise training improved fitness, adiposity, and HDL-cholesterol levels, but did not reduce arterial stiffness in children with excess weight. PWV improved as a function of insulin resistance, BP, BMI, and adiposity. Weight loss may be required to improve arterial stiffness. Exercise benefits waned after discontinuing the program.

Sex differences in management and outcomes of patients with stable symptoms suggestive of coronary artery disease: Insights from the PROMISE trial.

BACKGROUND: Although sex differences exist in the management of acute coronary syndromes, less is known about the management and outcomes of women and men with suspected coronary artery disease being evaluated with noninvasive testing (NIT). METHODS: We investigated sex-based differences in NIT results and subsequent clinical management in 4,720 women and 4,246 men randomized to CT angiography versus stress testing in the PROMISE trial. Logistic regression models assessed relationships between sex and referral for catheterization, revascularization, and aspirin or statin use. Cox regression models assessed the relationship between sex and the composite of all-cause death, myocardial infarction, or unstable angina. RESULTS: Women more often had normal NITs than men (61.0% vs 49.6%, P < .001) and less often had mild (29.3% vs 35.4%, P < .001), moderate (4.0% vs 6.8%, P < .001), or severe abnormalities (5.7% vs 8.3%, P < .001) found on NIT. Women were less likely to be referred for catheterization than men (7.6% vs 12.6%, adjusted OR 0.75 [0.62-0.90]; P = .002). Of those who underwent catheterization within 90 days of randomization (358 women, 534 men), fewer women than men had obstructive coronary artery disease (40.8% vs 60.9%, P < .001). At a 60-day visit, women were significantly less likely than men to report statin use when indicated (adjusted OR 0.81 [0.73-0.91]; P < .001) but were similarly likely to report aspirin use when indicated (adjusted OR 0.78 [0.56-1.08]; P = .13). Over a median follow-up of 25 months, women had better outcomes than men (adjusted OR 0.73 [0.57-0.94]; P = .017). CONCLUSIONS: Although women more frequently had normal NITs compared with men, those with abnormalities on NIT were less likely to be referred for catheterization or to receive statin therapy. The high rates of negative NIT in women, coupled with the better outcomes compared with men, strongly support the need for a sex-specific algorithm to guide NIT and chest pain management.

Nutrition, Obesity, and Cachexia in Patients With Heart Failure: A Consensus Statement from the Heart Failure Society of America Scientific Statements Committee.

Dietary guidance for patients with heart failure (HF) has traditionally focused on sodium and fluid intake restriction, but dietary quality is frequently poor in patients with HF and may contribute to morbidity and mortality. Restrictive diets can lead to inadequate intake of macronutrients and micronutrients by patients with HF, with the potential for deficiencies of calcium, magnesium, zinc, iron, thiamine, vitamins D, E, and K, and folate. Although inadequate intake and low plasma levels of micronutrients have been associated with adverse clinical outcomes, evidence supporting therapeutic repletion is limited. Intravenous iron, thiamine, and coenzyme Q10 have the most clinical trial data for supplementation. There is also limited evidence supporting protein intake goals. Obesity is a risk factor for incident HF, and weight loss is an established approach for preventing HF, with a role for bariatric surgery in patients with severe obesity. However weight loss for patients with existing HF and obesity is a more controversial topic owing to an obesity survival paradox. Dietary interventions and pharmacologic weight loss therapies are understudied in HF populations. There are also limited data for optimal strategies to identify and address cachexia and sarcopenia in patients with HF, with at least 10%-20% of patients with ambulatory systolic HF developing clinically significant wasting. Gaps in our knowledge about nutrition status in patients with HF are outlined in this Statement, and strategies to address the most clinically relevant questions are proposed.

A novel role for the Wnt inhibitor APCDD1 in adipocyte differentiation: Implications for diet-induced obesity.

Impaired adipogenic differentiation during diet-induced obesity (DIO) promotes adipocyte hypertrophy and inflammation, thereby contributing to metabolic disease. Adenomatosis polyposis coli down-regulated 1 (APCDD1) has recently been identified as an inhibitor of Wnt signaling, a key regulator of adipogenic differentiation. Here we report a novel role for APCDD1 in adipogenic differentiation via repression of Wnt signaling and an epigenetic linkage between miR-130 and APCDD1 in DIO. APCDD1 expression was significantly up-regulated in mature adipocytes compared with undifferentiated preadipocytes in both human and mouse subcutaneous adipose tissues. siRNA-based silencing of APCDD1 in 3T3-L1 preadipocytes markedly increased the expression of Wnt signaling proteins (Wnt3a, Wnt5a, Wnt10b, LRP5, and ß-catenin) and inhibited the expression of adipocyte differentiation markers (CCAAT/enhancer-binding protein α (C/EBPα) and peroxisome proliferator-activated receptor γ (PPARγ)) and lipid droplet accumulation, whereas adenovirus-mediated overexpression of APCDD1 enhanced adipogenic differentiation. Notably, DIO mice exhibited reduced APCDD1 expression and increased Wnt expression in both subcutaneous and visceral adipose tissues and impaired adipogenic differentiation in vitro Mechanistically, we found that miR-130, whose expression is up-regulated in adipose tissues of DIO mice, could directly target the 3'-untranslated region of the APCDD1 gene. Furthermore, transfection of an miR-130 inhibitor in preadipocytes enhanced, whereas an miR-130 mimic blunted, adipogenic differentiation, suggesting that miR-130 contributes to impaired adipogenic differentiation during DIO by repressing APCDD1 expression. Finally, human subcutaneous adipose tissues isolated from obese individuals exhibited reduced expression of APCDD1, C/EBPα, and PPARγ compared with those from non-obese subjects. Taken together, these novel findings suggest that APCDD1 positively regulates adipogenic differentiation and that its down-regulation by miR-130 during DIO may contribute to impaired adipogenic differentiation and obesity-related metabolic disease.

A single high-fat meal provokes pathological erythrocyte remodeling and increases myeloperoxidase levels: implications for acute coronary syndrome.

High-fat meal (HFM) consumption can produce acute lipemia and trigger myocardial infarction in patients with atherosclerosis, but the mechanisms are poorly understood. Erythrocytes (red blood cells, RBCs) intimately interact with inflammatory cells and blood vessels and play a complex role in regulating vascular function. Chronic high-fat feeding in mice induces pathological RBC remodeling, suggesting a novel link between HFM, RBCs, and vascular dysfunction. However, whether acute HFM can induce RBC remodeling in humans is unknown. Ten healthy individuals were subjected to biochemical testing and assessment of endothelial-dependent flow-mediated dilation (FMD) before and after a single HFM or iso-caloric meal (ICM). Following the HFM, triglyceride, cholesterol, and free fatty acid levels were all significantly increased, in conjunction with impaired post-prandial FMD. Additionally, peripheral blood smears demonstrated microcytes, remodeled RBCs, and fatty monocytes. Increased intracellular ROS and nitration of protein band 3 was detected in RBCs following the HFM. The HFM elevated plasma and RBC-bound myeloperoxidase (MPO), which was associated with impaired FMD and oxidation of HDL. Monocytic cells exposed to lipid in vitro released MPO, while porcine coronary arteries exposed to fatty acids ex vivo took up MPO. We demonstrate in humans that a single HFM induces pathological RBC remodeling and concurrently elevates MPO, which can potentially enter the blood vessel wall to trigger oxidative stress and destabilize vulnerable plaques. These novel findings may have implications for the short-term risk of HFM consumption and alimentary lipemia in patients with atherosclerosis.

Diagnostic accuracy of low and high tube voltage coronary CT angiography using an X-ray tube potential-tailored contrast medium injection protocol.

OBJECTIVES: To compare the diagnostic accuracy between low-kilovolt peak (kVp) (≤ 100) and high-kVp (> 100) third-generation dual-source coronary CT angiography (CCTA) using a kVp-tailored contrast media injection protocol. METHODS: One hundred twenty patients (mean age = 62.6 years, BMI = 29.0 kg/m2) who underwent catheter angiography and CCTA with automated kVp selection were separated into two cohorts (each n = 60, mean kVp = 84 and 117). Contrast media dose was tailored to the kVp level: 70 = 40 ml, 80 = 50 ml, 90 = 60 ml, 100 = 70 ml, 110 = 80 ml, and 120 = 90 ml. Contrast-to-noise ratio (CNR) was measured. Two observers evaluated image quality and the presence of significant coronary stenosis (> 50% luminal narrowing). RESULTS: Diagnostic accuracy (sensitivity/specificity) with ≤ 100 vs. > 100 kVp CCTA was comparable: per patient = 93.9/92.6% vs. 90.9/92.6%, per vessel = 91.5/97.8% vs. 94.0/96.8%, and per segment = 90.0/96.7% vs. 90.7/95.2% (all P > 0.64). CNR was similar (P > 0.18) in the low-kVp vs. high-kVp group (12.0 vs. 11.1), as ws subjective image quality (P = 0.38). Contrast media requirements were reduced by 38.1% in the low- vs. high-kVp cohort (53.6 vs. 86.6 ml, P < 0.001) and radiation dose by 59.6% (4.3 vs. 10.6 mSv, P < 0.001). CONCLUSIONS: Automated tube voltage selection with a tailored contrast media injection protocol allows CCTA to be performed at ≤ 100 kVp with substantial dose reductions and equivalent diagnostic accuracy for coronary stenosis detection compared to acquisitions at > 100 kVp. KEY POINTS: • Low-kVp coronary CT angiography (CCTA) enables reduced contrast and radiation dose. • Diagnostic accuracy is comparable between ≤ 100 and > 100 kVp CCTA. • Image quality is similar for low- and high-kVp CCTA. • Low-kVp image acquisition is facilitated by automated tube voltage selection. • Tailoring contrast injection protocols to the automatically selected kVp-level is feasible.

Glucose transporter 4-deficient hearts develop maladaptive hypertrophy in response to physiological or pathological stresses.

Pathological cardiac hypertrophy may be associated with reduced expression of glucose transporter 4 (GLUT4) in contrast to exercise-induced cardiac hypertrophy, where GLUT4 levels are increased. However, mice with cardiac-specific deletion of GLUT4 (G4H-/-) have normal cardiac function in the unstressed state. This study tested the hypothesis that cardiac GLUT4 is required for myocardial adaptations to hemodynamic demands. G4H-/- and control littermates were subjected to either a pathological model of left ventricular pressure overload [transverse aortic constriction (TAC)] or a physiological model of endurance exercise (swim training). As predicted after TAC, G4H-/- mice developed significantly greater hypertrophy and more severe contractile dysfunction. Somewhat surprisingly, after exercise training, G4H-/- mice developed increased fibrosis and apoptosis that was associated with dephosphorylation of the prosurvival kinase Akt in concert with an increase in protein levels of the upstream phosphatase protein phosphatase 2A (PP2A). Exercise has been shown to decrease levels of ceramide; G4H-/- hearts failed to decrease myocardial ceramide in response to exercise. Furthermore, G4H-/- hearts have reduced levels of the transcriptional coactivator peroxisome proliferator-activated receptor-γ coactivator-1, lower carnitine palmitoyl-transferase activity, and reduced hydroxyacyl-CoA dehydrogenase activity. These basal changes may also contribute to the impaired ability of G4H-/- hearts to adapt to hemodynamic stresses. In conclusion, GLUT4 is required for the maintenance of cardiac structure and function in response to physiological or pathological processes that increase energy demands, in part through secondary changes in mitochondrial metabolism and cellular stress survival pathways such as Akt.NEW & NOTEWORTHY Glucose transporter 4 (GLUT4) is required for myocardial adaptations to exercise, and its absence accelerates heart dysfunction after pressure overload. The requirement for GLUT4 may extend beyond glucose uptake to include defects in mitochondrial metabolism and survival signaling pathways that develop in its absence. Therefore, GLUT4 is critical for responses to hemodynamic stresses.

Coronary CT Angiography-derived Fractional Flow Reserve.

Invasive coronary angiography (ICA) with measurement of fractional flow reserve (FFR) by means of a pressure wire technique is the established reference standard for the functional assessment of coronary artery disease (CAD) ( 1 , 2 ). Coronary computed tomographic (CT) angiography has emerged as a noninvasive method for direct assessment of CAD and plaque characterization with high diagnostic accuracy compared with ICA ( 3 , 4 ). However, the solely anatomic assessment provided with both coronary CT angiography and ICA has poor discriminatory power for ischemia-inducing lesions. FFR derived from standard coronary CT angiography (FFRCT) data sets by using any of several advanced computational analytic approaches enables combined anatomic and hemodynamic assessment of a coronary lesion by a single noninvasive test. Current technical approaches to the calculation of FFRCT include algorithms based on full- and reduced-order computational fluid dynamic modeling, as well as artificial intelligence deep machine learning ( 5 , 6 ). A growing body of evidence has validated the diagnostic accuracy of FFRCT techniques compared with invasive FFR. Improved therapeutic guidance has been demonstrated, showing the potential of FFRCT to streamline and rationalize the care of patients suspected of having CAD and improve outcomes while reducing overall health care costs ( 7 , 8 ). The purpose of this review is to describe the scientific principles, clinical validation, and implementation of various FFRCT approaches, their precursors, and related imaging tests. © RSNA, 2017.

T(Rho) and magnetization transfer and INvErsion recovery (TRAMINER)-prepared imaging: A novel contrast-enhanced flow-independent dark-blood technique for the evaluation of myocardial late gadolinium enhancement in patients with myocardial infarction.

PURPOSE: To evaluate a new dark-blood late gadolinium enhancement (LGE) technique called "T(Rho) And Magnetization transfer and INvErsion Recovery" (TRAMINER) for the ability to detect myocardial LGE versus standard "bright-blood" inversion recovery (SIR) imaging. MATERIALS AND METHODS: This Institutional Review Board (IRB)-approved, Health Insurance Portability and Accountability Act (HIPAA)-compliant prospective study included 40 patients (62 ± 14 years [mean ± standard deviation (SD)], 29 males) with suspected myocardial infarction (MI) referred for the assessment of myocardial viability. The patients underwent a 1.5T cardiac magnetic resonance imaging (MRI) including postcontrast SIR and TRAMINER acquisitions. Normalized images were evaluated by two readers. Subjective (3-point Likert scale) and objective image qualities were compared using Mann-Whitney U-test and paired t-test, respectively. Interobserver agreement, LGE detection rate, and level of certainty were compared using Cohen's kappa, Wilcoxon-test, and Mann-Whitney U-test, respectively. Results are reported as mean ± SD or mean [95% confidence interval]. RESULTS: Overall, image quality was rated similar between TRAMINER and SIR; however, TRAMINER performed better on a visual assessment of the ability to differentiate LGE from blood (Likert scale: 3.0 [3.0-3.0] vs. 2.0 [1.7-2.2], P < 0.0001). TRAMINER provided significantly higher signal intensity range (69.8 ± 10.2 vs. 9.6 ± 7.6, P < 0.0001) and a 4-fold higher signal intensity ratio (4.2 ± 1.9 vs. 1.1 ± 0.1, P < 0.0001) between LGE and blood signals. TRAMINER detected more patients (19/40 vs. 17/40) and segments (91/649 vs. 79/649) with LGE with higher level of certainty (2.9 [2.8-3.0] vs. 2.7 [2.5-2.8], P = 0.0185). Interobserver agreement was good to excellent for LGE detection. CONCLUSION: TRAMINER provides better contrast between LGE and blood and consequently may have increased ability to discriminate thin subendocardial and papillary muscle enhancement from the blood signal, which can have an indistinct appearance using SIR. LEVEL OF EVIDENCE: 2 J. MAGN. RESON. IMAGING 2017;45:1429-1437.

Effect of inversion time on the precision of myocardial late gadolinium enhancement quantification evaluated with synthetic inversion recovery MR imaging.

OBJECTIVES: To evaluate the influence of inversion time (TI) on the precision of myocardial late gadolinium enhancement (LGE) quantification using synthetic inversion recovery (IR) imaging in patients with myocardial infarction (MI). METHODS: Fifty-three patients with suspected prior MI underwent 1.5-T cardiac MRI with conventional magnitude (MagIR) and phase-sensitive IR (PSIR) LGE imaging and T1 mapping at 15 min post-contrast. T1-based synthetic MagIR and PSIR images were calculated with a TI ranging from -100 to +150 ms at 5-ms intervals relative to the optimal TI (TI0). LGE was quantified using a five standard deviation (5SD) and full width at half-maximum (FWHM) thresholds. Measurements were compared using one-way analysis of variance. RESULTS: The MagIRsy technique provided precise assessment of LGE area at TIs ≥ TI0, while precision was decreased below TI0. The LGE area showed significant differences at ≤ -25 ms compared to TI0 using 5SD (P < 0.001) and at ≤ -65 ms using the FWHM approach (P < 0.001). LGE measurements did not show significant difference over the analysed TI range in the PSIRsy images using either of the quantification methods. CONCLUSIONS: T1 map-based PSIRsy images provide precise quantification of MI independent of TI at the investigated time point post-contrast. MagIRsy-based MI quantification is precise at TI0 and at longer TIs while showing decreased precision at TI values below TI0. KEY POINTS: • Synthetic IR imaging retrospectively generates LGE images at any theoretical TI • Synthetic IR imaging can simulate the effect of TI on LGE quantification • Fifteen minutes post-contrast MagIR sy accurately quantifies infarcts from TI 0 to TI 0 + 150 ms • Fifteen minutes post-contrast PSIR sy provides precise infarct size independent of TI • Synthetic IR imaging has further advantages in reducing operator dependence.

Low contrast medium-volume third-generation dual-source computed tomography angiography for transcatheter aortic valve replacement planning.

PURPOSE: To investigate feasibility, image quality and safety of low-tube-voltage, low-contrast-volume comprehensive cardiac and aortoiliac CT angiography (CTA) for planning transcatheter aortic valve replacement (TAVR). MATERIALS AND METHODS: Forty consecutive TAVR candidates prospectively underwent combined CTA of the aortic root and vascular access route (270 mgI/ml iodixanol). Patients were assigned to group A (second-generation dual-source CT [DSCT], 100 kV, 60 ml contrast, 4.0 ml/s flow rate) or group B (third-generation DSCT, 70 kV, 40 ml contrast, 2.5 ml/s flow rate). Vascular attenuation, noise, signal-to-noise (SNR) and contrast-to-noise ratios (CNR) were compared. Subjective image quality was assessed by two observers. Estimated glomerular filtration (eGFR) at CTA and follow-up were measured. RESULTS: Besides a higher body-mass-index in group B (24.8±3.8 kg/m2 vs. 28.1±5.4 kg/m2, P=0.0339), patient characteristics between groups were similar (P≥0.0922). Aortoiliac SNR (P=0.0003) was higher in group B. Cardiac SNR (P=0.0003) and CNR (P=0.0181) were higher in group A. Subjective image quality was similar (P≥0.213) except for aortoiliac image noise (4.42 vs. 4.12, P=0.0374). TAVR-planning measurements were successfully obtained in all patients. There were no significant changes in eGFR among and between groups during follow-up (P≥0.302). CONCLUSION: TAVR candidates can be safely and effectively evaluated by a comprehensive CTA protocol with low contrast volume using low-tube-voltage acquisition. KEY POINTS: • Third-generation dual-source CT facilitates low-tube-voltage acquisition. • TAVR planning can be performed with reduced contrast volume and radiation dose. • TAVR-planning CT did not result in changes in creatinine levels at follow-up. • TAVR candidates can be safely evaluated by comprehensive low-tube-voltage CT angiography.

Correlation and predictive value of aortic root calcification markers with coronary artery calcification and obstructive coronary artery disease.

OBJECTIVE: To evaluate the correlation between aortic root calcification (ARC) markers and coronary artery calcification (CAC) derived from coronary artery calcium scoring (CACS) and their ability to predict obstructive coronary artery disease (CAD). METHODS: We retrospectively analyzed 189 patients (47% male, age 60.3 ± 11.1 years) with an intermediate probability of CAD who underwent clinically indicated CACS and coronary CT angiography (CCTA). ARC markers [aortic root calcium score (ARCS) and volume (ARCV)] were calculated and compared to CAC markers: coronary artery calcium score (CACS), volume (CACV), and mass (CACM). CCTA datasets were visually evaluated for significant CAD (stenosis ≥ 50%) and the ability of ARC markers to predict obstructive CAD was assessed. RESULTS: ARCS (mean 67.7 ± 189.5) and ARCV (mean 67.3 ± 184.7) showed significant differences between patients with and without CAC (109.4 ± 238.6 vs 9.42 ± 31.4, p < 0.0001; 108.5 ± 232.4 vs 9.9 ± 30.5, p < 0.0001). A strong correlation was found for ARCS and ARCV with CACS, CACM, and CACV (all p < 0.0001). In a multivariate analysis, ARCS (OR 1.09, p = 0.033) and ARCV (OR 1.12, p = 0.046) were independent markers for CAC. Using a receiver-operating characteristics analysis, the AUC to detect severe CAC was 0.71 (p < 0.0001) and 0.71 (p < 0.0001) for ARCS and ARCV, respectively. ARCS (0.67, p < 0.0001) and ARCV (0.68, p < 0.0001) showed discriminatory power for predicting obstructive CAD, yielding sensitivities 61 and 78% and specificities of 62 and 80%, respectively. CONCLUSION: ARC markers are associated with and independently predict the presence of CAC and obstructive CAD. Further testing is required in patients with severe ARC and significant CAD in order to reliably obtain these markers from thoracic-CT or X-ray for proper risk classification.

Coronary CT angiography in obese patients using 3(rd) generation dual-source CT: effect of body mass index on image quality.

OBJECTIVES: To evaluate the image quality of coronary CT angiography (CCTA) in obese patients using a 3(rd) generation, dual-source CT scanner. METHODS: We retrospectively evaluated 102 overweight and obese patients who had undergone CCTA. Studies were performed with 3(rd) generation dual-source CT, prospectively ECG-triggered acquisition at 120 kV, and automated tube current modulation. Advanced modeled iterative reconstruction was used. Patients were divided into three BMI groups: 1)25-29.9 kg/m(2); 2)30-39.9 kg/m(2); 3) ≥ 40 kg/m(2). Vascular attenuation in the coronary arteries was measured. Contrast-to-noise ratio (CNR) was calculated. Image quality was subjectively evaluated using five-point scales. RESULTS: Image quality was considered diagnostic in 97.6 % of examinations. CNR was consistently adequate in all groups but decreased for groups 2 and 3 in comparison to group 1 as well as for group 3 compared to group 2 (p = 0.001, respectively). Subjective image quality was significantly higher in group 1 compared to group 3 (attenuation proximal: 4.8 ± 0.4 vs. 4.4 ± 0.6, p = 0.011; attenuation distal: 4.5 ± 0.7 vs. 4.0 ± 0.8, p = 0.019; noise: 4.7 ± 0.6 vs. 3.8 ± 0.7, p < 0.001). The mean effective dose was 9.5 ± 3.9 mSv for group 1, 11.4 ± 4.7 mSv for group 2 and 14.0 ± 6.4 mSv for group 3. CONCLUSION: Diagnostic image quality can be routinely obtained at CCTA in obese patients with 3(rd) generation DSCT at 120 kV. KEY POINTS: • Diagnostic CCTA can be routinely performed in obese patients with 3 (rd) generation DSCT. • 120-kV tube voltage allows diagnostic image quality in patients with BMI > 40 kg/m (2) . • 80-ml contrast medium can be administered without significant decline in vascular attenuation.

Antioxidant treatment normalizes mitochondrial energetics and myocardial insulin sensitivity independently of changes in systemic metabolic homeostasis in a mouse model of the metabolic syndrome.

Cardiac dysfunction in obesity is associated with mitochondrial dysfunction, oxidative stress and altered insulin sensitivity. Whether oxidative stress directly contributes to myocardial insulin resistance remains to be determined. This study tested the hypothesis that ROS scavenging will improve mitochondrial function and insulin sensitivity in the hearts of rodent models with varying degrees of insulin resistance and hyperglycemia. The catalytic antioxidant MnTBAP was administered to the uncoupling protein-diphtheria toxin A (UCP-DTA) mouse model of insulin resistance (IR) and obesity, at early and late time points in the evolution of IR, and to db/db mice with severe obesity and type-two diabetes. Mitochondrial function was measured in saponin-permeabilized cardiac fibers. Aconitase activity and hydrogen peroxide emission were measured in isolated mitochondria. Insulin-stimulated glucose oxidation, glycolysis and fatty acid oxidation rates were measured in isolated working hearts, and 2-deoxyglucose uptake was measured in isolated cardiomyocytes. Four weeks of MnTBAP attenuated glucose intolerance in 13-week-old UCP-DTA mice but was without effect in 24-week-old UCP-DTA mice and in db/db mice. Despite the absence of improvement in the systemic metabolic milieu, MnTBAP reversed cardiac mitochondrial oxidative stress and improved mitochondrial bioenergetics by increasing ATP generation and reducing mitochondrial uncoupling in all models. MnTBAP also improved myocardial insulin mediated glucose metabolism in 13 and 24-week-old UCP-DTA mice. Pharmacological ROS scavenging improves myocardial energy metabolism and insulin responsiveness in obesity and type 2 diabetes via direct effects that might be independent of changes in systemic metabolism.