Explore the vast range of titles available.

Mechanistic target of rapamycin (Mtor) is required for embryonic inner cell mass proliferation during early development. However, Mtor expression levels are very low in the mouse heart during embryogenesis. To determine if Mtor plays a role during mouse cardiac development, cardiomyocyte specific Mtor deletion was achieved using α myosin heavy chain (α-MHC) driven Cre recombinase. Initial mosaic expression of Cre between embryonic day (E) 10.5 and E11.5 eliminated a subset of cardiomyocytes with high Cre activity by apoptosis and reduced overall cardiac proliferative capacity. The remaining cardiomyocytes proliferated and expanded normally. However loss of 50% of cardiomyocytes defined a threshold that impairs the ability of the embryonic heart to sustain the embryo's circulatory requirements. As a result 92% of embryos with cardiomyocyte Mtor deficiency died by the end of gestation. Thus Mtor is required for survival and proliferation of cardiomyocytes in the developing heart.

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. A single high fat meal can induce pathological red blood cell (RBC) remodeling and oxidative stress, in conjunction with elevations in plasma, RBC-bound myeloperoxidase (MPO) and MPO-mediated high-density lipoprotein oxidation. These findings demonstrate that consumption of heavy meals enriched in fat may promote destabilization of vulnerable plaques leading to acute myocardial infarction.

This study investigated the performance of coronary computed tomography angiography (cCTA) with cCTA-derived fractional flow reserve (CT-FFR) compared with invasive coronary angiography (ICA) with fractional flow reserve (FFR) for therapeutic decision making in patients with suspected coronary artery disease (CAD). Seventy-four patients (62 ± 11 years, 62% men) with at least 1 coronary stenosis of ≥50% on clinically indicated dual-source cCTA, who had subsequently undergone ICA with FFR measurement, were retrospectively evaluated. CT-FFR values were computed using an on-site machine-learning algorithm to assess the functional significance of CAD. The therapeutic strategy (optimal medical therapy alone vs revascularization) and the appropriate revascularization procedure (percutaneous coronary intervention vs coronary artery bypass grafting) were selected using cCTA-CT-FFR. Thirty-six patients (49%) had a functionally significant CAD based on ICA-FFR. cCTA-CT-FFR correctly identified a functionally significant CAD and the need of revascularization in 35 of 36 patients (97%). When revascularization was deemed indicated, the same revascularization procedure (32 percutaneous coronary interventions and 3 coronary artery bypass grafting) was chosen in 35 of 35 patients (100%). Overall, identical management strategies were selected in 73 of the 74 patients (99%). cCTA-CT-FFR shows excellent performance to identify patients with and without the need for revascularization and to select the appropriate revascularization strategy. cCTA-CT-FFR as a noninvasive “one-stop shop” has the potential to change diagnostic workflows and to directly inform therapeutic decision making in patients with suspected CAD.

In patients with heart failure with preserved ejection fraction and obesity, treatment with tirzepatide led to a lower risk of death from cardiovascular causes or worsening heart-failure events than placebo.

Type 1 Diabetic Akita Mouse Hearts Are Insulin Sensitive but Manifest Structurally Abnormal Mitochondria That Remain Coupled Despite Increased Uncoupling Protein 3 Heiko Bugger 1 , Sihem Boudina 1 , Xiao Xuan Hu 1 , Joseph Tuinei 1 , Vlad G. Zaha 1 , Heather A. Theobald 1 , Ui Jeong Yun 1 , Alfred P. McQueen 2 , Benjamin Wayment 2 , Sheldon E. Litwin 2 and E. Dale Abel 1 1 Division of Endocrinology, Metabolism, and Diabetes and the Program in Human Molecular Biology and Genetics, University of Utah School of Medicine, Salt Lake City, Utah 2 Division of Cardiology, University of Utah School of Medicine, Salt Lake City, Utah Corresponding author: E. Dale Abel, dale.abel{at}hmbg.utah.edu Abstract OBJECTIVE— Fatty acid–induced mitochondrial uncoupling and oxidative stress have been proposed to reduce cardiac efficiency and contribute to cardiac dysfunction in type 2 diabetes. We hypothesized that mitochondrial uncoupling may also contribute to reduced cardiac efficiency and contractile dysfunction in the type 1 diabetic Akita mouse model (Akita). RESEARCH DESIGN AND METHODS— Cardiac function and substrate utilization were determined in isolated working hearts and in vivo function by echocardiography. Mitochondrial function and coupling were determined in saponin-permeabilized fibers, and proton leak kinetics was determined in isolated mitochondria. Hydrogen peroxide production and aconitase activity were measured in isolated mitochondria, and total reactive oxygen species (ROS) were measured in heart homogenates. RESULTS— Resting cardiac function was normal in Akita mice, and myocardial insulin sensitivity was preserved. Although Akita hearts oxidized more fatty acids, myocardial O 2 consumption was not increased, and cardiac efficiency was not reduced. ADP-stimulated mitochondrial oxygen consumption and ATP synthesis were decreased, and mitochondria showed grossly abnormal morphology in Akita. There was no evidence of oxidative stress, and despite a twofold increase in uncoupling protein 3 (UCP3) content, ATP-to-O ratios and proton leak kinetics were unchanged, even after perfusion of Akita hearts with 1 mmol/l palmitate. CONCLUSIONS— Insulin-deficient Akita hearts do not exhibit fatty acid–induced mitochondrial uncoupling, indicating important differences in the basis for mitochondrial dysfunction between insulin-responsive type 1 versus insulin-resistant type 2 diabetic hearts. Increased UCP3 levels do not automatically increase mitochondrial uncoupling in the heart, which supports the hypothesis that fatty acid–induced mitochondrial uncoupling as exists in type 2 diabetic hearts requires a concomitant increase in ROS generation. Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 4 August 2008. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted July 24, 2008. Received January 18, 2008. DIABETES

In patients with heart failure and preserved or mildly reduced ejection fractions (EF ≥40%), implantation of an interatrial shunt device (IASD) resulted in heterogenous changes of the left atrial (LA) volume. Baseline characteristics that correlate with a favorable decrease in LA volume are unknown. We hypothesized that a larger ratio of left to right atrial volume at baseline would correlate strongly with LA volume decongestion following IASD implantation. Reduce Elevated LA Pressure in Patients With Heart Failure was a multicenter study of the safety and feasibility of IASD implantation. Sixty-four patients with EF ≥40% underwent device implantation along with baseline conventional echocardiograms, speckle tracking echocardiography, and resting and exercise hemodynamics. Higher LA compliance (−4.2%, p = 0.048) and right atrial reservoir strain (−0.8%, p = 0.005) were independently associated with a percent decrease in the systolic LA volume index from baseline to 6-months. In conclusion, greater LA volume reduction following IASD implantation is associated with higher baseline compliance of the left atrium and higher reservoir strain of the right atrium.

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/m 2 vs. 28.1±5.4 kg/m 2 , 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 .

This study prospectively investigated the accuracy and radiation dose reduction of CT coronary artery calcium scoring (CACS) using a 100 kVp acquisition protocol with tin filtration (Sn100 kVp) compared with the standard 120 kVp acquisition protocol; 70 patients (59% men, 62.1 ± 10.7 years) who underwent a clinically indicated CACS acquisition using the standard 120 kVp protocol on a third-generation dual-source CT system were enrolled. An additional Sn100 kVp CACS scan was performed. Agatston scores and categories, percentile-based risk categorization, and radiation dose estimates were derived from 120 and Sn100 kVp studies and compared. Median Agatston scores from the Sn100 and 120 kVp acquisitions were 38.2 and 41.2, respectively (p <0.0001). Excellent correlation of Agatston scores was found between the 2 acquisitions (r = 0.99, p <0.0001). Although the Agatston scores were systematically lower with Sn100 than with 120 kVp, the comparison of Agatston score categories and percentile-based cardiac risk categories showed excellent agreement (κ = 0.98 and κ = 0.98). Image noise was 26.3 ± 5.7 Hounsfield units in Sn100 kVp and 17.6 ± 4.1 Hounsfield units in 120 kVP scans (p <0.0001). The dose-length product was 14.1 ± 3.7 mGy·cm with Sn100 kVp and 58.5 ± 23.5 mGy·cm with 120 kVp scans (p <0.0001), resulting in a significantly lower effective radiation dose (0.19 ± 0.05 vs 0.82 ± 0.32 mSv, p <0.0001) for Sn100 kVp scans. CACS using a low-voltage tin filtration protocol shows excellent correlation and agreement with the standard method with regard to the Agatston score and subsequent cardiac risk categorization, while achieving a 75% reduction in radiation dose.

Patients with obesity-related heart failure with preserved ejection fraction (HFpEF) display circulatory volume expansion and pressure overload contributing to cardiovascular–kidney end-organ damage. In the SUMMIT trial, patients with HFpEF and obesity were randomized to the long-acting glucose-dependent insulinotropic polypeptide receptor and glucagon-like peptide-1 receptor agonist tirzepatide ( n  = 364, 200 women) or placebo ( n  = 367, 193 women). As reported separately, tirzepatide decreased cardiovascular death or worsening heart failure. Here, in this mechanistic secondary analysis of the SUMMIT trial, tirzepatide treatment at 52 weeks, as compared with placebo, reduced systolic blood pressure (estimated treatment difference (ETD) −5 mmHg, 95% confidence interval (CI) −7 to −3; P  < 0.001), decreased estimated blood volume (ETD −0.58 l, 95% CI −0.63 to −0.52; P  < 0.001) and reduced C-reactive protein levels (ETD −37.2%, 95% CI −45.7 to −27.3; P  < 0.001). These changes were coupled with an increase in estimated glomerular filtration rate (ETD 2.90 ml min −1  1.73 m −2  yr −1 , 95% CI 0.94 to 4.86; P  = 0.004), a decrease in urine albumin–creatinine ratio (ETD 24 weeks, −25.0%, 95% CI −36 to −13%; P  < 0.001; 52 weeks, −15%, 95% CI −28 to 0.1; P  = 0.051), a reduction in N-terminal prohormone B-type natriuretic peptide levels (ETD 52 weeks −10.5%, 95% CI −20.7 to 1.0%; P  = 0.07) and a reduction in troponin T levels (ETD 52 weeks −10.4%, 95% CI −16.7 to −3.6; P  = 0.003). In post hoc exploratory analyses, decreased estimated blood volume with tirzepatide treatment was significantly correlated with decreased blood pressure, reduced microalbuminuria, improved Kansas City Cardiomyopathy Questionnaire Clinical Summary Score and increased 6-min walk distance. Moreover, decreased C-reactive protein levels were correlated with reduced troponin T levels and improved 6-min walk distance. In conclusion, tirzepatide reduced circulatory volume–pressure overload and systemic inflammation and mitigated cardiovascular–kidney end-organ injury in patients with HFpEF and obesity, providing new insights into the mechanisms of benefit from tirzepatide. ClinicalTrials.gov registration: NCT04847557 . In a mechanistic analysis of the SUMMIT trial that tested tirzepatide in patients with heart failure with preserved ejection fraction and obesity, treatment with this dual glucagon-like peptide-1 receptor and gastric inhibitory polypeptide agonist, as compared with placebo, reduced blood pressure and estimated circulatory volume–pressure overload, reduced systemic inflammation and mitigated cardiovascular and kidney injury.

The authors report 12-year follow-up results of Roux-en-Y gastric bypass versus no surgery. The results show long-term durability of weight loss and effective remission and prevention of type 2 diabetes, hypertension, and dyslipidemia after Roux-en-Y gastric bypass.