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Switching Site Selectivity in Alkoxyamine Hydration: From Lone-Pair Direction to Solvent Network Dominance
Physical Activity and Your Health
Pregnancy-Associated Spontaneous Coronary Dissection
Evolocumab in Patients With Prior Percutaneous Coronary Intervention and No Prior Myocardial Infarction: Results From the VESALIUS-CV Trial
BACKGROUND: The clinical benefit of intensive LDL cholesterol (LDL-C) lowering with evolocumab in patients with prior percutaneous coronary intervention (PCI) but without a prior myocardial infarction (MI) is not established. METHODS: VESALIUS-CV (The Effect of Evolocumabin Patients at High Cardiovascular Risk Without Prior Myocardial Infarction or Stroke) randomized patients with atherosclerosis or high-risk diabetes but without prior MI or stroke and with LDL-C ≥90 mg/dL to evolocumab versus placebo. The median follow-up was 4.6 years. The dual primary end points were coronary heart disease death, MI, or ischemic stroke (3-point major adverse cardiovascular event [MACE]) and the same composite plus ischemia-driven revascularization (4-point MACE). For this prespecified subgroup analysis, patients were categorized by whether they had undergone PCI at any time before trial enrollment. RESULTS: Among 12 257 randomized patients, 3627 (29.6%) had undergone prior PCI with a median time between PCI and enrollment of 4 years. Their median age was 66 years, and 30.7% were women. The median LDL-C in a lipid substudy at 48 weeks was 41.5 (26.0–67.0) mg/dL versus 107.0 (84.0–135.0) mg/dL in the evolocumab versus placebo arms ( P <0.0001). Evolocumab reduced the relative rate of 3-point MACE by 30% (5-year Kaplan-Meier rates 7.0% versus 9.5%; hazard ratio [HR], 0.70 [95% CI, 0.56–0.89]; P =0.004) and 4-point MACE by 18% (17.9% versus 21.7%; HR, 0.82 [95% CI, 0.71–0.96]; P =0.012) as well as both MI by 50% (3.0% versus 6.1%; HR, 0.50 [95% CI, 0.36–0.70]; P <0.001), with the effect apparent as soon as 6 months after randomization, and urgent coronary revascularization by 39% (HR, 0.61 [95% CI, 0.46–0.80]; P <0.001). There were nominally lower rates of cardiovascular death (2.6% versus 3.7%; HR, 0.66 [95% CI, 0.45–0.96]; P =0.030) and all-cause death (8.2% versus 10.2%; HR, 0.76 [95% CI, 0.60–0.95]; P =0.016) with evolocumab. CONCLUSIONS: Evolocumab reduced the risk of major cardiovascular events in stable patients with prior PCI but no MI. These findings support intensive LDL-C lowering in patients who have undergone PCI even in the absence of prior MI. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03872401.
<i>Circulation</i> Editors and Editorial Board
Lifestyle-Induced Visceral Fat Loss as a Key Target for Durable Cardiometabolic Health: MRI-Assessed 5- and 10-Year Follow-Up After 2 Clinical Trials
BACKGROUND: During the 18-month CENTRAL (Effect of Weight-Loss Diet Strategies and Exercise on Dynamics of Body Fat Depots and Metabolic Rate) and DIRECT-PLUS (Dietary Intervention Randomized Controlled Trial Polyphenols Unprocessed) randomized controlled trials, participants achieved considerable reductions in abdominal and ectopic fat. We examined the long-term postintervention cardiometabolic profile associated with these changes. METHODS: We invited participants from CENTRAL (2012–2014) and DIRECT-PLUS (2017–2018), which evaluated dietary patterns (low-fat, healthy dietary guidelines and Mediterranean diet variants, including standard, low-carbohydrate, and polyphenol-enriched “green” Mediterranean diets) combined with structured physical activity. Participants underwent additional magnetic resonance imaging of visceral adipose tissue, deep subcutaneous adipose tissue (SAT), superficial SAT, intrahepatic fat, and intrapancreatic fat, along with clinical follow-up measurements, 5 and 10 years after completion of the trials. RESULTS: We reached 366 out of 381 eligible participants (96%) for follow-up. Despite complete weight regain, waist circumference and abdominal fat depots, including visceral adipose tissue, deep SAT, and superficial SAT, partially preserved their intervention-induced achievements at long-term follow-up (false discovery rate ≤0.01 for all). In contrast, postintervention reductions of intrahepatic fat and intrapancreatic fat were fully and excessively gained during follow-up, respectively (false discovery rate ≤0.01 for both). Each 10% intervention-induced loss of visceral adipose tissue, superficial SAT, and intrapancreatic fat were associated with long-term postintervention improvements in Metabolic Score for Insulin Resistance, composite risk score, and Metabolic Syndrome Severity Score (meta-analysis models adjusted to weight change, Mediterranean diet adherence and physical activity scores at follow-up, and further measures; all P <0.05). Only 10% visceral adipose tissue loss, however, was independently associated with a 28% lower risk of incident type 2 diabetes (hazard ratio, 0.72 [95% CI, 0.54–0.94]; multivariable model) during follow-up. CONCLUSIONS: This 5- and 10-year follow-up of 18-month clinical trials suggests that diet and physical activity lifestyle interventions may yield long-term improvements in cardiometabolic measures despite weight regain. A 10% reduction in visceral fat due to lifestyle interventions may reduce future type 2 diabetes risk by nearly 30%. Visceral fat loss rather than weight loss emerges as a key target for durable cardiometabolic health. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifiers: NCT01530724 and NCT03020186.
Lipid Profile Testing and Interpretation
A New <i>Circulation</i> , For You
Obesity, Severe Obesity, and Abdominal Obesity in US Youth and Adults From 1999 to 2023
RND3 Enhances Cardiac Glucose Metabolism Through Inhibiting ACAT1-Dependent PDHA1 Acetylation and Protects Against Ischemia-Reperfusion Injury
BACKGROUND: Metabolic disturbances are key contributors to myocardial ischemia-reperfusion (I/R) injury, yet the underlying molecular mechanisms remain largely unclear. Rho family GTPase 3 (RND3), a cytosolic small guanosine triphosphatase (GTPase) known to antagonize ROCK1 (Rho-associated coiled-coil kinase 1), has been implicated in several cardiovascular disorders. However, its mitochondrial localization and functional role in cardiac energy metabolism and I/R injury remain unknown. METHODS: A murine model of myocardial I/R injury was established through left anterior descending coronary artery ligation. Mice with cardiomyocyte-specific knockout and overexpression of Rnd3 were generated. To investigate the role of RND3 in cardiac metabolism and I/R injury, we used 13 C-nuclear magnetic resonance, 18 F-fluorodeoxyglucose positron emission tomography/computed tomography scanning, seahorse mitochondrial energy metabolism assays, and 13 C-metabolic flux tracing. Mechanistic studies were conducted using RNA sequencing, coimmunoprecipitation, mass spectrometry, and glutathione S-transferase (GST) pulldown assays. RESULTS: Cardiomyocyte-specific deletion of Rnd3 ( Rnd3 conditional knockout, Rnd3 cKO ) resulted in impaired glucose oxidation and compensatory upregulation of fatty acid oxidation, leading to pronounced cardiac dysfunction and increased mortality. Rnd3 cKO hearts exhibited reduced pyruvate/malate-driven complex I respiration and marked uncoupling between glycolysis and the tricarboxylic acid cycle. Mechanistically, RND3 was identified as a novel mitochondrial matrix-localized small GTPase that directly binds to ACAT1 (acetyl-coenzyme A [CoA] acetyltransferase), disrupting its interaction with PDHA1 (pyruvate dehydrogenase E1α subunit) and thereby promoting PDHA1 acetylation and glucose oxidation. It is important to note that RND3 expression was significantly downregulated in both human and murine hearts after I/R insult. Loss of RND3 sensitized the hearts to I/R injury, as evidenced by reduced levels of phosphocreatine and ATP. Conversely, cardiac-specific overexpression of Rnd3 conferred protection against I/R injury, an effect that was abolished upon Pdha1 knockdown. CONCLUSIONS: Our results identify RND3 as a novel mitochondria-localized regulator of glucose oxidation that safeguards the heart against I/R injury. Therapeutic reconstitution of Rnd3 may represent a promising strategy to restore metabolic homeostasis and mitigate myocardial damage in the context of I/R.
Role of Physical Activity in Obesity Treatment and Cardiometabolic Health: A Scientific Statement From the American Heart Association
Weight loss and weight loss maintenance are prominent topics of discussion for clinicians and health professionals involved in treatment to reduce obesity and the risk of cardiovascular disease. Because physical activity is a key component of comprehensive obesity treatment, this scientific statement summarizes the role of physical activity in promoting weight loss, weight loss maintenance, and cardiometabolic health, complementing lifestyle, pharmacological, and surgical-based weight loss intervention strategies. Independently of weight loss, physical activity and exercise programs improve major cardiometabolic risk factors, including hypertension, insulin resistance, and dyslipidemia, which are highly prevalent in patients with overweight or obesity. As a single treatment modality, physical activity and exercise programs are unlikely to result in clinically meaningful weight loss (ie, at least 5% loss of initial body weight) unless aerobic physical activity levels are exceptionally high. When combined with diet-induced negative energy balance, obesity medication, or surgical treatment, increased physical activity can augment total weight loss and improve cardiometabolic outcomes. Because clinicians and health professionals play a pivotal role in fostering and sustaining patients’ health goals, this scientific statement also provides an overview of evidence-based strategies for targeted weight loss counseling and for leveraging digital technology, particularly to engage patients and achieve realistic physical activity goals.
Paclitaxel-Coated Balloon Versus Uncoated Balloon for Coronary In-Stent Restenosis: Two-Year Follow-Up of the AGENT-IDE Randomized Clinical Trial
A Bundle to Frame Guidelines and American Heart Association Statements
Physical Activity for Weight Loss and Health Promotion
Adolescent Cardiorespiratory Fitness and the Trade-Off Between Atrial Fibrillation Risk and Cardiovascular Benefits: A Nationwide Sibling-Controlled Cohort Study
BACKGROUND: Young athletes and adolescents with high cardiorespiratory fitness appear to have a higher risk of atrial fibrillation (AF), but the extent to which this reflects causal effects or shared genetic, behavioral, and environmental factors remains uncertain. METHODS: This cohort study with sibling control analysis comprised Swedish men who participated in mandatory military conscription examinations from 1972 to 1995 and completed cardiorespiratory fitness testing. The outcomes were AF and non-AF cardiovascular disease (CVD; eg, stroke and ischemic heart disease), defined as a composite end point of diagnosis or death in the National Patient Register and the Cause of Death Register, until December 31, 2023. Flexible parametric survival models estimated standardized cumulative risk differences (RDs) by deciles of fitness. RESULTS: Among 1 124 049 men (mean age, 18.3 years), 45 179 (4.0%) had a first AF event and 96 404 (8.6%) had a first non-AF CVD event at a median age of 54.8 and 54.4 years. In population-wide analysis controlling for measured confounders, compared with the lowest decile of fitness, the highest decile had a small excess in AF that exceeded the reduction in non-AF CVD during early adulthood, whereas the reduction in non-AF CVD became larger from 45 years of age onwards. In full-sibling comparisons controlling for shared familial factors, the age-dependent trade-off disappeared entirely, leaving no age window with a net cardiovascular disadvantage. Already from 35 years of age, the reduction in non-AF CVD was larger (RD, −0.11% [95% CI, −0.21% to −0.01%]) than the excess in AF (RD, 0.06% [95% CI, −0.01% to 0.12%]). By 65 years of age, the gap further widened, with an even larger reduction in non-AF CVD (RD, −3.91% [95% CI, −5.40% to −2.42%]) compared with the excess in AF (RD, 2.30% [95% CI, 1.15% to 3.45%]). CONCLUSIONS: High adolescent cardiorespiratory fitness is associated with a small excess in AF risk during early adulthood that is outweighed by larger reductions in non-AF CVD after controlling for familial confounders. These findings support population-level efforts to improve youth cardiorespiratory fitness and provide reassurance about the safety and benefits of high fitness levels.
Cardiovascular Risk Reduction With GLP-1 RA Drugs
GLP-1 (glucagon-like peptide-1) receptor agonists (RAs) have emerged as a major therapeutic advance in cardiometabolic medicine. Initially developed as glucose-lowering therapies for type 2 diabetes, these agents have demonstrated broad benefits that extend well beyond glycemic control. GLP-1 RAs enhance glucose-dependent insulin secretion and reduce appetite, leading to improved glycemia and sustained weight loss. In addition, GLP-1 signaling exerts vascular and myocardial effects, including improved endothelial function, reduced inflammation and oxidative stress, and favorable changes in cardiac metabolism and remodeling. Large randomized cardiovascular outcomes trials have consistently shown that several GLP-1 RAs reduce major adverse cardiovascular events, including myocardial infarction, stroke, cardiovascular death, and heart failure. Benefits have been observed across diverse populations, including individuals with established cardiovascular disease and those with obesity but without diabetes. Emerging therapies targeting multiple incretin pathways, such as dual GIP (glucose-dependent insulinotropic polypeptide)–GLP-1 RAs, may further extend these benefits. Collectively, these findings suggest that GLP-1 RAs influence multiple cardiometabolic pathways and may shift the underlying metabolic milieu toward a more favorable physiological state. In this Clinical Primer, we review the physiology of GLP-1 signaling, the evidence supporting cardiovascular risk reduction, and practical considerations for the clinical use of incretin-based therapies.