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Abstract Time-restricted feeding (TRF, animal-based studies) and time-restricted eating (TRE, humans) are an emerging behavioral intervention approach based on the understanding of the role of circadian rhythms in physiology and metabolism. In this approach, all calorie intake is restricted within a consistent interval of less than 12 hours without overtly attempting to reduce calories. This article will summarize the origin of TRF/TRE starting with concept of circadian rhythms and the role of chronic circadian rhythm disruption in increasing the risk for chronic metabolic diseases. Circadian rhythms are usually perceived as the sleep-wake cycle and dependent rhythms arising from the central nervous system. However, the recent discovery of circadian rhythms in peripheral organs and the plasticity of these rhythms in response to changes in nutrition availability raised the possibility that adopting a consistent daily short window of feeding can sustain robust circadian rhythm. Preclinical animal studies have demonstrated proof of concept and identified potential mechanisms driving TRF-related benefits. Pilot human intervention studies have reported promising results in reducing the risk for obesity, diabetes, and cardiovascular diseases. Epidemiological studies have indicated that maintaining a consistent long overnight fast, which is similar to TRE, can significantly reduce risks for chronic diseases. Despite these early successes, more clinical and mechanistic studies are needed to implement TRE alone or as adjuvant lifestyle intervention for the prevention and management of chronic metabolic diseases. Graphical Abstract Graphical Abstract

Metabolic syndrome (MetS) occurs in ~30% of adults and is associated with increased risk of cardiovascular disease and diabetes mellitus. MetS reflects the clustering of individual cardiometabolic risk factors including central obesity, elevated fasting plasma glucose, dyslipidemia, and elevated blood pressure. Erratic eating patterns such as eating over a prolonged period per day and irregular meal timing are common in patients with MetS. Misalignment between daily rhythms of food intake and circadian timing system can contribute to circadian rhythm disruption which results in abnormal metabolic regulation and adversely impacts cardiometabolic health. Novel approaches which aim at restoring robust circadian rhythms through modification of timing and duration of daily eating represent a promising strategy for patients with MetS. Restricting eating period during a day (time-restricted eating, TRE) can aid in mitigating circadian disruption and improving cardiometabolic outcomes. Previous pilot TRE study of patients with MetS showed the feasibility of TRE and improvements in body weight and fat, abdominal obesity, atherogenic lipids, and blood pressure, which were observed despite no overt attempt to change diet quantity and quality or physical activity. The present article aims at giving an overview of TRE human studies of individuals with MetS or its components, summarizing current clinical evidence for improving cardiometabolic health through TRE intervention in these populations, and presenting future perspectives for an implementation of TRE to treat and prevent MetS. Previous TRE trials laid the groundwork and indicate a need for further clinical research including large-scale controlled trials to determine TRE efficacy for reducing long-term cardiometabolic risk, providing tools for sustained lifestyle changes and, ultimately, improving overall health in individuals with MetS.

Postural orthostatic tachycardia syndrome (POTS) is a debilitating disease that predominantly affects young women. It is a multifactorial disorder that is characterized by severe tachycardia and orthostatic intolerance. Patients with POTS experience a variety of cardiac, neurological, and immunological symptoms that significantly reduce quality of life. In this review, a comprehensive framework is provided to aid in helping identify and treat patients with POTS. Given its heterogenous nature, it is crucial to understand each component of POTS in relation to one another instead of distinct parts. The framework highlights the overlap among the five main subtypes of POTS based on its pathophysiology (neuropathic, hypovolemic, primary hyperadrenergic, joint-hypermobility-related, and immune-related). Emphasis is placed on incorporating a multidisciplinary approach when treating patients with POTS, especially with a new focus towards immunotherapy. Although research has advanced our knowledge of POTS, there is still a critically unmet need to further our understanding and provide patients with the relief they need.

Gulf War illness (GWI) is an important exemplar of environmentally-triggered chronic multisymptom illness, and a potential model for accelerated aging. Inflammation is the main hypothesized mechanism for GWI, with mitochondrial impairment also proposed. No study has directly assessed mitochondrial respiratory chain function (MRCF) on muscle biopsy in veterans with GWI (VGWI). We recruited 42 participants, half VGWI, with biopsy material successfully secured in 36. Impaired MRCF indexed by complex I and II oxidative phosphorylation with glucose as a fuel source (CI&CIIOXPHOS) related significantly or borderline significantly in the predicted direction to 17 of 20 symptoms in the combined sample. Lower CI&CIIOXPHOS significantly predicted GWI severity in the combined sample and in VGWI separately, with or without adjustment for hsCRP. Higher-hsCRP (peripheral inflammation) related strongly to lower-MRCF (particularly fatty acid oxidation (FAO) indices) in VGWI, but not in controls. Despite this, whereas greater MRCF-impairment predicted greater GWI symptoms and severity, greater inflammation did not. Surprisingly, adjusted for MRCF, higher hsCRP significantly predicted lesser symptom severity in VGWI selectively. Findings comport with a hypothesis in which the increased inflammation observed in GWI is driven by FAO-defect-induced mitochondrial apoptosis. In conclusion, impaired mitochondrial function—but not peripheral inflammation—predicts greater GWI symptoms and severity.

Background Diabetic cardiomyopathy (DbCM) is characterized by asymptomatic stage B heart failure (SBHF) caused by diabetes-related metabolic alterations. DbCM is associated with an increased risk of progression to overt heart failure (HF). The prevalence of DbCM in patients with type 2 diabetes (T2D) is not well established. This study aims to determine prevalence of DbCM in adult T2D patients in real-world clinical practice. Methods Retrospective multi-step review of electronic medical records of patients with the diagnosis of T2D who had echocardiogram at UC San Diego Medical Center (UCSD) within 2010–2019 was conducted to identify T2D patients with SBHF. We defined “pure” DbCM when SBHF is associated solely with T2D and “mixed” SBHF when other medical conditions can contribute to SBHF. “Pure” DbCM was diagnosed in T2D patients with echocardiographic demonstration of SBHF defined as left atrial (LA) enlargement (LAE), as evidenced by LA volume index ≥ 34 mL/m 2 , in the presence of left ventricular ejection fraction (LVEF) ≥ 45%, while excluding overt HF and comorbidities that can contribute to SBHF. Results Of 778,314 UCSD patients in 2010–2019, 45,600 (5.9%) had T2D diagnosis. In this group, 15,182 T2D patients (33.3%) had echocardiogram and, among them, 13,680 (90.1%) had LVEF ≥ 45%. Out of 13,680 patients, 4,790 patients had LAE. Of them, 1,070 patients were excluded due to incomplete data and/or a lack of confirmed T2D according to the American Diabetes Association recommendations. Thus, 3,720 T2D patients with LVEF ≥ 45% and LAE were identified, regardless of HF symptoms. In this group, 1,604 patients (43.1%) had overt HF and were excluded. Thus, 2,116 T2D patients (56.9% of T2D patients with LVEF ≥ 45% and LAE) with asymptomatic SBHF were identified. Out of them, 1,773 patients (83.8%) were diagnosed with “mixed” SBHF due to comorbidities such as hypertension (58%), coronary artery disease (36%), and valvular heart disease (17%). Finally, 343 patients met the diagnostic criteria of “pure” DbCM, which represents 16.2% of T2D patients with SBHF, i.e., at least 2.9% of the entire T2D population in this study. Conclusions Our findings provide insights into prevalence of DbCM in real-world clinical practice and indicate that DbCM affects a significant portion of T2D patients.

Statins play an instrumental role in reducing and managing atherosclerotic cardiovascular disease (ASCVD) but can be difficult to tolerate due to muscle‐associated side effects. There remains an unmet need for strategies that improve statin tolerance and synergize their effect on atherogenic lipids. (−)‐Epicatechin (Epi) is a natural flavonoid that can improve lipid biomarkers and mitochondrial function. This study explored the capacity of Epi to augment statin's beneficial effects on lipid profile and ASCVD risk parameters. In total, 19 patients completed a randomized, double‐blind placebo‐controlled trial. The study consisted of two cohorts. Cohort 1 consisted of healthy patients with elevated low‐density lipoprotein (LDL) > 100 mg/dL and was used to determine appropriate Epi dosing. Cohort 2 consisted of patients with metabolic syndrome. Patients were randomized into statin‐only (n = 8; 5 in Cohort 2) or statin + Epi (n = 11; 8 in Cohort 2) for 3 months. VO2 max and lipid biomarkers were assessed at baseline and at the end of 3 months. Final analysis included Cohort 2 only. The statin + Epi group saw significant beneficial changes in total cholesterol (p = 0.002) and non‐HDL cholesterol (p = 0.007). There was a significantly larger increase in HDL (p = 0.037) and significantly greater decrease in LDL particle number (p = 0.0003) and small LDL particle number (p = 0.003) among the statin + Epi group compared to statin‐only. Ten‐year ASCVD risk was significantly lower at end‐of‐study for the statin + Epi arm compared to statin‐only (p < 0.05). No VO2 max differences were found. This is the first proof‐of‐concept study to show combination therapy of a statin with Epi is safe and effective in augmenting statin‐associated improvements in lipid biomarkers. Trial Registration: ClinicalTrials.gov: NCT02490527

Background Glycemic variability (GV) reflects glucose fluctuations, and increased GV is associated with adverse cardiovascular outcomes. We systematically evaluated the association between GV, measured by the mean amplitude of glycemic excursions (MAGE) and standard deviation (SD), and cardiovascular risk in patients with pre-existing cardiovascular disease (CVD). Materials and methods We searched PubMed, Embase, Scopus, Web of Science, and CENTRAL through May 2025 for studies on GV and cardiovascular outcomes in patients with established cardiovascular disease. Random-effects models with Knapp-Hartung adjustment were used to pool the risk ratios (RRs) and 95% confidence intervals (CIs). Subgroup, sensitivity, and meta-regression analyses were used to explore heterogeneity. The risk of bias was assessed using the ROBINS-I tool. Results Seventeen studies comprising 6,096 patients were included. In the categorical analysis, higher MAGE (RR: 2.18; 95% CI: 1.70, 2.80; I² = 15.6%) and SD (RR: 1.94; 95% CI: 1.32, 2.87; I² = 55.9%) were associated with increased risk of major adverse cardiovascular events (MACE). Continuous MAGE was also associated with MACE (RR: 1.66; 95% CI: 1.28, 2.14; I² = 65.65%), while continuous SD showed a non-significant association. The adjusted analyses for MAGE reinforced these findings. The MAGE cut-off thresholds significantly moderated the effect sizes in the meta-regression analysis. Subgroup analyses showed between-group differences in SD according to diabetes status and in MAGE according to country and follow-up duration. The certainty of evidence (GRADE) was very low for all contrasts. In outcome-specific analyses, both MAGE and SD were associated with acute heart failure and myocardial infarction, but not cardiovascular mortality. Conclusion GV, particularly when assessed using MAGE, is a significant predictor of cardiovascular risk in patients with pre-existing CVD. While these findings support its prognostic utility, limitations such as the observational design and residual confounding warrant cautious interpretation. Further studies should establish standardized thresholds and dose-response relationships. Registration PROSPERO CRD420251002622.

Multiple professional societies recommend the Mediterranean and/or Dietary Approaches to Stop Hypertension dietary patterns in their cardiovascular disease prevention guidelines because these diets can improve cardiometabolic health and reduce the risk of cardiovascular events. Furthermore, low sodium intake can be particularly beneficial for patients with hypertension. Carbohydrate restriction, with an emphasis on including high-quality carbohydrates and limiting refined starches and foods and beverages with added sugars, can promote weight loss and cardiometabolic benefits in the short term, compared with higher carbohydrate intake. Evidence is lacking for sustained, long-term effects of low carbohydrate and very low carbohydrate intake on cardiometabolic risk and cardiovascular outcomes. Time-restricted eating, in the context of an overall healthy dietary pattern, can promote cardiometabolic health by aligning food intake with the circadian rhythm, although its effect on hard clinical outcomes remains to be proven. Although there is no one dietary pattern that is appropriate for all patients, engaging in shared decision-making with patients, utilizing behaviour-change principles and engaging members of the health-care team, such as registered dietitian nutritionists, can lead to substantial improvement in the lifestyle and overall health trajectory of a patient. Emphasizing the similarities, rather than differences, of recommended dietary patterns, which include an emphasis on vegetables, fruits, legumes, nuts, whole grains and minimally processed protein foods, such as fatty fish or plant-based proteins, can simplify the process for both patients and clinicians alike. Various dietary patterns have been proposed to improve cardiometabolic health. In this Review, Pagidipati et al. emphasize the commonalities between recommendations on what to eat (Mediterranean, Dietary Approaches to Stop Hypertension and low-carbohydrate or ketogenic diets) and the possible benefits of time-restricted eating and intermittent fasting. Key points The Mediterranean and Dietary Approaches to Stop Hypertension dietary patterns have high-quality evidence to support improvement in cardiometabolic health. A low intake of sodium, in addition to a healthy dietary pattern, can be particularly beneficial for individuals with hypertension. If patients choose to follow a carbohydrate-restricted diet, high-quality carbohydrates (fruits, vegetables, whole grains and legumes) should be emphasized, whereas refined carbohydrates (refined starches, and foods and beverages with added sugars) should be limited. Carbohydrate restriction, versus higher carbohydrate intake, results in a significant reduction in body weight in the short term; evidence is lacking for long-term benefit on body weight, other cardiometabolic risk factors and clinical outcomes. Time-restricted eating might improve cardiometabolic health parameters, but its effect on long-term, hard clinical outcomes remains to be proven. Emphasizing the similarities between recommended dietary patterns (maximizing the consumption of vegetables, fruits, legumes, nuts, whole grains and minimally processed proteins) might enable clinicians to provide clear and concise guidance for patients.

Type 2 diabetes mellitus and congestive heart failure are highly prevalent diseases with significant morbidity and mortality. These 2 diseases often occur concurrently because of shared risk factors such as coronary artery disease, and also because type 2 diabetes mellitus has direct cardiotoxic effects. Type 2 diabetes mellitus likely has a causative role in the development and prognosis of patients with heart failure. Optimal prevention and treatment of type 2 diabetes mellitus and heart failure likely involves identifying and treating their shared pathophysiologic features. Novel drug therapies, such as sodium-glucose co-transporter 2 inhibitors, offer an exciting potential to better understand the relationship between type 2 diabetes mellitus and heart failure, and may prove to have beneficial effects on cardiovascular outcomes in patients affected by these diseases.

IntroductionCareer firefighters experience chronic circadian rhythm disruption, increasing their risk of cardiometabolic disease. The recent discovery that eating patterns regulate circadian rhythmicity in metabolic organs has raised the hypothesis that maintaining a consistent daily cycle of eating and fasting can support circadian rhythms and reduce disease risks. Preclinical animal studies and preliminary clinical trials have shown promising effects of time-restricted eating (TRE) to reduce disease risk without compromising physical performance. However, there is a lack of research on TRE in shift workers including firefighters. This study aims to investigate the feasibility and efficacy of 10-hour TRE on health parameters that contribute to cardiometabolic disease risks among career firefighters who work on a 24-hour shift schedule.Methods and analysesThe Healthy Heroes Study is a randomised controlled parallel open-label clinical trial with 150 firefighters over 1 year. Firefighters are randomised with a 1:1 ratio to either the control or intervention group. The control group receives Mediterranean diet nutritional counselling (standard of care, ‘SOC’). The intervention group receives the same SOC and a self-selected 10-hour TRE window. After the 2-week baseline, participants enter a 3-month monitored intervention, followed by a 9-month self-guided period with follow-up assessments. The impact of TRE on blood glucose, body weight, body composition, biomarkers (neuroendocrine, inflammatory and metabolic), sleep and mood is evaluated. These assessments occur at baseline, at the end of intervention and at 6, 9 and 12-month follow-ups. Temporal calorie intake is monitored with the smartphone application myCircadianClock throughout the study. Continuous glucose monitors, wrist-worn actigraphy device and questionnaires are used to monitor glucose levels, activity, sleep and light exposure.Ethics and disseminationThe study was approved by the Institutional Review Boards of the University of California San Diego and the Salk Institute for Biological Studies. Results will be disseminated through peer-reviewed manuscripts, reports and presentations.Trial registration numberNCT03533023; Pre result.