American journal of physiology. Heart and circulatory physiology最新文献

Diabetes mellitus (DM) is characterized by chronic hyperglycemia, and despite intensive glycemic control, the risk of heart failure in patients with diabetes remains high. Diabetes-induced heart failure (DHF) presents a unique metabolic challenge, driven by significant alterations in cardiac substrate metabolism, including increased reliance on fatty acid oxidation, reduced glucose utilization, and impaired mitochondrial function. These metabolic alterations lead to oxidative stress, lipotoxicity, and energy deficits, contributing to the progression of heart failure. Emerging research has identified novel mechanisms involved in the metabolic remodeling of diabetic hearts, such as autophagy dysregulation, epigenetic modifications, polyamine regulation, and branched-chain amino acid (BCAA) metabolism. These processes exacerbate mitochondrial dysfunction and metabolic inflexibility, further impairing cardiac function. Therapeutic interventions targeting these pathways-such as enhancing glucose oxidation, modulating fatty acid metabolism, and optimizing ketone body utilization-show promise in restoring metabolic homeostasis and improving cardiac outcomes. This review explores the key molecular mechanisms driving metabolic remodeling in diabetic hearts, highlights advanced methodologies, and presents the latest therapeutic strategies for mitigating the progression of DHF. Understanding these emerging pathways offers new opportunities to develop targeted therapies that address the root metabolic causes of heart failure in diabetes.

The triglyceride-glucose (TyG) index has been proposed as an independent predictor of coronary artery disease (CAD). In this retrospective study we further examine this association and its utility as a predictor for major adverse cardiovascular events (MACE). A total of 870 patients who underwent coronary angiography between May 2008 and June 2009 were included in this retrospective study. The TyG index was calculated using the formula Ln (fasting TG [mg/dL] × FBG [mg/dL]/2). The association of TyG index with the presence and severity of CAD, cardiovascular risk factors, and inflammatory markers was evaluated at baseline. In the longitudinal study, the multivariate adjusted Cox hazard model was used to investigate the associations of the TyG index with the occurrence of MACE during a 5-year follow-up, which was defined as endpoint. The TyG index was significantly associated with the presence and severity of CAD. Multiple linear regression analysis showed that a high TyG index, together with inflammatory markers and dyslipidemia, were independently associated with greater stenotic occlusion of coronary arteries (adjusted R² = 0.031, p<0.001). Kaplan-Meier survival curve (free of MACE) by tertiles of the TyG index showed a higher incidence of MACE in the upper tertile (log-rank test, p = 0.02). Multivariate Cox analysis demonstrated that the risk of incident MACE during the follow-up was associated with higher levels of TyG index, even after adjusting for inflammatory parameters and cardiovascular risk factors: hazard ratio (HR), 1.54 (95% confidence interval 1.18-2.13; p<0.01). We conclude that elevated TyG index is independently associated with a higher risk of CAD and a poor prognosis for MACE.

The endothelial microvasculature is essential for the regulation of vasodilation and vasoconstriction, and improved functioning of the endothelium is linked to improved outcomes for individuals with coronary artery disease (CAD). People with endothelial dysfunction exhibit a loss of NO-mediated vasodilation, achieving vasodilation instead through mitochondria-derived H₂O₂. Mitochondrial dynamics is an important autoregulatory mechanism that contributes to mitochondrial and endothelial homeostasis and plays a role in formation of reactive oxygen species (ROS), including H₂O₂. Dysregulation of mitochondrial dynamics leads to increased ROS production, decreased ATP production, impaired metabolism, activation of pathological signal transduction, impaired calcium sensing, and inflammation. We hypothesize that dysregulation of endothelial mitochondrial dynamics plays a crucial role in the endothelial microvascular dysfunction seen in individuals with CAD. Therefore, proper regulation of endothelial mitochondrial dynamics may be a suitable treatment for individuals with endothelial microvascular dysfunction and we furthermore postulate that improving this microvascular dysfunction will directly improve outcomes for those with CAD.

The lack of animal models which accurately represent heart failure with preserved ejection fraction (HFpEF) has been a major barrier to the mechanistic understanding and development of effective therapies for this prevalent and debilitating syndrome characterized by multisystem impairments. Herein, we describe the development and characterization of a novel large animal model of HFpEF in older, female sheep with chronic 2-kidney, 1-clip hypertension. At six weeks post-unilateral renal artery clipping, hypertensive HFpEF sheep had higher mean arterial pressure compared to similarly aged ewes without unilateral renal artery clipping (mean arterial pressure = 112.7±15.9 vs 76.0±10.1 mmHg, P < 0.0001). The hypertensive HFpEF sheep were characterized by (i) echocardiographic evidence of diastolic dysfunction (lateral e' = 0.11±0.02 vs 0.14±0.04 m/s, P = 0.011; lateral E/e' = 4.25±0.77 vs 3.63±0.54, P = 0.028) and concentric left ventricular hypertrophy without overt systolic impairment, (ii) elevated directly measured left ventricular end-diastolic pressure (13±5 vs 0.5±1 mmHg, P = 2.1x10^-6), and (iii) normal directly measured cardiac output. Crucially, these hypertensive HFpEF sheep had impaired exercise capacity as demonstrated by their (i) attenuated cardiac output (P = 0.001), (ii) augmented pulmonary capillary wedge pressure (P = 0.026), and (iii) attenuated hindlimb blood flow (P = 3.4x10^-4) responses, during graded treadmill exercise testing. In addition, exercise renal blood flow responses were also altered. Collectively, our data indicates that this novel ovine model of HFpEF may be a useful translational research tool since it exhibits similar and clinically relevant impairments as that of HFpEF patients.

Background: Heart failure (HF) is a major cause of hospitalization, and exercise capacity is a key prognostic marker. The six-minute walk test (6MWT) is widely used to assess exercise capacity, but six-minute walk distance (6MWD) varies among individuals, especially the elderly.

Aim: This study aimed to assess the hypothesis that ΔSpO₂-Ex, the average oxygen desaturation during the 6MWT, could enhance the prognostic value of 6MWD in elderly HF patients for cardiovascular risk prediction.

Methods: In this single-center, prospective observational study, 55 patients aged ≥ 65 years with acute HF were evaluated before discharge. Patients were divided into small and large ΔSpO₂-Ex groups and short and long 6MWD groups based on cut-off values of 6.7% and 220 m, respectively, obtained from the Receiver Operating Characteristics curve analysis. Patients were followed for one year to assess major adverse cardiovascular events, including rehospitalization for heart failure or cardiovascular death.

Results: The mean ΔSpO₂-Ex was 5.8 ± 4.3%, and the mean 6MWD was 237.5 ± 106.7 m. Patients with large ΔSpO₂-Ex had significantly higher event rates (HR 6.66, p < 0.001), while those with short 6MWD had HR of 2.40 (p = 0.03). Combining ΔSpO₂-Ex with 6MWD improved predictive accuracy (AUC 0.78) compared to either marker alone (AUC 0.72 for ΔSpO₂-Ex and 0.62 for 6MWD). Importantly, patients with both large ΔSpO₂-Ex and short 6MWD had the highest event rates, indicating the additive prognostic value of combining both markers.

Conclusion: ΔSpO₂-Ex is a complementary marker to 6MWD, improving risk stratification in elderly HF patients.