Basic Research in Cardiology最新文献

Macrophage depletion exacerbates pressure overload-induced heart failure, but therapeutic translation is hindered by macrophage subset heterogeneity. The functional role of CD163⁺ macrophages in heart failure remains unclear. Transverse aortic constriction (TAC) was employed to induce pressure overload. Cd163^−/− mice exhibited significantly aggravated TAC-induced left ventricular systolic dysfunction, as demonstrated by reduced ejection fraction, fractional shortening, and global longitudinal strain, compared to wild-type (WT) controls. RNA sequencing of cardiac tissues revealed significant differential gene expression between TAC-treated WT and Cd163^−/− mice, especially in pathways governing mitochondrial bioenergetics and homeostasis. Transmission electron microscopy confirmed greater accumulation of dysfunctional mitochondria in cardiomyocytes of Cd163^−/− mice relative to WT following TAC. Additionally, the proportion of CD163⁺ macrophages among cardiac macrophages increased post-TAC. Serum IL-10 levels and cardiac macrophage IL-10 expression were significantly diminished in Cd163^−/− mice compared to WT after TAC. IL-10 supplementation effectively reversed the TAC-induced impairment in left ventricular systolic function in both WT and Cd163^−/− mice, and reduced NADH/NAD⁺ ratios, reduced mitochondrial dysfunction, and improved mitochondrial membrane potential in Cd163^−/− mice. Cross-sectional clinical data supported these findings, showing decreased IL-10 levels as a significant risk factor for heart failure in hypertensive patients (odds ratio: 0.397; 95% CI 0.203–0.775; p = 0.007). Collectively, these results highlight the protective role of CD163⁺ macrophages against pressure overload-induced left ventricular dysfunction and mitochondrial dysfunction through IL-10-dependent pathways.

Our previous work demonstrated that the DNA-sensing receptor cyclic GMP-AMP synthase (cGAS) negatively affects post-infarct repair by promoting pro-inflammatory macrophages. However, whether cGAS and its downstream partner STING (Stimulator of Interferon Genes) regulate neutrophil production and function in the context of acute myocardial ischemia remains unclear. This study investigated the role of the cGAS-STING pathway in neutropoiesis (neutrophil production and differentiation) and examined whether ischemia primes neutrophils in the bone marrow via this pathway, enhancing their functionality and contributing to cardiac inflammatory injury. Using myocardial infarction (MI) models in wild-type (WT), Cgas^−/−, and Sting^−/− mice, we analyzed neutrophils from the bone marrow, peripheral blood, and infarcted tissue. Additionally, we generated neutrophil-specific conditional knockouts of Cgas and performed adoptive transfer experiments with Cgas-deficient neutrophils. RNA sequencing revealed that ischemia increased neutrophil production in the bone marrow and activated pathways involved in cytokine signaling, phagocytosis, chemotaxis, and degranulation. Inhibiting the cGAS-STING pathway reduced neutrophil production by decreasing lineage committed neutrophil precursors including early neutrophil precursors (eNP) and preNeu and downregulated ischemia-induced pathways. Neutrophil conditional Cgas deletion or adoptive transfer of Cgas-deficient neutrophils improved survival but did not significantly impact ischemia-induced remodeling. In conclusion, we demonstrate for the first time that ischemia enhanced neutrophil functionality before recruitment to infarcted tissue, and the cGAS-STING pathway played an important role in neutrophil production and priming. Furthermore, our findings demonstrate a neutrophil-specific role of cGAS in promoting cardiac rupture and mortality in MI. This study provides a more comprehensive understanding of the cGAS-STING pathway in acute ischemia and may support the translation of cGAS-STING modulators, an emerging therapeutic field.

Individuals with heart failure have significantly reduced exercise capacity, a critical life-limiting symptom for those living with the disease. Heart failure is negatively correlated with decreased heart rate variability, including the loss of heart rate variability in tune with breathing—termed respiratory heart rate variability (RespHRV). We tested the hypothesis that restoration of RespHRV would improve exercise tolerance. Heart failure was induced in adult female sheep using a microembolization technique, and the sheep were divided into two groups: RespHRV paced and monotonically paced. Following a 1-week baseline recording, the sheep underwent 2 weeks of pacing. Direct recordings of hemodynamic parameters, including arterial pressure, cardiac output, coronary artery blood flow, and heart rate, were taken at rest and during treadmill exercise. Reinstating RespHRV significantly increased resting cardiac output, a change not observed in monotonically paced sheep. Neither group showed a change in resting coronary artery blood flow. During exercise, RespHRV-paced sheep showed increased cardiac output, coronary artery blood flow, cardiac power output, and faster heart rate recovery post-exercise. In contrast, monotonically paced sheep showed no changes in exercise-induced cardiac function. A separate group of heart failure animals were studied to determine if these benefits would persist alongside heart failure medications. RespHRV pacing continued to improve resting cardiac output with concurrent heart failure medications. Our results indicate that reinstating RespHRV may be a novel approach for improving outcomes in heart failure, including exercise capacity.

A major obstacle to progress in heart failure with preserved ejection fraction (HFpEF) is the paucity of clinically relevant animal models. We developed a large, translationally relevant model in Ossabaw minipigs, which are genetically predisposed to the metabolic syndrome (MetS). Pigs were fed a “Western diet” high in calories, fructose, fat, cholesterol, and salt and received 1–2 deoxy-corticosterone acetate (DOCA) depots (n = 10). After 6 months, they exhibited liver function abnormalities and marked increases in body weight, arterial blood pressure, serum cholesterol and triglycerides, and plasma glucose and insulin levels (glucose tolerance test), indicating the development of a full MetS. Echocardiography demonstrated no change in LV ejection fraction but progressive concentric LV hypertrophy and left atrial dilatation. Doppler echocardiography showed increased E/e’ ratio and increased peak early (E) and peak late atrial (A) transmitral inflow velocities, with no change in E/A ratio. Right heart catheterization demonstrated increased central venous pressure, pulmonary arterial systolic pressure, and pulmonary capillary wedge pressure. Clinically, pigs exhibited impaired exercise capacity, assessed by treadmill tests, associated with chronotropic incompetence. Pathologic examination showed significant myocardial fibrosis, myocyte hypertrophy, and liver fibrosis. In contrast, lean pigs fed a standard diet (n = 3) did not show any changes at 6 months. The Ossabaw porcine model described herein is unique in that it recapitulates the entire constellation of major multiorgan comorbidities and hemodynamic, clinical, and metabolic features of MetS-driven human HFpEF: obesity, arterial hypertension, hyperlipidemia, glucose intolerance, insulin resistance, liver fibrosis and dysfunction, pulmonary hypertension, increased LV filling pressures, concentric LV hypertrophy, LV diastolic dysfunction with preserved systolic function, and impaired exercise capacity. Because of its high clinical relevance, this model is well-suited for exploring the pathophysiology of MetS-driven HFpEF and the efficacy of new therapies.