Exercise Regulates MicroRNAs to Preserve Coronary and Cardiac Function in the Diabetic Heart.

RATIONALE: Diabetic heart disease (DHD) is a debilitating manifestation of type 2 diabetes mellitus. Exercise has been proposed as a potential therapy for DHD, although the effectiveness of exercise in preventing or reversing the progression of DHD remains controversial. Cardiac function is critically dependent on the preservation of coronary vascular function. OBJECTIVE: We aimed to elucidate the effectiveness and mechanisms by which exercise facilitates coronary and cardiac-protection during the onset and progression of DHD. METHODS AND RESULTS: Diabetic db/db and nondiabetic mice, with or without underlying cardiac dysfunction (16 and 8 weeks old, respectively) were subjected to either moderate-intensity exercise or high-intensity exercise for 8 weeks. Subsequently, synchrotron microangiography, immunohistochemistry, Western blot, and real-time polymerase chain reaction were used to assess time-dependent changes in cardiac and coronary structure and function associated with diabetes mellitus and exercise and determine whether these changes reflect the observed changes in cardiac-enriched and vascular-enriched microRNAs (miRNAs). We show that, if exercise is initiated from 8 weeks of age, both moderate-intensity exercise and high-intensity exercise prevented the onset of coronary and cardiac dysfunction, apoptosis, fibrosis, microvascular rarefaction, and disruption of miRNA signaling, as seen in the nonexercised diabetic mice. Conversely, the cardiovascular benefits of moderate-intensity exercise were absent if the exercise was initiated after the diabetic mice had already established cardiac dysfunction (ie, from 16 weeks of age). The experimental silencing or upregulation of miRNA-126 activity suggests the mechanism underpinning the cardiovascular benefits of exercise were mediated, at least in part, through tissue-specific miRNAs. CONCLUSIONS: Our findings provide the first experimental evidence for the critical importance of early exercise intervention in ameliorating the onset and progression of DHD. Our results also suggest that the beneficial effects of exercise are mediated through the normalization of cardiovascular-enriched miRNAs, which are dysregulated in DHD.

Progressive Decrease in Coronary Vascular Function Associated With Type 2 Diabetic Heart Disease.

Background: The causal factors underpinning the onset and progression of diabetic heart disease (DHD) remain to be fully elucidated. Myocardial function is critically dependent on optimal coronary blood flow. Considering vascular disease occurs early in diabetes due to endothelial dysfunction, this study aimed to determine whether impaired coronary perfusion contributes to the origins of myocardial dysfunction in DHD, or whether coronary and cardiac dysfunction are independent pathologies associated with diabetes. Methods: Synchrotron radiation microangiography was used to image the coronary circulation of type-2 diabetic db/db and non-diabetic db/+ mice in vivo at 8, 16, and 24 weeks of age. We further assessed vascular function based on the vasodilatory responses to acetylcholine (ACh, 3 µg/kg/min), sodium nitroprusside (SNP, 5 µg/kg/min) and the Rho-kinase inhibitor, fasudil (20 mg/kg, i.v.). Cardiac function was assessed using echocardiography, and cardiac eNOS and ROCK expression were measured using immunohistochemistry. Results: Coronary and cardiac function were normal in 8-week-old diabetic mice. However, by 16 weeks of age, diabetic mice had advanced cardiac dysfunction. In comparison, normal coronary perfusion was preserved in diabetes until 24 weeks of age. Moreover, only the 24-week-old diabetic mice showed clear evidence of advanced coronary vascular dysfunction, based on (i) the absence of a vasodilatory response to ACh, and (ii) an exaggerated vasodilatory response to fasudil. Interestingly, fasudil also restored normal coronary perfusion in the 24-week-old diabetic heart by restoring blood flow to previously constricted vessels (diameter < 100 µm). Importantly, there was a ubiquitous decrease, and increase, in the cardiac expression of eNOS and ROCK, respectively. Conclusion: These results suggest that both cardiac and coronary dysfunction appear to have independent origins associated with diabetes and Rho-kinase pathway may be playing a role in the onset and progression of DHD.

Down-regulation of miR-15a/b accelerates fibrotic remodelling in the Type 2 diabetic human and mouse heart.

Aim: Myocardial fibrosis is a well-established cause of increased myocardial stiffness and subsequent diastolic dysfunction in the diabetic heart. The molecular regulators that drive the process of fibrotic events in the diabetic heart are still unknown. We determined the role of the microRNA (miR)-15 family in fibrotic remodelling of the diabetic heart.Methods and results: Right atrial appendage (RAA) and left ventricular (LV) biopsy tissues collected from diabetic and non-diabetic (ND) patients undergoing coronary artery bypass graft surgery showed significant down-regulation of miR-15a and -15b. This was associated with marked up-regulation of pro-fibrotic transforming growth factor-ß receptor-1 (TGFßR1) and connective tissue growth factor (CTGF), direct targets for miR-15a/b and pro-senescence p53 protein. Interestingly, down-regulation of miR-15a/b preceded the development of diastolic dysfunction and fibrosis in Type 2 diabetic mouse heart. Therapeutic restoration of miR-15a and -15b in HL-1 cardiomyocytes reduced the activation of pro-fibrotic TGFßR1 and CTGF, and the pro-senescence p53 protein expression, confirming a causal regulation of these fibrotic and senescence mediators by miR-15a/b. Moreover, conditioned medium (CM) collected from cardiomyocytes treated with miR-15a/b markedly diminished the differentiation of diabetic human cardiac fibroblasts.Conclusion: Our results provide first evidence that early down-regulation of miR-15a/b activates fibrotic signalling in diabetic heart, and hence could be a potential target for the treatment/prevention of diabetes-induced fibrotic remodelling of the heart.

Exercise mediated protection of diabetic heart through modulation of microRNA mediated molecular pathways.

Hyperglycaemia, hypertension, dyslipidemia and insulin resistance collectively impact on the myocardium of people with diabetes, triggering molecular, structural and myocardial abnormalities. These have been suggested to aggravate oxidative stress, systemic inflammation, myocardial lipotoxicity and impaired myocardial substrate utilization. As a consequence, this leads to the development of a spectrum of cardiovascular diseases, which may include but not limited to coronary endothelial dysfunction, and left ventricular remodelling and dysfunction. Diabetic heart disease (DHD) is the term used to describe the presence of heart disease specifically in diabetic patients. Despite significant advances in medical research and long clinical history of anti-diabetic medications, the risk of heart failure in people with diabetes never declines. Interestingly, sustainable and long-term exercise regimen has emerged as an effective synergistic therapy to combat the cardiovascular complications in people with diabetes, although the precise molecular mechanism(s) underlying this protection remain unclear. This review provides an overview of the underlying mechanisms of hyperglycaemia- and insulin resistance-mediated DHD with a detailed discussion on the role of different intensities of exercise in mitigating these molecular alterations in diabetic heart. In particular, we provide the possible role of exercise on microRNAs, the key molecular regulators of several pathophysiological processes.

Focused maternal ultrasound by midwives in rural Zambia.

Point-of-care ultrasound is being increasingly implemented in resource-poor settings in an ad hoc fashion. We developed a focused maternal ultrasound-training program for midwives in a rural health district in Zambia. Four hundred forty-one scans were recorded by 21 midwives during the 6-month study period. In 74 scans (17%), the ultrasound findings prompted a change in clinical decision-making. Eight of the midwives were evaluated with a 14-question observed structured clinical examination (OSCE) and demonstrated a slight overall improvement with mean scores at 2 and 6 months of 10.0/14 (71%) and 11.6/14 (83%), respectively. Our pilot project demonstrates that midwives in rural Zambia can be trained to perform basic obstetric ultrasound and that it impacts clinical decision-making. Ultrasound skills were retained over the study period. More data is necessary to determine whether the introduction of ultrasound ultimately improves outcomes of pregnant women in rural Zambia.