Belén Picatoste

Pathophysiology of Acute Coronary Syndrome

Despite improvements in interventional and pharmacological therapy for atherosclerotic disease, it is still the leading cause of death in the developed world. Hence, there is a need for further development of more effective therapeutic approaches. This requires better understanding of the molecular mechanisms and pathophysiology of the disease. Recent research in the last decade has changed our view of acute coronary syndrome (ACS): from a mere lipid deposition to an inflammatory disease; from ACS exclusively due to plaque rupture to the novel definitions of plaque erosion or calcified nodule; from the notion of a superimposed thrombus with necessary lethal consequences to the concept of healed plaques and thrombus contributing to plaque progression. In the hope of improving our understanding of ACS, all these recently discovered concepts are reviewed in this article.

Sitagliptin Reduces Cardiac Apoptosis, Hypertrophy and Fibrosis Primarily by Insulin-Dependent Mechanisms in Experimental type-II Diabetes. Potential Roles of GLP-1 Isoforms

Background Myocardial fibrosis is a key process in diabetic cardiomyopathy. However, their underlying mechanisms have not been elucidated, leading to a lack of therapy. The glucagon-like peptide-1 (GLP-1) enhancer, sitagliptin, reduces hyperglycemia but may also trigger direct effects on the heart. Methods Goto-Kakizaki (GK) rats developed type-II diabetes and received sitagliptin, an anti-hyperglycemic drug (metformin) or vehicle (n=10, each). After cardiac structure and function assessment, plasma and left ventricles were isolated for biochemical studies. Cultured cardiomyocytes and fibroblasts were used for in vitro assays. Results Untreated GK rats exhibited hyperglycemia, hyperlipidemia, plasma GLP-1 decrease, and cardiac cell-death, hypertrophy, fibrosis and prolonged deceleration time. Moreover, cardiac pro-apoptotic/necrotic, hypertrophic and fibrotic factors were up-regulated. Importantly, both sitagliptin and metformin lessened all these parameters. In cultured cardiomyocytes and cardiac fibroblasts, high-concentration of palmitate or glucose induced cell-death, hypertrophy and fibrosis. Interestingly, GLP-1 and its insulinotropic-inactive metabolite, GLP-1(9-36), alleviated these responses. In addition, despite a specific GLP-1 receptor was only detected in cardiomyocytes, GLP-1 isoforms attenuated the pro-fibrotic expression in cardiomyocytes and fibroblasts. In addition, GLP-1 receptor signalling may be linked to PPARδ activation, and metformin may also exhibit anti-apoptotic/necrotic and anti-fibrotic direct effects in cardiac cells. Conclusions Sitagliptin, via GLP-1 stabilization, promoted cardioprotection in type-II diabetic hearts primarily by limiting hyperglycemia e hyperlipidemia. However, GLP-1 and GLP-1(9-36) promoted survival and anti-hypertrophic/fibrotic effects on cultured cardiac cells, suggesting cell-autonomous cardioprotective actions.

Targeting metabolic disturbance in the diabetic heart

Diabetic cardiomyopathy is defined as ventricular dysfunction initiated by alterations in cardiac energy substrates in the absence of coronary artery disease and hypertension. In addition to the demonstrated burden of cardiovascular events associated with diabetes, diabetic cardiomyopathy partly explains why diabetic patients are subject to a greater risk of heart failure and a worse outcome after myocardial ischemia. The raising prevalence and accumulating costs of cardiovascular disease in diabetic patients underscore the deficiencies of tertiary prevention and call for a shift in medical treatment. It is becoming increasingly clearer that the effective prevention and treatment of diabetic cardiomyopathy require measures to regulate the metabolic derangement occurring in the heart rather than merely restoring suitable systemic parameters. Recent research has provided deeper insight into the metabolic etiology of diabetic cardiomyopathy and numerous heart-specific targets that may substitute or reinforce current strategies. From both experimental and translational perspectives, in this review we first discuss the progress made with conventional therapies, and then focus on the need for prospective metabolic targets that may avert myocardial vulnerability and functional decline in next-generation diabetic care.

Increased Stiffness Is the Major Early Abnormality in a Pig Model of Severe Aortic Stenosis and Predisposes to Congestive Heart Failure in the Absence of Systolic Dysfunction

Background It remains unclear whether abnormal systolic function and relaxation are essential for developing heart failure in pathophysiology of severe aortic stenosis. Methods and Results Yorkshire pigs underwent surgical banding of the ascending aorta. The animals were followed for up to 5 months after surgery, and cardiac function was assessed comprehensively by invasive pressure–volume measurements, 3-dimensional echocardiography, echocardiographic speckle-tracking strain, and postmortem molecular and histological analyses. Pigs with aortic banding (n=6) exhibited significant left ventricular hypertrophy with increased stiffness compared with the control pigs (n=7) (end-diastolic pressure–volume relationship β: 0.053±0.017 versus 0.028±0.009 mm Hg/mL, P=0.007); however, all other parameters corresponding to systolic function, including ejection fraction, end-systolic pressure–volume relationship, preload recruitable stroke work, echocardiographic circumferential strain, and longitudinal strain, were not impaired in pigs with aortic banding. Relaxation parameters were also similar between groups. Sarcoplasmic reticulum calcium (Ca2+) ATPase protein levels in the left ventricle were similar. There were significant increases in 3-dimensional echocardiographic left atrial volumes, suggesting the usefulness of these indexes to detect increased stiffness. Right atrial pacing with a heart rate of 120 beats per minute induced increased end-diastolic pressure in pigs with aortic banding in contrast to decreased end-diastolic pressure in the control pigs. Histological evaluation revealed that increased stiffness was accompanied by cardiomyocyte hypertrophy and increased perimysial and perivascular fibrosis. Conclusion Increased stiffness is the major early pathological process that predisposes to congestive heart failure without abnormalities in systolic function and relaxation in a clinically relevant animal model of aortic stenosis.

MYOCARDIAL OXYGENATION USING BLOOD LEVEL-OXYGEN DEPENDENT SEQUENCE IN MAGNETIC RESONANCE DETERMINES MYOCARDIAL ENERGETICS AND CAPILLARY DENSITY

Background: By exploiting the paramagnetic properties of deoxyhemoglobin, blood oxygen-level dependent (BOLD) cardiac magnetic resonance (CMR) can detect myocardial ischemia. Our aim was to validate whether BOLD detects microvascular abnormalities. We employed a porcine model of post-infarction LV