The Role of Platelet-Derived Growth Factor Signaling in Healing Myocardial Infarcts

ObjectivesThis study sought to examine the role of platelet-derived growth factor (PDGF) signaling in healing myocardial infarcts.BackgroundPlatelet-derived growth factor isoforms exert potent fibrogenic effects through interactions with PDGF receptor (PDGFR)-α and PDGFR-β. In addition, PDGFR-β signaling mediates coating of developing vessels with mural cells, leading to the formation of a mature vasculature. We hypothesized that PDGFR activation may regulate fibrosis and vascular maturation in healing myocardial infarcts.MethodsMice undergoing reperfused infarction protocols were injected daily with a neutralizing anti–PDGFR-β antibody (APB5), an anti-PDGFR-α antibody (APA5), or control immunoglobulin G, and were killed after 7 days of reperfusion.ResultsThe PDGF-B, PDGFR-α, and PDGFR-β mRNA expression was induced in reperfused mouse infarcts. Perivascular cells expressing phosphorylated PDGFR-β were identified in the infarct after 7 days of reperfusion, indicating activation of the PDGF-BB/PDGFR-β pathway. The PDGFR-β blockade resulted in impaired maturation of the infarct vasculature, enhanced capillary density, and formation of dilated uncoated vessels. Defective vascular maturation in antibody-treated mice was associated with increased and prolonged extravasation of red blood cells and monocyte/macrophages, suggesting increased permeability. These defects resulted in decreased collagen content in the healing infarct. In contrast, PDGFR-α inhibition did not affect vascular maturation, but significantly decreased collagen deposition in the infarct.ConclusionsPlatelet-derived growth factor signaling critically regulates postinfarction repair. Both PDGFR-β– and PDGFR-α–mediated pathways promote collagen deposition in the infarct. Activation of PDGF-B/PDGFR-β is also involved in recruitment of mural cells by neovessels, regulating maturation of the infarct vasculature. Acquisition of a mural coat and maturation of the vasculature promotes resolution of inflammation and stabilization of the scar

Increased myocardial susceptibility to repetitive ischemia with high-fat diet-induced obesity.

Obesity and diabetes are frequently associated with cardiovascular disease. When a normal heart is subjected to brief/sublethal repetitive ischemia and reperfusion (I/R), adaptive responses are activated to preserve cardiac structure and function. These responses include but are not limited to alterations in cardiac metabolism, reduced calcium responsiveness, and induction of antioxidant enzymes. In a model of ischemic cardiomyopathy inducible by brief repetitive I/R, we hypothesized that dysregulation of these adaptive responses in diet-induced obese (DIO) mice would contribute to enhanced myocardial injury. DIO C57BL/6J mice were subjected to 15 min of daily repetitive I/R while under short-acting anesthesia, a protocol that results in the development of fibrotic cardiomyopathy. Cardiac lipids and candidate gene expression were analyzed at 3 days, and histology at 5 days of repetitive I/R. Total free fatty acids (FFAs) in the cardiac extracts of DIO mice were significantly elevated, reflecting primarily the dietary fatty acid (FA) composition. Compared with lean controls, cardiac FA oxidation (FAO) capacity of DIO mice was significantly higher, concurrent with increased expression of FA metabolism gene transcripts. Following 15 min of daily repetitive I/R for 3 or 5 days, DIO mice exhibited increased susceptibility to I/R and, in contrast to lean mice, developed microinfarction, which was associated with an exaggerated inflammatory response. Repetitive I/R in DIO mice was associated with more profound significant downregulation of FA metabolism gene transcripts and elevated FFAs and triglycerides. Maladaptive metabolic changes of FA metabolism contribute to enhanced myocardial injury in diet-induced obesity

An Intense and Short-Lasting Burst of Neutrophil Activation Differentiates Early Acute Myocardial Infarction from Systemic Inflammatory Syndromes

BACKGROUND: Neutrophils are involved in thrombus formation. We investigated whether specific features of neutrophil activation characterize patients with acute coronary syndromes (ACS) compared to stable angina and to systemic inflammatory diseases. METHODS AND FINDINGS: The myeloperoxidase (MPO) content of circulating neutrophils was determined by flow cytometry in 330 subjects: 69 consecutive patients with acute coronary syndromes (ACS), 69 with chronic stable angina (CSA), 50 with inflammation due to either non-infectious (acute bone fracture), infectious (sepsis) or autoimmune diseases (small and large vessel systemic vasculitis, rheumatoid arthritis). Four patients have also been studied before and after sterile acute injury of the myocardium (septal alcoholization). One hundred thirty-eight healthy donors were studied in parallel. Neutrophils with normal MPO content were 96% in controls, >92% in patients undergoing septal alcoholization, 91% in CSA patients, but only 35 and 30% in unstable angina and AMI (STEMI and NSTEMI) patients, compared to 80%, 75% and 2% of patients with giant cell arteritis, acute bone fracture and severe sepsis. In addition, in 32/33 STEMI and 9/21 NSTEMI patients respectively, 20% and 12% of neutrophils had complete MPO depletion during the first 4 hours after the onset of symptoms, a feature not observed in any other group of patients. MPO depletion was associated with platelet activation, indicated by P-selectin expression, activation and transactivation of leukocyte β2-integrins and formation of platelet neutrophil and -monocyte aggregates. The injection of activated platelets in mice produced transient, P-selectin dependent, complete MPO depletion in about 50% of neutrophils. CONCLUSIONS: ACS are characterized by intense neutrophil activation, like other systemic inflammatory syndromes. In the very early phase of acute myocardial infarction only a subpopulation of neutrophils is massively activated, possibly via platelet-P selectin interactions. This paroxysmal activation could contribute to occlusive thrombosis

Beat-to-beat vectorcardiographic analysis of ventricular depolarization and repolarization in myocardial infarction

OBJECTIVES: Increased beat-to-beat variability in the QT interval has been associated with heart disease and mortality. The purpose of this study was to investigate the beat-to-beat spatial and temporal variations of ventricular depolarization and repolarization in vectorcardiogram (VCG) for characterising myocardial infarction (MI) patients. METHODS: Standard 12-lead ECGs of 84 MI patients (22 f, 63±12 yrs; 62 m, 56±10 yrs) and 69 healthy subjects (17 f, 42±18 yrs; 52 m, 40±13 yrs) were investigated. To extract the beat-to-beat QT intervals, a template-matching algorithm and the singular value decomposition method have been applied to synthesise the ECG data to VCG. Spatial and temporal variations in the QRS complex and T-wave loops were studied by investigating several descriptors (point-to-point distance variability, mean loop length, T-wave morphology dispersion, percentage of loop area, total cosine R-to-T). RESULTS: Point-to-point distance variability of QRS and T-loops (0.13±.04 vs. 0.10±0.04, p<0.0001 and 0.16±.07 vs. 0.13±.06, p<0.05) were significantly larger in the MI group than in the control group. The average T-wave morphology dispersion was significantly higher in the MI group than in the control group (62±8 vs. 38±16, p<.0001). Further, its beat-to-beat variability appeared significantly lower in the MI group than in the control group (12±5 v. 15±6u, p<0.005). Moreover, the average percentage of the T-loop area was found significantly lower in the MI group than the controls (46±17 vs. 55±15, p<.001). Finally, the average and beat-to-beat variability of total cosine R-to-T were not found statistically significant between both groups. CONCLUSIONS: Beat-to-beat assessment of VCG parameters may have diagnostic attributes that might help in identifying MI patients.Muhammad A. Hasan, Derek Abbott and Mathias Baumer

Why animal model studies are lost in translation

The development of novel therapies based on understanding the pathophysiologic basis of disease is a major goal of biomedical research. Despite an explosion in new knowledge on the molecular mechanisms of disease derived from animal model investigations, translation into effective treatment for human patients has been disappointingly slow. Several fundamental problems may explain the translational failures. First, the emphasis on novel and highly significant findings selectively rewards implausible, low-probability observations and high-magnitude effects, providing a biased perspective of the pathophysiology of disease that underappreciates the complexity and redundancy of biological systems. Second, even when a sound targetable mechanism is identified, animal models cannot recapitulate the pathophysiologic heterogeneity of the human disease, and are poor predictors of therapeutic success. Third, traditional classifications of most complex diseases are based primarily on clinical criteria and do not reflect the diverse pathophysiologic mechanisms that may be involved. The development of a flexible and dynamic conceptual paradigm that takes into account the totality of the evidence on the mechanisms of disease, and pathophysiologic stratification of patients to identify subpopulations with distinct pathogenetic mechanisms, are crucial for the development of new therapeutics