Alda Huqi

Obstructive coronary atherosclerosis and ischemic heart disease: An elusive link!

In the current pathophysiological model of chronic ischemic heart disease (IHD), myocardial ischemia and exertional angina are caused by obstructive atherosclerotic plaque, and the clinical management of IHD is centered on the identification and removal of the stenosis. Although this approach has been in place for years, several lines of evidence, including poor prognostic impact, suggest that this direct relationship may present an oversimplified view of IHD. Indeed, a large number of studies have found that IHD can occur in the presence or absence of obstructive coronary artery disease and that atherosclerosis is just 1 element in a complex multifactorial pathophysiological process that includes inflammation, microvascular coronary dysfunction, endothelial dysfunction, thrombosis, and angiogenesis. Furthermore, the high recurrence rates underscore the fact that removing stenosis in patients with stable IHD does not address the underlying pathological mechanisms that lead to the progression of nonculprit lesions. The model proposed herein shifts the focus away from obstructive epicardial coronary atherosclerosis and centers it on the microvasculature and myocardial cell where the ischemia is taking place. If the myocardial cell is placed at the center of the model, all the potential pathological inputs can be considered, and strategies that protect the cardiomyocytes from ischemic damage, regardless of the causative mechanism, can be developed.

Effect of Fatty Acids on Human Bone Marrow Mesenchymal Stem Cell Energy Metabolism and Survival

Successful stem cell therapy requires the optimal proliferation, engraftment, and differentiation of stem cells into the desired cell lineage of tissues. However, stem cell therapy clinical trials to date have had limited success, suggesting that a better understanding of stem cell biology is needed. This includes a better understanding of stem cell energy metabolism because of the importance of energy metabolism in stem cell proliferation and differentiation. We report here the first direct evidence that human bone marrow mesenchymal stem cell (BMMSC) energy metabolism is highly glycolytic with low rates of mitochondrial oxidative metabolism. The contribution of glycolysis to ATP production is greater than 97% in undifferentiated BMMSCs, while glucose and fatty acid oxidation combined only contribute 3% of ATP production. We also assessed the effect of physiological levels of fatty acids on human BMMSC survival and energy metabolism. We found that the saturated fatty acid palmitate induces BMMSC apoptosis and decreases proliferation, an effect prevented by the unsaturated fatty acid oleate. Interestingly, chronic exposure of human BMMSCs to physiological levels of palmitate (for 24 hr) reduces palmitate oxidation rates. This decrease in palmitate oxidation is prevented by chronic exposure of the BMMSCs to oleate. These results suggest that reducing saturated fatty acid oxidation can decrease human BMMSC proliferation and cause cell death. These results also suggest that saturated fatty acids may be involved in the long-term impairment of BMMSC survival in vivo.

Reduced levels of putative endothelial progenitor and CXCR4+ cells in coronary artery disease: Kinetics following percutaneous coronary intervention and association with clinical characteristics

Levels of circulating endothelial progenitor cells (EPCs) and CXCR4-positive cells are decreased in patients with coronary artery disease (CAD); however, their ability to change in response to acute vascular injury remains to be elucidated. Progenitor and CXCR4-positive cells were analysed by flow cytometry from the peripheral blood of 23 healthy controls and 23 patients with CAD, of which 13 patients underwent angiogram and 10 patients received percutaneous coronary intervention (PCI) with stent implantation. Baseline levels of progenitor and CXCR4-positive cells were substantially reduced in CAD patients compared to controls, although they were still capable of increasing in response to vascular injury. Levels of progenitor and CXCR4-positive cells were increased to a greater extent in the PCI group compared to angiogram patients. At presentation, levels of putative endothelial progenitor and CXCR4-positive cells were found to be negatively correlated with disease severity. A one-year follow-up revealed that out of the cell populations examined, only levels of CXCR4-positive cells were positively correlated with angina frequency in the PCI group, but not in patients receiving angiogram. Baseline levels of progenitor cells are differentially increased depending upon the severity of vascular injury incurred, regardless of a significant deficit in baseline levels in CAD patients. Levels of putative EPCs and CXCR4-positive cells were negatively correlated with disease severity at presentation, however, only CXCR4-positive cells were associated with patient condition in a one-year follow-up.

Acute liver carnitine palmitoyltransferase I overexpression recapitulates reduced palmitate oxidation of cardiac hypertrophy.

Rationale: Muscle carnitine palmitoyltransferase I is predominant in the heart, but the liver isoform (liver carnitine palmitoyltransferase I [L-CPT1]) is elevated in hearts with low long chain fatty acid oxidation, such as fetal and hypertrophied hearts. Objective: This work examined the effect of acute L-CPT1 expression on the regulation of palmitate oxidation and energy metabolism in intact functioning rat hearts for comparison with findings in hypertrophied hearts. Methods and Results: L-CPT1 was expressed in vivo in rat hearts by coronary perfusion of Adv.cmv.L-CPT1 (L-CPT1, n=15) vs phosphate-buffered saline (PBS) infusion (PBS, n=7) or empty virus (empty, n=5). L-CPT1 was elevated 5-fold at 72 hours after Adv.cmv.L-CPT1 infusion (P<0.05), but muscle carnitine palmitoyltransferase I was unaffected. Despite similar tricarboxylic acid cycle rates, palmitate oxidation rates were reduced with L-CPT1 (1.12 ± 0.29 &mgr;mol/min per gram of dry weight, mean±SE) vs PBS (1.6 ± 0.34). Acetyl CoA production from palmitate was reduced with L-CPT1 (69 ± 0.02%; P<0.05; PBS=79 ± 0.01%; empty=81 ± 0.02%), similar to what occurs in hypertrophied hearts, and with no difference in malonyl CoA content. Glucose oxidation was elevated with L-CPT1 (by 60%). Surprisingly, L-CPT1 hearts contained elevated atrial natriuretic peptide, indicating induction of hypertrophic signaling. Conclusions: The results link L-CPT1 expression to reduced palmitate oxidation in a nondiseased adult heart, recapitulating the phenotype of reduced long chain fatty acid oxidation in cardiac hypertrophy. The implications are that L-CPT1 expression induces metabolic remodeling hypertrophic signaling and that regulatory factors beyond malonyl CoA in the heart regulate long chain fatty acid oxidation via L-CPT1.

Cardiac hypertrophy in the newborn delays the maturation of fatty acid β-oxidation and compromises postischemic functional recovery

During the neonatal period, cardiac energy metabolism progresses from a fetal glycolytic profile towards one more dependent on mitochondrial oxidative metabolism. In this study, we identified the effects of cardiac hypertrophy on neonatal cardiac metabolic maturation and its impact on neonatal postischemic functional recovery. Seven-day-old rabbits were subjected to either a sham or a surgical procedure to induce a left-to-right shunt via an aortocaval fistula to cause RV volume-overload. At 3 wk of age, hearts were isolated from both groups and perfused as isolated, biventricular preparations to assess cardiac energy metabolism. Volume-overload resulted in cardiac hypertrophy (16% increase in cardiac mass, P < 0.05) without evidence of cardiac dysfunction in vivo or in vitro. Fatty acid oxidation rates were 60% lower (P < 0.05) in hypertrophied hearts than controls, whereas glycolysis increased 246% (P < 0.05). In contrast, glucose and lactate oxidation rates were unchanged. Overall ATP production rates were significantly lower in hypertrophied hearts, resulting in increased AMP-to-ATP ratios in both aerobic hearts and ischemia-reperfused hearts. The lowered energy generation of hypertrophied hearts depressed functional recovery from ischemia. Decreased fatty acid oxidation rates were accompanied by increased malonyl-CoA levels due to decreased malonyl-CoA decarboxylase activity/expression. Increased glycolysis in hypertrophied hearts was accompanied by a significant increase in hypoxia-inducible factor-1α expression, a key transcriptional regulator of glycolysis. Cardiac hypertrophy in the neonatal heart results in a reemergence of the fetal metabolic profile, which compromises ATP production in the rapidly maturing heart and impairs recovery of function following ischemia.

Pharmacological approaches to coronary microvascular dysfunction

In recent decades coronary microvascular dysfunction has been increasingly identified as a relevant contributor to several cardiovascular conditions. Indeed, coronary microvascular abnormalities have been recognized in patients suffering acute myocardial infarction, chronic stable angina and cardiomyopathies, and also in patients with hypertension, obesity and diabetes. In this review, we will examine pathophysiological information needed to understand pharmacological approaches to coronary microvascular dysfunction in these different clinical contexts. Well-established drugs and new pharmacological agents, including those for which only preclinical data are available, will be covered in detail.

Activating PPARα Prevents Post–Ischemic Contractile Dysfunction in Hypertrophied Neonatal Hearts

RATIONALE Post-ischemic contractile dysfunction is a contributor to morbidity and mortality after the surgical correction of congenital heart defects in neonatal patients. Pre-existing hypertrophy in the newborn heart can exacerbate these ischemic injuries, which may partly be due to a decreased energy supply to the heart resulting from low fatty acid β-oxidation rates. OBJECTIVE We determined whether stimulating fatty acid β-oxidation with GW7647, a peroxisome proliferator-activated receptor-α (PPARα) activator, would improve cardiac energy production and post-ischemic functional recovery in neonatal rabbit hearts subjected to volume overload-induced cardiac hypertrophy. METHODS AND RESULTS Volume-overload cardiac hypertrophy was produced in 7-day-old rabbits via an aorto-caval shunt, after which, the rabbits were treated with or without GW7647 (3 mg/kg per day) for 14 days. Biventricular working hearts were subjected to 35 minutes of aerobic perfusion, 25 minutes of global no-flow ischemia, and 30 minutes of aerobic reperfusion. GW7647 treatment did not prevent the development of cardiac hypertrophy, but did prevent the decline in left ventricular ejection fraction in vivo. GW7647 treatment increased cardiac fatty acid β-oxidation rates before and after ischemia, which resulted in a significant increase in overall ATP production and an improved in vitro post-ischemic functional recovery. A decrease in post-ischemic proton production and endoplasmic reticulum stress, as well as an activation of sarcoplasmic reticulum calcium ATPase isoform 2 and citrate synthase, was evident in GW7647-treated hearts. CONCLUSIONS Stimulating fatty acid β-oxidation in neonatal hearts may present a novel cardioprotective intervention to limit post-ischemic contractile dysfunction.

Persistent angina: the Araba Phoenix of cardiology.

Percutaneous coronary intervention (PCI) has not been shown to reduce mortality in patients with stable coronary artery disease (CAD). The long-term clinical success of PCI is defined as the persistent relief of signs and symptoms of myocardial ischemia for more than 6 months after the index procedure. Data from large trials investigating the use of PCI in patients with stable CAD show that angina is still experienced in a large number of patients one year after the procedure and that this proportion increases over time. These data are, however, largely from post-hoc analyses of studies powered to measure other end points. We conducted the first prospective study investigating the incidence of persistent angina and inducible ischemia in patients with stable CAD undergoing PCI rated as ‘successful’ by the interventional cardiologist, and present an interim analysis of data from 220 patients. The mean age of our patients was 65 years; they were mostly male, mildly obese, hypertensive and dyslipidemic. Most patients had single-vessel disease affecting the left anterior descending artery and received a drug-eluting stent, and all patients had a positive stress test before PCI. At the follow-up visit, which was performed within 4 weeks of the index procedure, 52% of patients still had a positive stress test. Before PCI, 66% of patients reported experiencing angina on exertion. At the follow-up visit, one-third of those patients were still experiencing angina. Patients experiencing persistent angina (21% of the study population) graded their symptoms as improved (66%), unchanged (33%) or worsened (1%) after the procedure. We hypothesize that coronary microvascular dysfunction is a possible cause of persistent angina in this highly select group of patients. Risk factors for microvascular dysfunction include dyslipidemia, smoking and diabetes. It is currently difficult to dissect the relative contributions of coronary artery stenosis and microvascular dysfunction in precipitating myocardial ischemia. A better understanding of these mechanisms could reduce the number of unnecessary PCI procedures. Moreover, treatment options in patients who continue to experience angina despite ‘optimal’ medical therapy and ‘successful’ PCI are urgently required.

Microvascular Function/Dysfunction Downstream a Coronary Stenosis

For decades coronary macrovascular atherosclerosis has been considered the principal manifestation of coronary heart disease, with most of our effort dedicated to identifying and removal of coronary stenosis. However, growing body of literature indicates that coronary microcirculation also contributes substantially to the pathophysiology of cardiovascular disease. An understanding of mechanisms regulating microvascular function is of critical importance in understanding its role in disease, especially because these regulatory mechanisms vary substantially across species, vascular bed and due to comorbidities. Indeed, the most obvious consequence of coronary stenosis is that it may limit blood supply to the dependent myocardium to the point of causing ischaemia during exercise or even at rest. However, this flow limiting effect is not only due to the passive hydraulic effect of a narrowed conduit, but also to active responses in the coronary microcirculation triggered by the presence of an epicardial stenosis. To understand this problem it is important to review the inter-related mechanisms that regulate flow to the left ventricular wall and modulate transmural distribution of flow. These regulatory mechanisms operate hierarchically and are heterogeneously distributed along the coronary vascular tree. It is also important to discuss the effect of myocardial performance in modulating both blood flow demands and coronary resistance. Some of the interactions between coronary stenosis and microcirculation are transient, like those documented in acute coronary syndromes or during percutaneous interventions. However, microcirculatory remodeling may be triggered by a chronic coronary stenosis, leading to a sustained impairment of blood supply even after successful removal of the epicardial stenosis. A deeper understanding of these phenomena may explain paradoxical findings in patients undergoing coronary revascularization, particularly when functional tests are used in their assessment. These aspects are discussed in detail in this review.

Independent and Incremental Value of Severely Enlarged Left Atrium in Risk Stratification of Very Elderly Patients With Chronic Systolic Heart Failure

The authors sought to assess the impact on survival of demographic, clinical, and echo-Doppler parameters in patients with chronic heart failure due to left ventricular systolic dysfunction divided according to age groups. This study included 734 patients (age 69±11 years) who were classified into tertiles of age: I (22-66 years), II (67-76 years), and III (77-94 years). Severely enlarged left atrial size was defined as ≥52 mm in men and ≥47 mm in women. Multivariable analysis identified male sex (P=.018) and severely enlarged left atrium (P=.024) as significant correlates of all-cause mortality in the very elderly cohort, while restrictive filling pattern (RFP) (P=.004) and New York Heart Association class III or IV (P=.005) among patients of the first tertile and RFP (P=.028) among patients in the second tertile were independently associated with mortality after 30±21 months of follow-up. At the interactive stepwise model in the very elderly population, a severely enlarged left atrium, added to the model after clinical parameters and ejection fraction, moved the chi-square value from 20.7 to 25.8 (P=.048). RFP emerged as the single best predictor of all-cause mortality in the younger and intermediate ranges, whereas severely enlarged left atrium was the best predictor in the very elderly.