Doralisa Morrone

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.

Lipid-altering efficacy of ezetimibe plus statin and statin monotherapy and identification of factors associated with treatment response: A pooled analysis of over 21,000 subjects from 27 clinical trials

OBJECTIVE Patients with dyslipoproteinemia constitute the largest risk group for development of atherosclerosis and cardiovascular disease (CVD). Despite extensive statin use, many patients with CVD risk do not achieve guideline-recommended low-density lipoprotein cholesterol (LDL-C) targets. This pooled analysis of 27 previously published clinical trials conducted between 1999 and 2008 evaluated the lipid-altering efficacy and factors related to treatment response of ezetimibe combined with statin and statin monotherapy. METHODS Patient-level data were combined from double-blind, placebo-controlled or active comparator studies randomizing adult subjects to ezetimibe 10mg plus statin (n=11,714) versus statin alone (n=10,517) for 6-24 weeks (mean=9 weeks). Association of factors with treatment response, percent change from baseline LDL-C and other lipids, and attainment of guideline-recommended lipid and lipoprotein targets were evaluated. RESULTS Higher baseline LDL-C, diabetes mellitus, Black race, greater age, and male gender were associated with small but significantly greater percent reductions in LDL-C regardless of treatment. Treatment influenced efficacy, with ezetimibe plus statin producing significantly greater reductions in LDL-C, total-cholesterol, non-HDL-C, ApoB, triglycerides, lipid ratios, hs-CRP; significantly larger increases in HDL-C and ApoA1; and significantly higher achievement of LDL-C (<70mg/dl, <100mg/dl), non-HDL-C (<100mg/dl, <130mg/dl), and ApoB (<80mg/dl, <90mg/dl) targets than statin monotherapy at statin potencies compared (p<0.0001 for all). Differential treatment effects were seen with first-/second-line therapy and statin potency. CONCLUSION These results suggest that patient characteristics have a limited influence on response to lipid-lowering therapy and demonstrate the consistent treatment effect of ezetimibe combined with statin and statin monotherapy across a diverse patient population.

Right ventricular dysfunction is associated with chronic kidney disease and predicts survival in patients with chronic systolic heart failure.

Chronic kidney disease (CKD) and right ventricular (RV) dysfunction are important predictors of prognosis in heart failure (HF). We investigated the relationship between RV dysfunction and CKD in outpatients with chronic systolic HF, an association which remains poorly defined.

Safety profile of statins alone or combined with ezetimibe: a pooled analysis of 27 studies including over 22,000 patients treated for 6–24 weeks

Aims:  The aim of this analysis was to assess the overall safety and tolerability profiles of various statins + ezetimibe vs. statin monotherapy and to explore tolerability in sub‐populations grouped by age, race, and sex.

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.

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.

Pharmacological Agents Targeting Myocardial Metabolism for the Management of Chronic Stable Angina : an Update

Despite continuous advances in myocardial revascularization procedures and intracoronary devices, patients with ischemic heart disease (IHD) still experience worse prognosis and poor quality of life (QoL). Indeed, chronic stable angina (CSA) is a common disease with a large burden on healthcare costs. Traditionally, CSA is interpreted as episodes of reversible myocardial ischemia related to the presence of stable coronary artery plaque causing myocardial demand/supply mismatch when myocardial oxygen consumption increases. Accordingly, revascularization procedures are performed with the aim to remove the flow limiting stenosis, whereas traditional medical therapy (hemodynamic agents) aims at reducing myocardial oxygen demands. However, although effective, none of these treatment strategies or their combination is either able to confer symptomatic relief in all patients, nor to reduce mortality. Failure to significantly improve QoL and prognosis may be attributed at least in part to this “restrictive” understanding of IHD. Despite for many years myocardial metabolic derangement has been overlooked, recently it has gained increased attention with the development of new pharmacological agents (metabolic modulators) able to influence myocardial substrate selection and utilization thus improving cardiac efficiency. Shifting cardiac metabolism from free fatty acids (FA) towards glucose is a promising approach for the treatment of patients with stable angina, independently of the underling disease (macrovascular and/or microvascular disease). In this sense cardiac metabolic modulators open the way to a “revolutionary” understanding of ischemic heart disease and its common clinical manifestations, where myocardial ischemia is no longer considered as the mere oxygen and metabolites demand/supply unbalance, but as an energetic disorder. Keeping in mind such an alternative approach to the disease, development of new pharmacological agents directed toward multiple metabolic targets is mandatory.

Influence of depression and anxiety on circulating endothelial progenitor cells in patients with acute coronary syndromes.

Circulating endothelial progenitor cells (EPCs) are related to endothelial function and progression of coronary artery disease. There is evidence of decreased numbers of circulating EPCs in patients with a current episode of major depression. We investigated the relationships between the level of circulating EPCs and depression and anxiety in patients with acute coronary syndrome (ACS).

Therapy Against Ischemic Injury

The advent of reperfusion therapy constituted a historical change for the management of myocardial infarction (MI) patients. However, shortly after, experimental models recognized an intrinsic damage, related to reperfusion itself, which was termed as ischemiareperfusion injury (IRI). Clinical studies attribute IRI a significant burden of morbidity and mortality observed in patients undergoing successful epicardial reperfusion. Several mechanisms have been identified and, as many strategies, have been investigated to address the phenomenon. In this review we will discuss the current evidence for IRI, pharmacological and non-pharmacological preventive strategies adopted both in experimental models and in clinical practice. Finally, we will try to provide a critical appraisal to the lack of consistent benefit observed in translational medicine.