Amir Lerman

Long-Term Follow-Up of Patients With Mild Coronary Artery Disease and Endothelial Dysfunction

BACKGROUND Coronary endothelial dysfunction is characterized by vasoconstrictive response to the endothelium-dependent vasodilator acetylcholine. Although endothelial dysfunction is considered an early phase of coronary atherosclerosis, there is a paucity of information regarding the outcome of these patients. Thus, this study was designed to evaluate the outcome of patients with mild coronary artery disease on the basis of their endothelial function. METHODS AND RESULTS Follow-up was obtained in 157 patients with mildly diseased coronary arteries who had undergone coronary vascular reactivity evaluation by graded administration of intracoronary acetylcholine, adenosine, and nitroglycerin and intracoronary ultrasound at the time of diagnostic study. Patients were divided on the basis of their response to acetylcholine into 3 groups: group 1 (n=83), patients with normal endothelial function; group 2 (n=32), patients with mild endothelial dysfunction; and group 3 (n=42), patients with severe endothelial dysfunction. Over an average 28-month follow-up (range, 11 to 52 months), none of the patients from group 1 or 2 had cardiac events. However, 6 (14%) with severe endothelial dysfunction had 10 cardiac events (P<0.05 versus groups 1 and 2). Cardiac events included myocardial infarction, percutaneous or surgical coronary revascularization, and/or cardiac death. CONCLUSIONS Severe endothelial dysfunction in the absence of obstructive coronary artery disease is associated with increased cardiac events. This study supports the concept that coronary endothelial dysfunction may play a role in the progression of coronary atherosclerosis.

Endothelial Dysfunction A Marker of Atherosclerotic Risk

Abstract—Endothelial dysfunction is a systemic disorder and a key variable in the pathogenesis of atherosclerosis and its complications. Current evidence suggests that endothelial status is not determined solely by the individual risk factor burden but rather, may be regarded as an integrated index of all atherogenic and atheroprotective factors present in an individual, including known as well as yet-unknown variables and genetic predisposition. Endothelial dysfunction reflects a vascular phenotype prone to atherogenesis and may therefore serve as a marker of the inherent atherosclerotic risk in an individual. In line with this hypothesis, dysfunction of either the coronary or peripheral vascular endothelium was shown to constitute an independent predictor of cardiovascular events, providing valuable prognostic information additional to that derived from conventional risk factor assessment. Interventions like risk factor modification and treatment with various drugs, including statins and angiotensin-converting enzyme inhibitors, may improve endothelial function and thereby, potentially prognosis. Hence, given its reversibility and granted the availability of a diagnostic tool to identify patients at risk and to control the efficacy of therapy in clinical practice, endothelial dysfunction may be an attractive primary target in the effort to optimize individualized therapeutic strategies to reduce cardiovascular morbidity and mortality.

Systematic review: transient left ventricular apical ballooning: a syndrome that mimics ST-segment elevation myocardial infarction.

Key Summary Points The transient left ventricular apical ballooning syndrome is a novel cardiac syndrome. It is characterized by peculiar transient apical ballooning of the left ventricle, which is the result of characteristic wall-motion abnormalities in the left ventricular apex and mid-ventricle. Despite the absence of obstructive epicardial coronary artery disease, clinical presentation in patients with the syndrome is similar to that of patients with ST-segment elevation myocardial infarction. Postmenopausal women seem to be most at risk for developing the syndrome. An episode of acute emotional or physiologic stress seems to often precede presentation with the syndrome. Patients with the syndrome should be monitored and treated for left heart failure, dynamic intraventricular obstruction, arrhythmias, and mechanical complications, should they develop. Patients with the syndrome seem to have a favorable in-hospital prognosis despite the development of acute left-sided heart failure and hemodynamic instability in many patients. The cause of the syndrome is not yet known. The transient left ventricular apical ballooning syndrome, also known as takotsubo cardiomyopathy, is a recently described novel acute cardiac syndrome. The syndrome is characterized by peculiar, yet characteristic, transient regional systolic dysfunction involving the left ventricular apex and mid-ventricle with hyperkinesis of the basal left ventricular segments. The syndrome was initially recognized and reported in the Japanese population (1-6). Dote and colleagues (1) were one of the first to describe the syndrome, which was given the moniker tako-tsubo-like left ventricular dysfunction, naming it after a round-bottomed narrow-necked Japanese fishing pot used for trapping octopus (Figure 1, parts A, B, and C). More recently, the condition has been called transient left ventricular apical ballooning syndrome in reference to the associated left ventricular morphologic features that accompany the syndrome. After the initial recognition and description of the transient left ventricular apical ballooning syndrome in the Japanese population, subsequent recent reports have documented the syndrome in the United States (7) and Belgium (8). Despite the acute onset of transient left ventricular systolic dysfunction involving the left ventricular apex and mid-ventricle, patients with the transient left ventricular apical ballooning syndrome do not have obstructive atherosclerotic coronary disease. The cause of the syndrome is unknown. Figure 1. Left ventriculograms (end-systole) of 2 patients with the transient left ventricular apical ballooning syndrome and examples of a tako-tsubo. A. B C D E D E American Heart Journal Available case series of the transient left ventricular apical ballooning syndrome have included relatively few patients. This review presents reported case series of the syndrome in order to more precisely summarize the demographic characteristics, clinical characteristics, and outcomes of patients presenting with the syndrome. In addition, we review the available literature evaluating possible pathophysiologic mechanisms responsible for the syndrome. Methods Literature Search and Identification of Relevant Studies We identified relevant English-language articles pertaining to the transient left ventricular apical ballooning syndrome by searching the PubMed and EMBASE databases (through June 2004). The following search terms were used to identify primary articles: left ventricular apical ballooning syndrome, takotsubo cardiomyopathy, ampulla cardiomyopathy, and transient left ventricular dysfunction. We then manually searched references from the primary articles. We included only peer-reviewed reports and did not search for unpublished data. When more than 1 case series was reported from the same medical center, we included the case series reporting on the largest number of patients and excluded those with fewer patients to avoid duplicate reporting. Only case series reporting on at least 5 consecutive patients with the transient left ventricular apical ballooning syndrome were initially identified and assessed for potential inclusion in this case series review. Case reports and small case series reporting on fewer than 5 patients were not included in the review in an attempt to minimize potential reporting bias of uncharacteristic or nonrepresentative cases. We included prospective and retrospective case series. Figure 2 outlines the search and selection process. Figure 2. Study identification. Case Series and Data Assessment We identified 13 case series for potential inclusion in this review. Of these, 10 reported on unselected, consecutive patients with the transient left ventricular apical ballooning syndrome. Seven of these 10 case series reported on patients who met the following criteria and were subsequently included in this review. First, the patient must have had transient apical and midleft ventricular wall-motion abnormalities resulting in the left ventricular morphologic appearance of apical ballooning. Second, coronary angiography data that excluded obstructive atherothrombotic coronary artery disease as the causative mechanism for left ventricular dysfunction had to be available. Third, the study had to report on patient demographic characteristics, presenting symptoms, clinical presentation, electrocardiographic characteristics, laboratory data, cardiac catheterization data, clinical complications, and clinical outcome. Of the 3 excluded series reporting on consecutive patients, 2 were excluded because they lacked coronary angiography data for all patients (9, 10), and 1 was excluded because it reported on only 2 patients (11). In addition, data that addressed potential pathophysiologic mechanisms responsible for the transient left ventricular apical ballooning syndrome were identified by using the search strategy described earlier. These data were then reviewed and summarized. One author read and assessed all studies. Results Table 1 summarizes the 7 case series that met the inclusion criteria for this review. Of these, 5 reports were from Japan (2-6), 1 was from the United States (7), and 1 was from Belgium (8). Three studies reported prospectively collected data, 2 studies reported retrospective data, and 2 studies did not specify the prospective or retrospective nature of the study. Table 1. Demographic and Clinical Characteristics of Consecutive Patients Given a Diagnosis of the Transient Left Ventricular Apical Ballooning Syndrome Demographic Characteristics and Presenting Symptoms All 7 case series consistently reported a sex discrepancy in patients presenting with the transient left ventricular apical ballooning syndrome: Most patients were women (range, 82% to 100%). The mean age of patients presenting with the syndrome was 62 to 75 years (overall range, 10 to 88 years). Patients often presented with chest pain at rest (33% to 71%), although dyspnea as the initial symptom was not uncommon. Isolated cases of syncope as the presenting symptom have been reported (2, 4, 5, 7). Electrocardiographic Data The most common finding on the admission electrocardiogram was ST-segment elevation (range, 46% to 100% of patients). All series except 1 reported ST-segment elevation in at least 81% of patients. ST-segment elevation, when present, was most often reported in the precordial leads. Concomitant ST-segment elevation in the inferior leads has been reported in a few cases, and isolated inferior or lateral ST-segment elevation seems to be an unusual electrocardiographic finding in patients presenting with the transient left ventricular apical ballooning syndrome. New left and right bundle-branch block on the presenting electrocardiogram has been reported. Almost all series patients developed evolutionary T-wave inversions that were usually present in most leads. New pathologic Q waves on the electrocardiogram were reported in 6% to 31% of patients; in some instances, the Q waves were transient. The corrected QT interval on the presenting electrocardiogram was prolonged; it ranged from a mean of 450 milliseconds to 501 milliseconds. Cardiac Enzyme and Biomarker Release Most patients had a small, rapid increase in cardiac enzyme and biomarker levels. Fifty-six percent to 100% of patients had a peak cardiac enzyme or biomarker level above the upper limit of normal. The series reporting a 56% incidence of cardiac enzyme increase assessed only creatine kinase (3), whereas the 2 series reporting a 100% incidence of biomarker release evaluated cardiac troponin (7, 8). Several series have reported that peak cardiac biomarker levels are often those drawn at the time of initial presentation; they appear to not follow the slow rise-and- fall kinetics observed with conventional myocardial infarction. Angiographic Data and Left Ventricular Function Patients with the transient left ventricular apical ballooning syndrome had either no angiographically detectable coronary disease (range, 25% to 100% of patients) or nonobstructive coronary disease (range, 0% to 75% of patients). None of the patients had epicardial stenosis greater than 50% of the luminal coronary artery diameter. Patients with the syndrome had an abnormal left ventricular ejection fraction at presentation (mean, 0.39 to 0.49) that improved rapidly over a period of days to weeks (mean follow-up left ventricular ejection fraction, 0.60 to 0.76). Apical and mid-ventricular regional wall-motion abnormalities completely resolved in most patients and followed a time course similar to that of the associated improvement in left ventricular ejection fraction. Four studies reported endomyocardial biopsy results in the acute phase of the syndrome (n= 18), with no evidence of myocarditis (2, 4-6). Evaluations of Endothelial Function and Coronary Microcirculation Either spontaneous or provocable multivessel epicardial spasm was present in a few patients; the incidence of provoca

Apical ballooning syndrome (Tako-Tsubo or stress cardiomyopathy): A mimic of acute myocardial infarction

Apical ballooning syndrome (ABS) is a unique reversible cardiomyopathy that is frequently precipitated by a stressful event and has a clinical presentation that is indistinguishable from a myocardial infarction. We review the best evidence regarding the pathophysiology, clinical features, investigation, and management of ABS. The incidence of ABS is estimated to be 1% to 2% of patients presenting with an acute myocardial infarction. The pathophysiology remains unknown, but catecholamine mediated myocardial stunning is the most favored explanation. Chest pain and dyspnea are the typical presenting symptoms. Transient ST elevation may be present on the electrocardiogram, and a small rise in cardiac troponin T is invariable. Typically, there is hypokinesis or akinesis of the mid and apical segments of the left ventricle with sparing of the basal systolic function without obstructive coronary lesions. Supportive treatment leads to spontaneous rapid recovery in nearly all patients. The prognosis is excellent, and a recurrence occurs in <10% of patients. Apical ballooning syndrome should be included in the differential diagnosis of patients with an apparent acute coronary syndrome with left ventricular regional wall motion abnormality and absence of obstructive coronary artery disease, especially in the setting of a stressful trigger.

Circulating and Tissue Endothelin Immunoreactivity in Advanced Atherosclerosis

BACKGROUND Atherosclerosis is characterized by endothelial injury and the proliferation of arterial smooth-muscle cells. The latter may be a result of the release of growth factors from the vessel wall; such growth factors may include an endothelium-derived vasoconstrictor for peptide with mitogenic properties. We tested the hypothesis that plasma endothelin concentrations are elevated in persons with symptomatic atherosclerosis, independently of age. METHODS We measured plasma endothelin levels in 100 normal subjects and in 40 patients with atherosclerosis predominantly of the following types: aortic and peripheral vascular disease (14 patients), renovascular disease (9 patients) coronary artery disease (9 patients), and carotid disease (8 patients). We also performed immunohistochemical staining for endothelin in the walls of atherosclerotic vessels. RESULTS In the normal subjects, the mean (+/- SD) plasma endothelin concentration was 1.4 +/- 0.2 pmol per liter, with no correlation between age and plasma endothelin concentration (r = 0.13, P = 0.2). In the patients with symptomatic atherosclerosis, the mean plasma endothelin concentration was 3.2 +/- 1.2 pmol per liter (P less than 0.001), and there was a significant correlation between plasma endothelin and the number of sites of disease involvement (r = 0.89, P less than 0.001). In the immunohistochemical studies, endothelin-1-like immunoreactivity was observed in vascular smooth muscle as well as in endothelial cells. CONCLUSIONS Endothelin may be a marker for arterial vascular disease. Whether it participates in the atherogenic process or is merely released from damaged endothelial cells is unclear.

Endothelin in human congestive heart failure

BACKGROUND Although recent investigations report the elevation of plasma endothelin (ET) in congestive heart failure (CHF), it remains unclear if this elevation is that of the biologically active peptide ET-1 or of its precursor big-ET. Furthermore, it is unclear if such elevation is associated with increased myocardial ET and if the molecular form from cardiac tissue is altered ET. Last, it remains to be established whether circulating ET is increased at the earliest stage of CHF in patients with asymptomatic left ventricular dysfunction and correlates with the magnitude of ventricular dysfunction. METHODS AND RESULTS The present study was designed to investigate concentrations and molecular forms of ET in plasma and cardiac tissue in healthy subjects and CHF patients with New York Heart Association (NYHA) class I through IV using cardiac radionuclide angiogram, cardiac myocardial biopsy, radioimmunoassay, gel permeation chromatography (GPC), and immunohistochemical staining (IHCS). Plasma ET was increased only in patients with moderate (NYHA class III) or severe (NYHA class IV) CHF compared with healthy subjects and individuals with asymptomatic (NYHA class I) or mild (NYHA class II) CHF. The elevation of circulating ET in CHF showed a negative correlation with left ventricular ejection fraction and cardiac index and a positive correlation with functional class and left ventricular end-diastolic volume index. GPC demonstrated that immunoreactive plasma ET was ET-1 in healthy subjects and both mature ET-1 and its precursor big-ET in severe CHF patients, with big-ET the predominant molecular form. Cardiac tissue concentrations and IHCS revealed ET presence in healthy atrial and ventricular tissue, which were not different in severe CHF. GPC revealed that the molecular form of cardiac ET was ET-1 in both healthy and CHF hearts. CONCLUSIONS The present study establishes for the first time that the elevation of plasma ET in severe human CHF represents principally elevation of big-ET. Second, ET is present in healthy and failing myocardia, and its activity by both immunohistochemistry and radioimmunoassay is not changed in CHF. Furthermore, the elevated plasma ET is characteristic of severe CHF and not asymptomatic or mild CHF. In addition, the degree of plasma elevation of ET correlates with the magnitude of alterations in cardiac hemodynamics and functional class. The present study confirms and extends previous investigations of ET in human CHF and establishes the evolution of circulating and local cardiac ET in the spectrum of human CHF.

Endothelial function and dysfunction. Part I: Methodological issues for assessment in the different vascular beds: a statement by the Working Group on Endothelin and Endothelial Factors of the European Society of Hypertension.

An enormous number of studies in the last two decades have been devoted to investigating the role of the endothelium in cardiovascular diseases. Nonetheless, the optimal methodology for investigating the multifaceted aspects of endothelial dysfunction is still under debate. Biochemical markers, molecular genetic tests and invasive and non-invasive tools with and without pharmacological and physiological stimuli have been introduced. Furthermore newer pharmacological tools have been proposed. However, the application of these methodologies should fulfil a number of requirements in order to provide conclusive answers in this area of research. Thus, the most relevant methodological issues in the research on endothelial function and dysfunction are summarized in this paper.

The Assessment of Endothelial Function From Research Into Clinical Practice

The discovery of nitric oxide (NO) as a crucial endothelium-derived molecule for vascular relaxation and the recognition of the endothelium as more than a passive interface between blood and the vessel wall led to substantial progress in the field of vascular research.1 Endothelial dysfunction is a pathological condition characterized mainly by an imbalance between substances with vasodilating, antimitogenic, and antithrombogenic properties (endothelium-derived relaxing factors)2 and substances with vasoconstricting, prothrombotic, and proliferative characteristics (endothelium-derived contracting factors).3 Among the most important vasodilator molecules, particularly in muscular arteries, is NO, which also inhibits other key events in the development of atherosclerosis such as platelet adhesion and aggregation, leukocyte adhesion and migration, and smooth muscle cell proliferation. Particularly in the microcirculation, prostacyclin and endothelium-derived hyperpolarization factors (an umbrella term for substances and signals hyperpolarizing vascular myocytes by opening voltage channels4) also play an important role. Generally, loss of NO bioavailability indicates a broadly dysfunctional phenotype across many properties of the endothelium. Thus, the assessment of its vasodilator properties resulting from NO and other molecules may provide information on the integrity and function of the endothelium. Interestingly, most, if not all, cardiovascular risk factors are associated with endothelial dysfunction,5 and risk factor modification leads to improvement in vascular function. Endothelial dysfunction has been detected in the coronary epicardial and resistance vasculature and in peripheral arteries, so endothelial dysfunction can be regarded as a systemic condition.6 Importantly, the process of atherosclerosis begins early in life, and endothelial dysfunction contributes to atherogenesis and precedes the development of morphological vascular changes.7 Over the past 25 years, many methodological approaches have been developed to measure the (patho)physiological function of the endothelium in humans.8 Although the ability to measure endothelial function has boosted clinical research in this field, its use as a …

Statin effects beyond lipid lowering—are they clinically relevant?

Currently, five different statins (simvastatin,pravastatin, lovastatin, fluvastatin, and atorvastatin) are approved for treatment of hypercholesterolemia in humans and two new compounds (rosuvastatin and NK-104) are under investigation.1,2 Despite differences in their pharmacokinetic profiles, all statins have at least onecharacteristic in common: they block the conversion of HMG-CoA to mevalonic acid with consecutive attenuation of the biosynthesis of cholesterol (Fig. 1), which is associated with a reduction in serum total and low-density lipoprotein (LDL) cholesterol of as much as 20–31 and 28–42% during chronic treatment.3 Because of these properties, statins have become the most widely prescribed lipid-lowering drugs in patients with elevatedserum cholesterol levels. Several large trialsdemonstrated that statins are not only safe and well tolerated but also significantly decrease cardiovascular morbidity and mortality in hypercholesterolemic patients in both primary and secondary prevention.4–8 However, the striking benefit achieved with statin treatment in patients with a wide range of cholesterol levels, which cannot be attributed to their cholesterol lowering effect alone, has raised the question about the possible presence of additional effects of statins beyond their impact on serum cholesterol levels. Indeed, in recent years a substantial quantity of data has accumulated showing that statins exert variouseffects on multiple targets, which are independent of their plasma cholesterol lowering properties. Fig. 1 The effect of statins on the mevalonate pathway. Statins inhibit conversion of HMG-CoA to mevalonate by competitive inhibition of the rate limiting enzyme HMG-CoA reductase. Herewith, statins not only inhibit the cellular production of cholesterol but also the biosynthesis of several intermediates of the mevalonate pathway (e.g. farnesylpyrophosphate and geranylgeranylpyrophosphate). These so-called isoprenoids are essential for the posttranslational modification of several proteins involved in important intracellular signaling pathways (e.g. the small GTP-binding proteins Ras and Rho). Many of these so-called pleiotropic effects have been shown to be secondary to the …

Natriuretic peptide system in human heart failure.

BACKGROUND Atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP) are a family of structurally related peptides that participate in the integrated control of renal and cardiovascular function. Previous studies suggest a functional role for these hormonal peptides in cardiorenal regulation in congestive heart failure (CHF). METHODS AND RESULTS The present studies were performed in normal subjects (n = 6) and in patients with mild (New York Heart Association [NYHA] class I to II, n = 20) and severe (NYHA class III to IV, n = 20) CHF by use of radioimmunoassay and immunohistochemical staining (IHCS). Plasma ANP was significantly increased in both mild and severe CHF compared with normal subjects. In contrast, plasma BNP was only moderately increased in the severe CHF group, and plasma CNP concentration was unchanged in CHF compared with normal subjects. Atrial tissue concentrations of the natriuretic peptides did not parallel circulating concentrations. ANP predominated in normal atrial tissue, but BNP predominated in CHF. In ventricular tissue, IHCS staining was present for all three peptides in normal ventricular myocardium and was markedly enhanced in CHF. CONCLUSIONS These studies support a differential regulation of ANP, BNP, and CNP circulating concentrations and tissue activity in human CHF.