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Showing papers in "Circulation in 1995"


Journal ArticleDOI
TL;DR: The histological classification of human atherosclerotic lesions found in the second part of this report led to the earlier definitions of precursor lesions, and the appearance of lesions noted in clinical imaging studies with histological lesion types and corresponding clinical syndromes was attempted.
Abstract: This report is the continuation of two earlier reports that defined human arterial intima and precursors of advanced atherosclerotic lesions in humans. This report describes the characteristic components and pathogenic mechanisms of the various advanced atherosclerotic lesions. These, with the earlier definitions of precursor lesions, led to the histological classification of human atherosclerotic lesions found in the second part of this report. The Committee on Vascular Lesions also attempted to correlate the appearance of lesions noted in clinical imaging studies with histological lesion types and corresponding clinical syndromes. In the histological classification, lesions are designated by Roman numerals, which indicate the usual sequence of lesions progression. The initial (type I) lesion contains enough atherogenic lipoprotein to elicit an increase in macrophages and formation of scattered macrophage foam cells. As in subsequent lesion types, the changes are more marked in locations of arteries with adaptive intimal thickening. (Adaptive thickenings, which are present at constant locations in everyone from birth, do not obstruct the lumen and represent adaptations to local mechanical forces). Type II lesions consist primarily of layers of macrophage foam cells and lipid-laden smooth muscle cells and include lesions grossly designated as fatty streaks. Type III is the intermediate stage between type II and type IV (atheroma, a lesion that is potentially symptom-producing). In addition to the lipid-laden cells of type II, type III lesions contain scattered collections of extracellular lipid droplets and particles that disrupt the coherence of some intimal smooth muscle cells. This extracellular lipid is the immediate precursor of the larger, confluent, and more disruptive core of extracellular lipid that characterizes type IV lesions. Beginning around the fourth decade of life, lesions that usually have a lipid core may also contain thick layers of fibrous connective tissue (type V lesion) and/or fissure, hematoma, and thrombus (type VI lesion). Some type V lesions are largely calcified (type Vb), and some consist mainly of fibrous connective tissue and little or no accumulated lipid or calcium (type Vc).

3,698 citations


Journal ArticleDOI
TL;DR: This review will explore potential mechanisms responsible for the sudden conversion of a stable atherosclerotic plaque to an unstable and life-threatening atherothrombotic lesion—an event known as plaque fissuring, rupture, or disruption.
Abstract: Coronary atherosclerosis is by far the most frequent cause of ischemic heart disease, and plaque disruption with superimposed thrombosis is the main cause of the acute coronary syndromes of unstable angina, myocardial infarction, and sudden death.1 2 3 4 5 Therefore, for event-free survival, the vital question is not why atherosclerosis develops but rather why, after years of indolent growth, it suddenly becomes complicated by life-threatening thrombosis. The composition and vulnerability of plaque rather than its volume or the consequent severity of stenosis produced have emerged as being the most important determinants for the development of the thrombus-mediated acute coronary syndromes; lipid-rich and soft plaques are more dangerous than collagen-rich and hard plaques because they are more unstable and rupture-prone and highly thrombogenic after disruption.6 This review will explore potential mechanisms responsible for the sudden conversion of a stable atherosclerotic plaque to an unstable and life-threatening atherothrombotic lesion—an event known as plaque fissuring, rupture, or disruption.7 8 Atherosclerosis is the result of a complex interaction between blood elements, disturbed flow, and vessel wall abnormality, involving several pathological processes: inflammation, with increased endothelial permeability, endothelial activation, and monocyte recruitment9 10 11 12 13 14 ; growth, with smooth muscle cell (SMC) proliferation, migration, and matrix synthesis15 16 ; degeneration, with lipid accumulation17 18 ; necrosis, possibly related to the cytotoxic effect of oxidized lipid19 ; calcification/ossification, which may represent an active rather than a dystrophic process20 21 ; and thrombosis, with platelet recruitment and fibrin formation.1 22 23 Thrombotic factors may play a role early during atherogenesis, but a flow-limiting thrombus does not develop until mature plaques are present, which is why thrombosis often is classified as a complication rather than a genuine component of atherosclerosis. ### Mature Plaques: Atherosis and Sclerosis As the name atherosclerosis implies, mature …

3,493 citations


Journal ArticleDOI
TL;DR: Artificial maintenance of AF leads to a marked shortening of AERP, a reversion of its physiological rate adaptation, and an increase in rate, inducibility and stability of AF.
Abstract: Background In this study we tested the hypothesis that atrial fibrillation (AF) causes electrophysiological changes of the atrial myocardium which might explain the progressive nature of the arrhythmia. Methods and Results Twelve goats were chronically instrumented with multiple electrodes sutured to the epicardium of both atria. Two to 3 Weeks after implantation, the animals were connected to a fibrillation pacemaker which artificially maintained AF. Whereas during control episodes of AF were short lasting (6±3 seconds), artificial maintenance of AF resulted in a progressive increase in the duration of AF to become sustained (>24 hours) after 7.1±4.8 days (10 of 11 goats). During the first 24 hours of AF the median fibrillation interval shortened from 145±18 to 108±8 ms and the inducibility of AF by a single premature stimulus increased from 24% to 76%. The atrial effective refractory period (AERP) shortened from 146±19 to 95±20 ms (−35%) (S1S1, 400 ms). At high pacing rates the shortening was less (−12%...

3,430 citations


Journal ArticleDOI
TL;DR: In this article, the Coronary Artery Risk Development in (Young) Adults (CARDIA) Study, an epidemiological study of coronary risk factors, 4111 men and women 23 to 35 years of age selected from the general population of four urban centers had technically satisfactory echocardiographic studies during 1987 through 1988.
Abstract: Background Hypertrophic cardiomyopathy (HCM) is a genetically transmitted disease and an important cause of morbidity and sudden cardiac death in young people, including competitive athletes. At present, however, few data exist to estimate the prevalence of this disease in large populations. Methods and Results As part of the Coronary Artery Risk Development in (Young) Adults (CARDIA) Study, an epidemiological study of coronary risk factors, 4111 men and women 23 to 35 years of age selected from the general population of four urban centers had technically satisfactory echocardiographic studies during 1987 through 1988. Probable or definite echocardiographic evidence of HCM was present in 7 subjects (0.17%) on the basis of identification of a hypertrophied, nondilated left ventricle and maximal wall thickness ≥15 mm that were not associated with systemic hypertension. Prevalence in men and women was 0.26:0.09%; in blacks and whites, 0.24:0.10%. Ventricular septal thickness was 15 to 21 mm (mean, 17 mm) in ...

1,918 citations


Journal ArticleDOI
TL;DR: In the latter half of this century, the advent of coronary arteriography permitted definition in the living patient of coronary stenoses due to atherosclerosis, which allowed the development of rational treatment modalities such as coronary artery bypass surgery and percutaneous transluminal coronary angioplasty as discussed by the authors.
Abstract: The acute coronary syndromes, including unstable angina and acute myocardial infarction, currently constitute a major preoccupation of clinical cardiology. This century has witnessed a remarkable evolution in our clinical concepts of these syndromes. Herrick1 described the survival of patients with acute coronary thrombosis early in the century. The introduction of the ECG led to major clinical advances in the definition of acute myocardial infarction during the first half of this century and furnished the basis of modern coronary care. In the latter half of this century, the advent of coronary arteriography permitted definition in the living patient of coronary stenoses due to atherosclerosis. The introduction of this diagnostic technique allowed the development of rational treatment modalities such as coronary artery bypass surgery and, subsequently, percutaneous transluminal coronary angioplasty. Until recently, it seemed that we had achieved a firm understanding of the pathophysiology of human coronary artery disease and had devised appropriate modes of therapy for its major manifestations. Yet, recent clinical data suggest that we still have much to learn about the pathophysiology of the acute coronary syndromes. Bypass surgery and angioplasty aim to restore blood flow to sites beyond hemodynamically significant stenoses in the coronary arteries. These revascularization therapies effectively relieve angina pectoris in many cases (although often not permanently). Quite naturally, the availability of these modalities led the cardiology community to focus on high-grade coronary stenosis, visible by angiography, as the critical issue in coronary heart disease. Much of the basis of contemporary cardiology and cardiac surgery rests on the axiom: the greater the stenosis, the greater the risk of a clinical event such as myocardial infarction or unstable angina pectoris. However, data emerging from clinical and pathological studies over the past decade have occasioned a reassessment of this central dogma of clinical cardiology.2 First, the …

1,879 citations


Journal ArticleDOI
TL;DR: Enzymes associated with HDL may play an important role in protecting against lipid oxidation in the artery wall and may account in part for the inverse relation between HDL and risk for atherosclerotic clinical events.
Abstract: The clinical events resulting from atherosclerosis are directly related to the oxidation of lipids in LDLs that become trapped in the extracellular matrix of the subendothelial space. These oxidized lipids activate an NFκB-like transcription factor and induce the expression of genes containing NFκB binding sites. The protein products of these genes initiate an inflammatory response that initially leads to the development of the fatty streak. The progression of the lesion is associated with the activation of genes that induce arterial calcification, which changes the mechanical characteristics of the artery wall and predisposes to plaque rupture at sites of monocytic infiltration. Plaque rupture exposes the flowing blood to tissue factor in the lesion, and this induces thrombosis, which is the proximate cause of the clinical event. There appear to be potent genetically determined systems for preventing lipid oxidation, inactivating biologically important oxidized lipids, and/or modulating the infl...

1,800 citations


Journal ArticleDOI
TL;DR: No, but not prostacyclin, is essential for flow-mediated dilatation of large human arteries, and this response can be used as a test for the L-arginine/NO pathway in clinical studies.
Abstract: Background Experimental evidence suggests that flow-dependent dilatation of conduit arteries is mediated by nitric oxide (NO) and/or prostacyclin. The present study was designed to assess whether NO or prostacyclin also contributes to flow-dependent dilatation of conduit arteries in humans. Methods and Results Radial artery internal diameter (ID) was measured continuously in 16 healthy volunteers (age, 24±1 years) with a transcutaneous A-mode echo-tracking system coupled to a Doppler device for the measurement of radial blood flow. In 8 subjects, a catheter was inserted into the brachial artery for measurement of arterial pressure and infusion of the NO synthase inhibitor NG-monomethyl-l-arginine (L-NMMA; 8 μmol/min for 7 minutes; infusion rate, 0.8 mL/min). Flow-dependent dilatation was evaluated before and after L-NMMA or aspirin as the response of the radial artery to an acute increase in flow (reactive hyperemia after a 3-minute cuff wrist occlusion). Under control conditions, release of the occlusion...

1,665 citations


Journal ArticleDOI
TL;DR: Depression while in the hospital after an MI is a significant predictor of 18-month post- MI cardiac mortality and significantly improves a risk-stratification model based on traditional post-MI risks, including previous MI, Killip class, and PVCs.
Abstract: Background We previously reported that major depression in patients in the hospital after a myocardial infarction (MI) substantially increases the risk of mortality during the first 6 months. We examined the impact of depression over 18 months and present additional evidence concerning potential mechanisms linking depression and mortality. Methods and Results Two-hundred twenty-two patients responded to a modified version of the National Institute of Mental Health Diagnostic Interview Schedule (DIS) for a major depressive episode at approximately 7 days after MI. The Beck Depression Inventory (BDI), which measures depressive symptomatology, was also completed by 218 of the patients. All patients and/or families were contacted at 18 months to determine survival status. Thirty-five patients met the modified DIS criteria for major in-hospital depression after the MI. Sixty-eight had BDI scores ≥10, indicative of mild to moderate symptoms of depression. There were 21 deaths during the follow-up period, includ...

1,571 citations


Journal ArticleDOI
TL;DR: This histopathologic study confirms an intimate relation between whole heart, coronary artery, and segmental coronary atherosclerotic plaque area and EBCT coronary calcium area but suggests that there is a threshold value for plaque area below which coronary calcium is either absent or not detectable by this methodology.
Abstract: Background Coronary calcium identified by electron-beam computed tomography (EBCT) correlates poorly with luminal atherosclerotic narrowing, but calcium, an intimate part of coronary plaque, may be more directly related to atheromatous plaque area. Methods and Results Thirty-eight coronary arteries from 13 autopsy hearts were dissected, straightened, and scanned with EBCT in 3-mm contiguous increments. Coronary calcium area was defined as one or more pixels with a density >130 Hounsfield units (0.18 mm 2 /pixel). Each artery was divided into corresponding 3-mm segments, representative histological sections were stained, and atherosclerotic plaque area per segment (mm 2 ) was quantified. Coronary artery calcium and coronary artery plaque areas were correlated for the hearts as a whole, for individual coronary arteries, and for individual coronary artery segments. The sums of histological plaque areas versus the sums of calcium areas were highly correlated for each heart and for each coronary artery. However, coronary plaque area was on the order of five times greater than calcium area. Furthermore, minimal diffuse segmental coronary plaque could be present despite the absence of coronary calcium detectable by EBCT. Conclusions This histopathologic study confirms an intimate relation between whole heart, coronary artery, and segmental coronary atherosclerotic plaque area and EBCT coronary calcium area but suggests that there is a threshold value for plaque area below which coronary calcium is either absent or not detectable by this methodology.

1,435 citations


Journal ArticleDOI
TL;DR: The Palmaz-Schatz stent can be safely inserted in coronary arteries without subsequent anticoagulation provided that stent expansion is adequate and there are no other flow-limiting lesions present.
Abstract: Background The placement of stents in coronary arteries has been shown to reduce restenosis in comparison to balloon angioplasty. However, clinical use of intracoronary stents is impeded by the risk of subacute stent thrombosis and complications associated with the anticoagulant regimen. To reduce these complications, the hypothesis that systemic anticoagulation is not necessary when adequate stent expansion is achieved was prospectively evaluated on a consecutive series of patients who received intracoronary stents. Methods and Results From March 1993 to January 1994, 359 patients underwent Palmaz-Schatz coronary stent insertion. After an initial successful angiographic result with Conclusions The Palmaz-Schatz stent can be safely inserted in coronary arteries without subsequent anticoagulation provided that stent expansion is adequate and there are no other flow-limiting lesions present. The use of high-pressure final balloon dilatations and confirmation of adequate stent expansion by intravascular ultrasound provide assurance that anticoagulation therapy can be safely omitted. This technique significantly reduces hospital time and vascular complications and has a low stent thrombosis rate.

1,389 citations


Journal ArticleDOI
TL;DR: In patients with coronary disease, the use of short-acting nifedipine in moderate to high doses causes an increase in total mortality, and other calcium antagonists may have similar adverse effects, in particular those of the dihydropyridine type.
Abstract: Background The purpose of this study was to assess the effect of the dose of nifedipine, a dihydropyridine calcium antagonist, on the increased risk of mortality seen in the randomized secondary-prevention trials and to review the mechanisms by which this adverse effect might occur. Methods and Results We restricted the dose-response meta-analysis to the 16 randomized secondary-prevention trials of nifedipine for which mortality data were available. Recent trials of any calcium antagonist and formulation were also reviewed for information about the possible mechanisms of action that might increase mortality. Overall, the use of nifedipine was associated with a significant adverse effect on total mortality (risk ratio, 1.16, with a 95% CI of 1.01 to 1.33). This summary estimate fails to draw attention to an important dose-response relationship. For daily doses of 30 to 50, 60, and 80 mg, the risk ratios for total mortality were 1.06 (95% CI, 0.89 to 1.27), 1.18 (95% CI, 0.93 to 1.50), and 2.83 (95% CI, 1.35 to 5.93), respectively. In a formal test of dose response, the high doses of nifedipine were significantly associated with increased mortality ( P =.01). While the mechanism of this adverse effect is not known, there are several plausible explanations, including the established proischemic effect, negative inotropic effects, marked hypotension, recently reported prohemorrhagic effects attributed to antiplatelet and vasodilatory actions of calcium antagonists, and possibly proarrhythmic effects. Conclusions In patients with coronary disease, the use of short-acting nifedipine in moderate to high doses causes an increase in total mortality. Other calcium antagonists may have similar adverse effects, in particular those of the dihydropyridine type. Long-term safety data are lacking for most calcium antagonists.

Journal ArticleDOI
TL;DR: Evidence is outlined that the current preoccupation with coronary "luminology" may be misguided and a rational paradigm for future practice and investigation is proposed to achieve the desired clinical end point: promoting survival and long-term freedom from myocardial infarction and the disabling symptoms of coronary heart disease.
Abstract: Nearly 40 years after its invention, the angiogram is still considered by most physicians to be the “gold standard” for defining coronary anatomy. Careful investigations have revealed many deficiencies inherent in this approach. The purpose of this article is to outline the evidence that our current preoccupation with coronary “luminology” may be misguided and to propose a rational paradigm for future practice and investigation. Angiography depicts coronary anatomy from a planar two-dimensional silhouette of the lumen. Angiography is limited in resolution to four or five line pairs per millimeter. Confounding factors include vessel tortuosity, overlap of structures, and the effects of lumen shape. After intervention, a hazy, broadened silhouette may overestimate the actual gain in lumen size. Studies show marked disparity between the apparent severity of lesions and their physiological effects. After myocardial infarction, cardiologists too often do not make an attempt to demonstrate the physiolo...

Journal ArticleDOI
TL;DR: In this article, the authors performed a comprehensive analysis of relations between baseline clinical data and 30-day mortality and developed a multivariable statistical model for risk assessment in candidates for thrombolytic therapy.
Abstract: Background Despite remarkable advances in the treatment of acute myocardial infarction, substantial early patient mortality remains. Appropriate choices among alternative therapies and the use of clinical resources depend on an estimate of the patient's risk. Individual patients reflect a combination of clinical features that influence prognosis, and these factors must be appropriately weighted to produce an accurate assessment of risk. Prior studies to define prognosis either were performed before widespread use of thrombolysis or were limited in sample size or spectrum of data. Using the large population of the GUSTO-I trial, we performed a comprehensive analysis of relations between baseline clinical data and 30-day mortality and developed a multivariable statistical model for risk assessment in candidates for thrombolytic therapy. Methods and Results For the 41 021 patients enrolled in GUSTO-I, a randomized trial of four thrombolytic strategies, relations between clinical descriptors routinely collected at initial presentation, and death within 30 days (which occurred in 7% of the population) were examined with both univariable and multivariable analyses. Variables studied included demographics, history and risk factors, presenting characteristics, and treatment assignment. Risk modeling was performed with logistic multiple regression and validated with bootstrapping techniques. Multivariable analysis identified age as the most significant factor influencing 30-day mortality, with rates of 1.1% in the youngest decile ( 75 (adjusted chi(2)=717, P<.0001). Other factors most significantly associated with increased mortality were lower systolic blood pressure (chi(2)=550, P<.0001), higher Killip class (chi(2)=350, P<.0001), elevated heart rate (chi(2)=275, P<.0001), and anterior infarction (chi(2)=143, P<.0001). Together, these five characteristics contained 90% of the prognostic information in the baseline clinical data. Other significant though less important factors included previous myocardial infarction, height, time to treatment, diabetes, weight, smoking status, type of thrombolytic, previous bypass surgery, hypertension, and prior cerebrovascular disease. Combining prognostic variables through logistic regression, we produced a validated model that stratified patient risk and accurately estimated the likelihood of death. Conclusions The clinical determinants of mortality in patients treated with thrombolytic therapy within 6 hours of symptom onset are multifactorial and the relations complex. Although a few variables contain most of the prognostic information, many others contribute additional independent prognostic information. Through consideration of multiple characteristics, including age, medical history, physiological significance of the infarction, and medical treatment, the prognosis of an individual patient can be accurately estimated.

Journal ArticleDOI
TL;DR: In this article, two-dimensional echocardiography was performed in 11 dogs to assess the effects of rapid atrial pacing on atrial size, which was defined as the ability to induce sustained repetitive atrial responses during programmed electrical stimulation and was assessed by extrastimulus and burst-pacing techniqu...
Abstract: Background Despite the clinical importance of atrial fibrillation (AF), the development of chronic nonvalvular AF models has been difficult. Animal models of sustained AF have been developed primarily in the short-term setting. Recently, models of chronic ventricular myopathy and fibrillation have been developed after several weeks of continuous rapid ventricular pacing. We hypothesized that chronic rapid atrial pacing would lead to atrial myopathy, yielding a reproducible model of sustained AF. Methods and Results Twenty-two halothane-anesthetized mongrel dogs underwent insertion of a transvenous lead at the right atrial appendage that was continuously paced at 400 beats per minute for 6 weeks. Two-dimensional echocardiography was performed in 11 dogs to assess the effects of rapid atrial pacing on atrial size. Atrial vulnerability was defined as the ability to induce sustained repetitive atrial responses during programmed electrical stimulation and was assessed by extrastimulus and burst-pacing techniqu...

Journal ArticleDOI
TL;DR: After multivariable adjustment, LA enlargement remained a significant predictor of stroke in men and death in both sexes and appears to be partially mediated by LV mass.
Abstract: Background The medical literature contains conflicting reports on the association of left atrial (LA) enlargement with risk of stroke. The relation of LA size to risk of stroke and death in the general population remains largely unexplored. Methods and Results Subjects 50 years of age and older from the Framingham Heart Study were studied to assess the relations between echocardiographic LA size and risk of stroke and death. During 8 years of follow-up, 64 of 1371 (4.7%) men and 73 of 1728 (4.2%) women sustained a stroke, and 296 (21.6%) men and 271 (15.7%) women died. Sex-specific Cox proportional-hazards models were adjusted for age, hypertension, diabetes, atrial fibrillation, smoking, ECG left ventricular (LV) hypertrophy, and congestive heart failure or myocardial infarction. After multivariable adjustment, for every 10-mm increase in LA size, the relative risk of stroke was 2.4 in men (95% CI, 1.6 to 3.7) and 1.4 in women (95% CI, 0.9 to 2.1); the relative risk of death was 1.3 in men (95% CI, 1.0 t...

Journal ArticleDOI
TL;DR: After heart surgery in neonates and infants, both low-flow bypass and circulatory arrest perfusion strategies have comparable effects on the nonneurological postoperative course and hemodynamic profile.
Abstract: Background The neurological morbidity associated with prolonged periods of circulatory arrest has led some cardiac surgical teams to promote continuous low-flow cardiopulmonary bypass as an alternative strategy. The nonneurological postoperative effects of both techniques have been previously studied only in a limited fashion. Methods and Results We compared the hemodynamic profile (cardiac index and systemic and pulmonary vascular resistances), intraoperative and postoperative fluid balance, and perioperative course after deep hypothermia and support consisting predominantly of total circulatory arrest or low-flow cardiopulmonary bypass in a randomized, single-center trial. Eligibility criteria included a diagnosis of transposition of the great arteries and a planned arterial switch operation before the age of 3 months. Of the 171 patients, 129 (66 assigned to circulatory arrest and 63 to low-flow bypass) had an intact ventricular septum and 42 (21 assigned to circulatory arrest and 21 to low-flow bypass...

Journal ArticleDOI
TL;DR: The primary ventricular arrhythmia, consisting of isolated polymorphic ventricular extrasystoles followed by salvoes of bidirectional and polymorphic tachycardia susceptible to degeneration into ventricular fibrillation, was reproducibly induced by any form of increasing adrenergic stimulation.
Abstract: Background Primary ventricular tachyarrhythmias are rarely seen in children. Among them, catecholaminergic polymorphic ventricular tachycardia has a poor spontaneous outcome. Its diagnosis is often delayed after the first symptoms, which is unacceptable because treatment with the appropriate β-blocker prevents sudden death. Methods and Results We observed 21 children (mean±SD age, 9.9±4 years) at the time of the diagnosis who had no structural heart disease and a normal QT interval on routine ECG. They were referred for stress- or emotion-induced syncope related to ventricular polymorphic tachyarrhythmias. The arrhythmia, consisting of isolated polymorphic ventricular extrasystoles followed by salvoes of bidirectional and polymorphic tachycardia susceptible to degeneration into ventricular fibrillation, was reproducibly induced by any form of increasing adrenergic stimulation. There was a familial history of syncope or sudden death in 30% of our patients. On receiving therapy with the appropriate β-blocke...

Journal ArticleDOI
TL;DR: In symptomatic men with significant coronary atherosclerosis and normal to moderately elevated serum cholesterol, less progression of coronary atheosclerosis and fewer new cardiovascular events were observed in the group of patients treated with pravastatin than in the placebo group.
Abstract: Background Intensive lowering of serum cholesterol may retard progression of coronary atherosclerosis in selected groups of patients. However, few data are available on the potential benefit of serum cholesterol reduction in the broad range of patients with coronary atherosclerosis and normal to moderately elevated serum cholesterol levels who undergo various forms of treatment. The Regression Growth Evaluation Statin Study (REGRESS) addresses this group of patients. Methods and Results REGRESS is a double-blind, placebo-controlled multicenter study to assess the effects of 2 years of treatment with the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor pravastatin on progression and regression of coronary atherosclerosis in 885 male patients with a serum cholesterol level between 4 and 8 mmol/L (155 and 310 mg/dL) by quantitative coronary arteriography. Primary end points were (1) change in average mean segment diameter per patient and (2) change in average minimum obstruction diameter per patient...

Journal ArticleDOI
TL;DR: A value of FFRmyo of 0.74 reliably discriminates coronary stenosis, whether associated with inducible ischemia or not, and is a useful index to determine the functional significance of an epicardial coronary stenoses and may facilitate clinical decision making in patients with an equivocal coronary stenotic.
Abstract: Background Fractional flow reserve (FFR), defined as the ratio of maximum flow in the presence of a stenosis to normal maximum flow, is a lesion-specific index of stenosis severity that can be calculated by simultaneous measurement of mean arterial, distal coronary, and central venous pressure (P a , P d , and P v , respectively), during pharmacological vasodilation. The aims of this study were to define ranges of FFR values, whether associated with inducible ischemia or not, and to investigate FFR in normal coronary arteries. Methods and Results In 60 patients accepted for percutaneous transluminal coronary angioplasty (PTCA) of single-vessel disease, with a positive exercise test (ET) a was measured by the guiding catheter, P d by an 0.018-in fiber-optic pressure-monitoring wire, and P v by a multipurpose catheter. The ET was repeated after 5 to 7 days, and only if this second ET had reverted to normal was the pre-PTCA value of FFR definitely considered to be associated with inducible ischemia and the post-PTCA value not. Myocardial FFR (FFR myo ) increased from 0.53±0.15 before PTCA to 0.88±0.07 after PTCA. Coronary FFR increased from 0.38±0.19 to 0.83±0.12. In all patients, values of FFR myo definitely associated with ischemia were ≤0.74, whereas all except two values not associated with inducible ischemia exceeded 0.74. Moreover, FFR myo in 18 coronary arteries in 5 normal patients equaled 0.98±0.03. Conclusions A value of FFR myo of 0.74 reliably discriminates coronary stenosis, whether associated with inducible ischemia or not. Therefore, FFR myo is a useful index to determine the functional significance of an epicardial coronary stenosis and may facilitate clinical decision making in patients with an equivocal coronary stenosis.

Journal ArticleDOI
TL;DR: Elevated cardiac ACE activity in subjects who died of noncardiac disorders may result in increased cardiac angiotensin II levels, and this may be a mechanism underlying the reported association between the ACE deletion polymorphism and the increased risk for several cardiovascular disorders.
Abstract: Background An insertion (I)/deletion (D) polymorphism of the angiotensin-converting enzyme (ACE) gene has been associated with differences in the plasma levels of ACE as well as with myocardial infarction, cardiomyopathy, left ventricular hypertrophy, and coronary artery disease. Methods and Results We determined the cardiac ACE activity and the ACE genotype in 71 subjects who died of noncardiac disorders. Cardiac ACE activity was significantly higher (P<.01) in subjects with the ACE DD genotype (12.7±1.9 mU/g wet wt) compared with subjects with the ID (8.7±0.8 mU/g) and the II (9.1±1.0 mU/g) genotypes. This difference was independent of sex, age, and the time required for tissue collection. Conclusions Cardiac ACE activity is highest in subjects with the DD genotype. Elevated cardiac ACE activity in these subjects may result in increased cardiac angiotensin II levels, and this may be a mechanism underlying the reported association between the ACE deletion polymorphism and the increased risk for several c...

Journal ArticleDOI
TL;DR: This is the first study to demonstrate differential responses of LQTS patients to interventions targeted to their specific genetic defect, and it is suggested that LQT3 patients may be more likely to benefit from Na+ channel blockers and from cardiac pacing because they would be at higher risk of arrhythmia at slow heart rates.
Abstract: Background The genes for the long QT syndrome (LQTS) linked to chromosomes 3 (LQT3) and 7 (LQT2) were identified as SCN5A, the cardiac Na+ channel gene, and as HERG, a K+ channel gene. These findings opened the possibility of attempting gene-specific control of ventricular repolarization. We tested the hypothesis that the QT interval would shorten more in LQT3 than in LQT2 patients in response to mexiletine and also in response to increases in heart rate. Methods and Results Fifteen LQTS patients were studied. Six LQT3 and 7 LQT2 patients were treated with mexiletine, and its effects on QT and QTc were measured. Mexiletine significantly shortened the QT interval among LQT3 patients (QTc from 535±32 to 445±31 ms, P<.005) but not among LQT2 patients (QTc from 530±79 to 503±60 ms, P=NS). LQT3 patients (n=7) shortened their QT interval in response to increases in heart rate much more than LQT2 patients (n=4) and also more than 18 healthy control subjects (9.45±3.3 versus 3.95±1.97 and 2.83±1.33, P<.05; data e...

Journal ArticleDOI
TL;DR: Valve repair significantly improves postoperative outcome in patients with mitral regurgitation and should be the preferred mode of surgical correction.
Abstract: Background Mitral valve repair has been suggested as providing a better postoperative outcome than valve replacement for mitral regurgitation, but this impression has been obscured by differences in baseline characteristics and has not been confirmed in multivariate analyses. Methods and Results The outcomes in 195 patients with valve repair and 214 with replacement for organic mitral regurgitation were compared using multivariate analysis. All patients had preoperative echocardiographic assessment of left ventricular function. Before surgery, patients with valve repair were less symptomatic than those with replacement (42% in New York Heart Association functional class I or II versus 24%, respectively; P=.001), had less atrial fibrillation (41% versus 53%; P=.017), and had a better ejection fraction (63±9% versus 60±12%, P=.016). After valve repair, compared with valve replacement, overall survival at 10 years was 68±6% versus 52±4% (P=.0004), overall operative mortality was 2.6% versus 10.3% (P=.002), o...

Journal ArticleDOI
TL;DR: HCM is a heterogeneous disease genotypic, phenotypically, pathophysiologically, clinically, and therapeutically and in decisions on the management of these patients, it is important to recognize this heterogeneity and to direct therapy at the predominant abnormalities.
Abstract: HCM is a heterogeneous disease genotypically, phenotypically, pathophysiologically, clinically, and therapeutically. In decisions on the management of these patients, it is important to recognize this heterogeneity and to direct therapy at the predominant abnormalities.

Journal Article
TL;DR: The hypothesis that increased macrophage density and/or activation in the atherosclerotic plaque may induce collagen breakdown in the fibrous cap by secreting MMPs and possibly other proteases, thus contributing to vulnerability to plaque rupture is supported.
Abstract: Background Rupture of the fibrous cap of the atherosclerotic plaque is a key event that predisposes to coronary thrombosis, leading to acute coronary syndromes. Recent studies have shown that the fibrous caps of vulnerable and ruptured atherosclerotic plaques have reduced collagen and glycosaminoglycan content in association with an increased macrophage density and a reduced smooth muscle cell density. Since collagen breakdown in the fibrous caps may contribute to a thinning and weakening of the cap, increasing its vulnerability to rupture, we tested the hypothesis that monocyte-derived macrophages, by producing matrix-degrading metalloproteinases (MMPs), could induce collagen breakdown in human atherosclerotic fibrous caps. Methods and Results Monocytes were isolated from human blood by Ficoll-Paque density gradient and allowed to grow in cell culture until phenotypic and staining characteristics indicated transformation into macrophages (4 to 7 days). Fibrous caps were dissected from human aortic or carotid plaques and incubated for 48 hours with macrophages in serum-free medium without (n=21) and with (n=10) an MMP inhibitor or with cell- and serum-free medium only (n=9). Hydroxyproline released in the culture medium was measured by a spectrophotometric method and used as evidence of collagen breakdown in the fibrous caps. Immunocytochemistry with specific monoclonal antibodies was used to identify expression of MMP-1 (interstitial collagenase) and MMP-2 (72-kD gelatinase) in cell culture, and zymography was used to detect MMP activity in the culture supernatant. The amount of hydroxyproline released was significantly greater when fibrous caps were incubated with macrophages than when incubated with cell-free medium (0.42±0.16 μg-mL -1 .mg -1 versus 0.02±0.03 μg mL -1 .mg -1 of tissue ; P<.04 by Mann-Whitney test). There was no hydroxyproline release when fibrous caps were incubated with macrophages in the presence of an MMP inhibitor. Immunocytochemistry demonstrated MMP-1 and MMP-2 expression by macrophages between days 4 and 7, and zymography confirmed the presence of MMP-2 activity in the supernatant. Conclusions In this study, human monocyte-derived macrophages were shown to induce collagen breakdown in fibrous caps of human atherosclerotic plaques associated with cellular expression and zymographic evidence of MMP activity ; no evidence of collagen breakdown was found in the presence of an MMP inhibitor. These findings support the hypothesis that increased macrophage density and/or activation in the atherosclerotic plaque may induce collagen breakdown in the fibrous cap by secreting MMPs and possibly other proteases, thus contributing to vulnerability to plaque rupture. (Circulation. 1995 ;92 :1565-1569.)

Journal ArticleDOI
TL;DR: Chronic right ventricular volume overload after tetralogy of Fallot repair is related to diastolic function and correlated with QRS prolongation and the risk of symptomatic arrhythmia is high when markedright ventricular enlargement and QRS prolongedation develop.
Abstract: Background Life-threatening ventricular arrhythmia and sudden death remain serious late complications after tetralogy of Fallot repair. Nevertheless, there remains no clear way of predicting which patients are at risk. Methods and Results The study population included a total of 178 adult survivors (mean follow-up, 21.4 years) of tetralogy of Fallot repair who were currently attending our clinic. Mechanoelectrical relations were sought in 41 of the patients (mean follow-up, 23.6 years) who were operated on by one surgeon and who were prospectively studied with a 12-lead ECG, chest radiography, and two-dimensional and Doppler echocardiography. Nine patients (mean follow-up, 17 years) from the total group of 178 were identified as having had sustained ventricular tachycardia (8 with near-miss sudden death), and their ECGs, Holter monitor readings, electrophysiological studies, and chest radiographs were reviewed. The case notes of an additional 4 patients with postoperative sudden cardiac death also were av...

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TL;DR: There is a blunted response to acetylcholine with advancing age in both normotensive control subjects and essential hypertensive patients, suggesting that aging is associated with reduced endothelium-dependent vasodilation in humans.
Abstract: Background Experimental data from normotensive and hypertensive animals indicate that aging is associated with impaired endothelium-dependent relaxations to acetylcholine, and this possibility appears to be confirmed in the human coronary artery. In the present study, we evaluated the effect of age on endothelial responsiveness in the forearm vessels of either normotensive control subjects or essential hypertensive patients. Methods and Results Within the normotensive or hypertensive group (n=53 and n=57, respectively), subjects were selected with similar blood pressure, plasma cholesterol, and glucose values, and hypercholesterolemic subjects, diabetics, and smokers were excluded. We evaluated forearm blood flow (by strain-gauge plethysmography) modifications induced by intrabrachial acetylcholine (0.15, 0.45, 1.5, 4.5, and 15 μg/100 mL per minute), an endothelium-dependent vasodilator, and sodium nitroprusside (1, 2, and 4 μg/100 mL per minute), an endothelium-independent vasodilator. Acetylcholine caused a dose-dependent vasodilation that was significantly ( P <.01) lower in essential hypertensive patients than in normotensive control subjects. However, a significant negative correlation was observed between acetylcholine-induced vasodilation and patient age in both normotensive ( r =−.86, P <.001) and hypertensive ( r =−.85, P <.001) patients. In contrast, vasodilation to sodium nitroprusside was similar in normotensive control subjects and essential hypertensive patients with a poorer inverse correlation with patient age (normotensive control subjects, r =−.37; hypertensive patients, r =−.36) compared with acetylcholine. Conclusions The present data indicate that there is a blunted response to acetylcholine with advancing age in both normotensive control subjects and essential hypertensive patients, suggesting that aging is associated with reduced endothelium-dependent vasodilation in humans.

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TL;DR: A task force of the American College of Cardiology and the American Heart Association shall develop guidelines relative to the role of new therapeutic approaches and of specific noninvasive and invasive procedures in the diagnosis and management of cardiovascular disease.
Abstract: It is becoming more apparent each day that despite a strong national commitment to excellence in health care, the resources and personnel are finite. It is, therefore, appropriate that the medical profession examine the impact of developing technology and new therapeutic modalities on the practice of cardiology. Such analysis, carefully conducted, could potentially have an impact on the cost of medical care without diminishing the effectiveness of that care. To this end, the American College of Cardiology and the American Heart Association in 1980 established a Task Force on Assessment of Diagnostic and Therapeutic Cardiovascular Procedures (now the ACC/AHA Task Force on Practice Guidelines) with the following charge: The task force of the American College of Cardiology and the American Heart Association shall develop guidelines relative to the role of new therapeutic approaches and of specific noninvasive and invasive procedures in the diagnosis and management of cardiovascular disease. The task force shall address, when appropriate, the contribution, uniqueness, sensitivity, specificity, indications, contraindications and cost-effectiveness of such diagnostic procedures and therapeutic modalities. The task force shall emphasize the role and values of the developed guidelines as an educational resource. The task force shall include a chair and eight members, four representatives from the American Heart Association and four representatives from the American College of Cardiology. The task force may select ad hoc members as needed upon the approval of the presidents of both organizations. Recommendations of the Task Force are forwarded to the President of each organization. The members of the task force are Melvin D. Cheitlin, MD, Kim A. Eagle, MD, Timothy J. Gardner, MD, Arthur Garson, Jr, MD, MPH, Raymond J. Gibbons, MD, Richard P. Lewis, MD, Robert A. O’Rourke, MD, Thomas J. Ryan, MD, and James L. Ritchie, MD, Chair. The Committee to Develop Guidelines on the Evaluation …

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TL;DR: The findings of the present study suggest that apoptosis may modulate the cellularity of lesions that produce human vascular obstruction, particularly those with evidence of more extensive proliferative activity.
Abstract: Background Apoptosis has been recognized in normal, including rapidly proliferating, cell populations and is inferred to be potentially responsible for the maintenance of stable cell numbers in tissues with various degrees of proliferative activity. Previous studies performed in rats indicated that despite the persistence of a relatively high level of injury-induced proliferative activity, total arterial smooth muscle content at 12 weeks remained unchanged from that measured at 2 weeks, suggesting that accrual of vascular smooth muscle cells is mitigated by cell death. The extent to which apoptosis may be observed in human atherosclerosis and/or restenosis, however, has not been previously established. Methods and Results We performed immunohistochemical studies on 56 specimens retrieved from patients undergoing directional atherectomy for primary atherosclerotic lesions or recurrent arterial narrowing after percutaneous revascularization (restenosis). Immunohistochemical staining disclosed evidence of apoptosis in 35 (63%) of the 56 specimens studied. When present, immunohistochemical evidence of apoptosis was typically limited to <2% of cells in the specimen. The finding of apoptosis, however, was not distributed equally among four groups of specimens studied. Specimens retrieved from patients with restenosis were more frequently observed to contain foci of apoptosis than specimens retrieved from patients with primary atherosclerotic lesions. Among 14 peripheral arterial specimens from patients with restenosis, 13 (93%) contained foci of apoptosis; in contrast, apoptosis was observed in only 6 (43%) of 14 peripheral specimens from patients with primary lesions ( P =.0046). Among coronary arterial specimens, apoptosis was observed in 12 (86%) of 14 specimens from patients with restenosis versus 6 (29%) of 14 specimens from patients with primary obstructions ( P <.0075). Conclusions Apoptosis is a feature of human vascular pathology, including restenotic lesions and, to a lesser extent, primary atherosclerotic lesions. The findings of the present study suggest that apoptosis may modulate the cellularity of lesions that produce human vascular obstruction, particularly those with evidence of more extensive proliferative activity.

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TL;DR: In this article, the authors found that emotionally stressful events, and more specifically, anger, immediately precede and appear to trigger the onset of acute myocardial infarction.
Abstract: Background Many anecdotes and several uncontrolled case series have suggested that emotionally stressful events, and more specifically, anger, immediately precede and appear to trigger the onset of acute myocardial infarction. However, controlled studies to determine the relative risk of myocardial infarction after episodes of anger have not been reported. Methods and Results We interviewed 1623 patients (501 women) an average of 4 days after myocardial infarction. The interview identified the time, place, and quality of myocardial infarction pain and other symptoms, the estimated usual frequency of anger during the previous year, and the intensity and timing of anger and other potentially triggering factors during the 26 hours before the onset of myocardial infarction. Anger was assessed by the onset anger scale, a single-item, seven-level, self-report scale, and the state anger subscale of the State-Trait Personality Inventory. Occurrence of anger in the 2 hours preceding the onset of myocardial infarct...

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TL;DR: Combined administration of VEGF and bFGF stimulates significantly greater and more rapid augmentation of collateral circulation, resulting in superior hemodynamic improvement compared with either V EGF or bF GF alone.
Abstract: Background Recent studies have suggested that vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) may have synergistic effects on the induction of angiogenesis in vitro. Therefore, we investigated the hypothesis that the simultaneous administration of VEGF and bFGF, each having been previously shown to independently enhance collateral development in an animal model of hind limb ischemia, could have a synergistic effect in vivo. Methods and Results Ten days after surgical induction of unilateral hind limb ischemia, New Zealand White rabbits were randomized to receive either VEGF 500 μg alone (n=6), bFGF 10 μg alone (n=7), VEGF 500 μg, immediately followed by 10 μg bFGF (n=7), or vehicle only (control animals, n=8) in each case administered intra-arterially via a catheter in the internal iliac artery of the ischemic limb. BP ratio (BPR, ischemic/healthy limb) at day 10 for the VEGF+bFGF group was 0.82±0.01, much superior (P<.0005) to that of either the VEGF group (0.52±0.02) ...