bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of intensive lipid-lowering therapy on the coronary arteries of asymptomatic subjects with elevated apolipoprotein B.
Authors: Zhao X Q , Brown B G , Hillger L , Sacco D , Bisson B , Fisher L , Albers J J
Published: June 2012

BACKGROUND

Do the benefits of intensive lipid-lowering therapy seen in symptomatic patients extend to high-risk subjects who have never had symptoms?

METHODS AND RESULTS

Of 120 men completing the FATS trial, 91 were symptomatic and 29 asymptomatic. All had apolipoprotein B > or = 125 mg/dL, a positive family history, and coronary atherosclerosis. All were counseled in diet and randomized to intensive therapy: colestipol 10 g TID plus either niacin 1 g QID or lovastatin 20 mg BID or to conventional therapy: placebos, or colestipol if low-density lipoprotein cholesterol was elevated. End points included quantitative arteriographic disease change and clinical events over a 2.5-year interval. At baseline, symptomatic and asymptomatic patients had comparable risk profiles, but proximal stenosis severity averaged 36% for symptomatic and 23% for asymptomatic patients (P < .001). Among the 91 symptomatic patients, those in the intensive group experienced definite (> or = 10%S) proximal lesion progression less frequently than conventional (24% of intensive versus 48% of conventional) and definite regression more frequently (36% of intensive versus 15% of conventional) (P = .009). Similarly, among the 29 asymptomatic patients, 19% of intensive versus 38% of conventional had progression and 31% of intensive versus 0% of conventional, regression (P = .04). Ischemia on baseline exercise tolerance testing was associated with significantly greater proximal disease progression among the asymptomatic patients. Clinical cardiovascular events (death, infarction, or revascularization) occurred in 10 of 38 symptomatic patients originally assigned to conventional therapy, compared with 5 of 76 symptomatic patients assigned to intensive (P < .01); no asymptomatic patient had an event.

CONCLUSIONS

Asymptomatic subjects with this high-risk profile have less coronary disease at baseline than comparable symptomatic patients, and they have an excellent short-term clinical prognosis. However, asymptomatic subjects are indistinguishable from symptomatic patients in terms of their arterial disease progression with conventional therapy and their regression with intensive. These findings may justify an active treatment strategy in such subjects, particularly those with provokable ischemia.
Alcohol consumption and ultrasonographically assessed carotid artery wall thickness and distensibility. The Atherosclerosis Risk in Communities (ARIC) Study Investigators.
Authors: Demirovic J , Nabulsi A , Folsom A R , Carpenter M A , Szklo M , Sorlie P D , Barnes R W
Published: June 2012

BACKGROUND

Although much has been written in recent years about the relation between alcohol and atherosclerotic disease, controversy exists as to whether and how alcohol exerts an effect on atherosclerosis in different sites.

METHODS AND RESULTS

We tested the hypothesis that alcohol consumption is associated inversely with carotid atherosclerosis in a population sample of 45- to 64-year-old men and women who participated in the Atherosclerosis Risk in Communities (ARIC) Study and were free of cardiovascular disease at a baseline examination in 1987 to 1989. B-mode ultrasonography was used to determine carotid artery intimal-medial wall thickness and distensibility as indices of the degree of atherosclerosis. The level of alcohol consumption in the ARIC sample was generally low. Age-adjusted mean values of alcohol consumed (grams per week) were 72.0 for white and 74.3 for nonwhite men and 24.8 for white and 11.2 for nonwhite women. After adjustments for age, artery depth, education, body mass index, sport index, cigarette-years of smoking, low-density lipoprotein cholesterol, and diabetes mellitus, there was no significant cross-sectional association of reported current alcohol intake with either carotid artery wall thickness (among white and nonwhite men and nonwhite women) or distensibility (in any of the four sex-race groups). Among white women, the adjusted mean value of carotid artery wall thickness tended to be higher in light to moderate drinkers than in never or rare drinkers, but the difference across drinking status categories was of borderline statistical significance (P = .04) and may be of little biological importance.

CONCLUSIONS

The ARIC Study found no material cross-sectional association between current alcohol intake and carotid atherosclerosis but provides an opportunity in the future to study atherosclerosis progression and incident events in relation to alcohol consumption in a large population sample of men and women.
Effects of different training intensities on 24-hour blood pressure in hypertensive subjects.
Authors: Marceau M , Kouamé N , Lacourcière Y , Cléroux J
Published: June 2012

BACKGROUND

It is generally accepted that physical training decreases blood pressure in hypertensive subjects, but the importance of training intensity has not been established. This study compared the effects of endurance training at different intensities on ambulatory blood pressure and on blood pressure load (percentage of readings above 140/90 and 120/80 mm Hg during the waking and sleeping periods, respectively).

METHODS AND RESULTS

Previously sedentary subjects with mild to moderate hypertension were evaluated in a crossover fashion according to a Latin square after a sedentary control period and after training at low and at moderate intensity corresponding to 50% and 70% of maximal oxygen uptake, respectively. Each period lasted 10 weeks. After training at moderate intensity, a higher maximal oxygen uptake was found compared with sedentary values but not after training at low intensity. Both training intensities exerted a similar antihypertensive effect of about 5 mm Hg for systolic and diastolic 24-hour blood pressures. However, training at low intensity reduced blood pressure exclusively during the walking hours, whereas training at a moderate intensity reduced blood pressure only during the evening and sleeping hours. Waking blood pressure load decreased from 66% to 49% after training at low intensity, whereas sleeping blood pressure load decreased from 61% to 34% after training at moderate intensity (both P < .05).

CONCLUSIONS

Low- and moderate-intensity training produce similar 24-hour blood pressure reductions, but each training intensity may interfere with different pathogenic effects associated with different blood pressure profiles.
Electrical and mechanical alternans in canine myocardium in vivo. Dependence on intracellular calcium cycling.
Authors: Hirayama Y , Saitoh H , Atarashi H , Hayakawa H
Published: June 2012

BACKGROUND

Electrical and mechanical alternans are thought to result from a common cellular mechanism. To confirm this phenomenon in vivo and extend our understanding, we investigated the effects of temperature, verapamil, and caffeine on alternans in intact beating hearts.

METHODS AND RESULTS

We recorded surface ECG, monophasic action potential (MAP) using suction electrodes, and left ventricular pressure (LVP). Alternans of MAP configurations and of LVP were evaluated in 20 dogs. MAPs were recorded from the apex, base, and midportion of the left ventricle with LVP. The hearts were driven from the left ventricular apex at a basic cycle length of 1000 milliseconds, and alternans was induced with an abrupt shortening of the cycle length to 400 milliseconds. MAPD30/100, the ratio between the MAP durations (MAPD) at 30% and 100% repolarization levels, was measured as an index of MAP configuration. The magnitude of MAP or LVP alternans was defined as the difference in MAPD30/100 or in LVP between the fifth and sixth paced beats. The magnitude of MAP alternans differed by recording site but correlated with activation time. Lowering the temperature increased the magnitude. MAP alternans was always associated with LVP alternans under control conditions. Verapamil significantly attenuated the magnitude of MAP alternans but did not change that of LVP alternans. Caffeine attenuated the magnitude of both MAP and LVP alternans. T wave alternans was suppressed by verapamil or caffeine.

CONCLUSIONS

Activation time is one of the factors modifying electrical alternans. Delayed intracellular Ca2+ cycling plays a role in the concomitant occurrence of electrical and mechanical alternans.
Differences in the electrophysiological response of canine ventricular epicardium and endocardium to ischemia. Role of the transient outward current.
Authors: Lukas A , Antzelevitch C
Published: June 2012

BACKGROUND

Acute ischemia is known to produce more severe electrophysiological disturbances in canine ventricular epicardium than endocardium, although the mechanism for the differential sensitivity is still unresolved. Recent studies have demonstrated the presence of a prominent transient outward current (Ito) in ventricular epicardium but not endocardium. The present study was designed to test the hypothesis that the differential sensitivity of these two tissues to ischemia results, at least in part, from a more prominent Ito in epicardium than in endocardium.

METHODS AND RESULTS

Isolated canine ventricular epicardial and endocardial tissues and myocytes were studied by standard microelectrode techniques. Simulated ischemia (hyperkalemia, hypoxia, and acidosis) abolished the action potential plateau and caused a 50% to 60% shortening of action potential duration in epicardium but only a 10% to 20% shortening in endocardium. 4-Aminopyridine, an Ito inhibitor, restored the plateau in epicardium and reduced the dispersion of action potential duration between epicardium and endocardium. Stimulation protocols that minimized the contribution of Ito, such as acceleration of the stimulation rate or introduction of early premature beats, produced a paradoxical prolongation of the epicardial response caused by restoration of the action potential dome. Thus, ischemia-induced dispersion of repolarization was greatly diminished at rapid rates and after premature beats. Similar results were obtained in tissues and myocytes obtained from the same myocardial layers, suggesting that the differential sensitivities of epicardium and endocardium to ischemia are largely a result of inherent differences in cellular properties.

CONCLUSIONS

Our data suggest that the presence of a prominent Ito in epicardium but not endocardium contributes importantly to the selective electrical depression of epicardium by simulated ischemia. The repolarizing influence of Ito serves to amplify the ischemia-induced changes in inward (ICa and INa) and outward (calcium-activated) currents. By facilitating loss of the dome in epicardium, Ito contributes to the development of a marked dispersion of repolarization between normal and ischemic epicardium and between epicardium and endocardium, thereby providing the electrophysiological substrate for the genesis of reentrant arrhythmias.
Medical advances in the treatment of congestive heart failure.
Authors: Armstrong P W , Moe G W
Published: June 2012

The increased incidence and prevalence of congestive heart failure place a high priority on novel treatment strategies. Left ventricular ejection fraction remains the single most valuable measurement providing both diagnostic and prognostic insights. The most systematic approach to heart failure involves an objective assessment of functional disability, to include exercise tests such as a 6-minute walk under standardized conditions. Left ventricular dysfunction incites a host of neurohumoral compensations that are of fundamental importance in the heart failure syndrome expression. Both vasoconstrictor and vasodilator neurohormones are stimulated and provide new therapeutic opportunities. The therapeutic approach to heart failure begins with a strong emphasis on prevention, patient education, and self-participation in therapy with respect to both its monitoring and adjustment. Diuretics remain a mainstay of therapy but, in the face of severe heart failure, may become ineffectual, requiring constant infusion of loop-active diuretics, combination diuretics, or diuretics in association with concomitant low-dose dopamine infusion. Vasodilator therapy has been an important advance: combination hydralazine and nitrate therapy was initially shown to be efficacious in improving survival, and more recently, angiotensin-converting enzyme (ACE) inhibitors, in the form of enalapril, have shown incremental benefit on survival over this combination. Interestingly, there is now evidence from both SOLVD and SAVE to demonstrate an unexpected and, as yet, unexplained reduction in the frequency of both unstable angina and myocardial infarction. Although, on balance, the weight of evidence concerning the long-term efficacy of inotropic agents has been disappointing, especially as it relates to their unfavorable effects on survival, recent information on vesnarinone, an agent with a complex and diversified mechanism of action, suggests that with appropriate doses, improved symptoms and survival are possible. A substantial amount of new information from randomized placebo-controlled trials attests to the symptomatic relief, hemodynamic improvement, and gain in exercise performance achieved by digoxin. A long-term survival study is ongoing to assess its effects on mortality. beta-Blockers, especially metoprolol, appear beneficial in some patients with heart failure, possibly related to their reduction in sympathetic nervous activity and restoration of beta-receptor population, with resultant improved contractile performance, enhanced myocardial relaxation, and overall increase in cardiac efficiency. Based on available evidence, the best contemporary approach to treatment involves the use of ACE inhibitors coupled with diuretic therapy, either continuous or intermittent, to relieve central or peripheral congestion. The addition of digoxin or a hydralazine nitrate combination is a logical next step, with commencement of low-dose beta-blocker a reasonable option.(ABSTRACT TRUNCATED AT 400 WORDS)
Assessment of the immediate effects of cardiopulmonary bypass on left ventricular performance by on-line pressure-area relations.
Authors: Gorcsan J , Gasior T A , Mandarino W A , Deneault L G , Hattler B G , Pinsky M R
Published: June 2012

BACKGROUND

Pressure-volume relations have been established as useful measures of left ventricular (LV) performance. Application of these methods to the intraoperative setting have been limited because of difficulties acquiring LV volume data. Transesophageal echocardiographic automated border detection can measure LV cross-sectional area as an index of volume, which can be coupled with pressure data to construct pressure-area loops on-line. The purpose of this study was to evaluate intraoperative LV performance in patients undergoing coronary bypass surgery before and immediately after cardiopulmonary bypass using on-line pressure-area relations.

METHODS AND RESULTS

Studies were attempted in 13 consecutive patients. Simultaneous measures of LV cross-sectional area, LV pressure, and electromagnetic flow probe-derived aortic flow recorded on a computer work station interfaced with the ultrasound system. Pressure-area loops were compared with simultaneous pressure-volume loops constructed from pressure and flow data during inferior vena caval occlusions before and after bypass. Pressure-volume calculations (end-systolic elastance, maximal elastance, and preload-recruitable stroke work) were then applied to pressure-area loops with area substituted for volume data. Changes in stroke force from pressure-area loops were closely correlated with changes in estimates of stroke work from pressure-volume loops for individual patients before bypass (r = .99 +/- .03, SEE = 5 +/- 2%, n = 10) and after bypass (r = .96 +/- .05, SEE = 5 +/- 2%, n = 9). Pressure-area estimates of end-systolic elastance, maximal elastance, and preload-recruitable stroke force decreased significantly from before to after cardiopulmonary bypass in the 7 patients with paired data sets. Load-dependent measures of LV function (stroke volume, cardiac output, and fractional area change) were unchanged after surgery in these same patients.

CONCLUSIONS

Intraoperative pressure-area loops may be acquired and displayed on-line using transesophageal echocardiographic automated border detection and readily analyzed in a manner similar to pressure-volume loops. LV performance was depressed immediately after cardiopulmonary bypass compared with before. On-line pressure-area relations may be clinically useful to assess LV performance in patients undergoing cardiac surgery in whom load and contractility may be expected to vary rapidly.
Serial echocardiographic assessment of left ventricular geometry and function after large myocardial infarction in the rat.
Authors: Litwin S E , Katz S E , Morgan J P , Douglas P S
Published: June 2012

BACKGROUND

The development of heart failure after acute myocardial infarction (MI) may be related to alterations of left ventricular (LV) structure and function. Pathological LV remodeling may exacerbate systolic and diastolic dysfunction because increased cavity dimensions tend to increase LV wall stress. Unfortunately, many complicating factors have made it difficult to clearly define the time course of LV remodeling after myocardial infarction in patients, and the contribution of structural changes to altered function has not been fully explored.

METHODS AND RESULTS

To determine the type, magnitude, and time course of changes in LV geometry and function, we performed transthoracic Doppler echocardiographic examinations in rats before and 1 and 6 weeks after transmural MI induced by coronary ligation. LV internal diastolic dimension was greater in infarcted than in sham-operated rats at 1 and 6 weeks after MI (9.4 +/- 0.6 versus 8.0 +/- 0.5 and 10.1 +/- 0.9 versus 8.5 +/- 0.9 mm, respectively; P < .05 compared with sham-operated rats). There was significant thinning of the infarcted anterior wall at 1 and 6 weeks (0.99 +/- 0.2 versus 1.33 +/- 0.19 and 0.96 +/- 0.22 versus 1.51 +/- 0.18 mm, P < .05), while the thickness of the noninfarcted posterior wall increased but was not different from normal growth in sham-operated rats. Six weeks after surgery, fractional shortening was impaired (11 +/- 5% versus 35 +/- 5%, P < .05), and systolic thickening of the noninfarcted posterior wall was depressed (38 +/- 9% versus 67 +/- 18%, P < .05) in infarcted rats compared with shams. These changes in structure and systolic function were accompanied by progressive alterations in LV diastolic filling. Peak early filling velocity increased at 1 and 6 weeks in MI rats (91 +/- 9 versus 79 +/- 9 and 100 +/- 14 versus 74 +/- 11 cm/s, P < .05), and the deceleration rate of the early filling wave was more rapid in rats with MI (21.6 +/- 5.0 versus 15.6 +/- 3.1 and 26.1 +/- 9.8 versus 11.2 +/- 2.7 m/s2, P < .05). Late filling velocity was decreased (16 +/- 15 versus 33 +/- 7 and 15 +/- 18 versus 34 +/- 5 cm/s, P < .05), resulting in a marked increase in the ratio of early to late filling. The peak velocity and the velocity-time integral of LV outflow did not change after MI.

CONCLUSIONS

Postinfarction LV remodeling in the rat is characterized by progressive cavity dilatation, inadequate hypertrophy of the surviving myocardium, the gradual development of regional contractile dysfunction in noninfarcted segments, and marked abnormalities of diastolic filling. These changes can be tracked longitudinally with transthoracic echocardiography.
Effect of calcitonin gene-related peptide on coronary microvessels and its role in acute myocardial ischemia.
Authors: Sekiguchi N , Kanatsuka H , Sato K , Wang Y , Akai K , Komaru T , Takishima T
Published: June 2012

BACKGROUND

Calcitonin gene-related peptide (CGRP) is a potent dilator of epicardial conduit vessels and is released during myocardial ischemia in humans. However, the effect of CGRP on coronary arterial microvessels is still unclear, and it is unknown if CGRP modulates the tone of coronary arterial microvessels during acute myocardial ischemia.

METHODS AND RESULTS

Epimyocardial microvessels were observed through a microscope equipped with a floating objective system in anesthetized open-chest dogs. Heart rate and aortic pressure were maintained at control levels. Flow velocity of the left anterior descending coronary artery (LAD) was measured with a suction-cup Doppler probe. When CGRP was cumulatively infused into the LAD (0.05, 0.5, 5.0, and 50 pmol/kg per minute) or superfused (0.03, 0.3, 3.0, and 30 nmol/L) over the left ventricular surface, arterial control microvessels > 100 microns in diameter dilated dose dependently at dosages of 0.5 to 50 pmol/kg per minute (infused) or 0.3 to 30 nmol/L (superfused), but those < 100 microns dilated only at the highest dose, and those > 100 microns had greater dilation in both groups. Only the highest dose of CGRP (infused) significantly increased coronary flow. The superfusion of CGRP(8-37) (CGRP receptor antagonist, 300 nmol/L) did not affect the control diameters of coronary arterial microvessels but completely abolished CGRP-induced vasodilation at the same doses (infused and superfused). However, 300 nmol/L of CGRP(8-37) did not affect the response of coronary arterial microvessels to the LAD occlusion in any size.

CONCLUSIONS

CGRP preferentially dilates the coronary arterial microvessels > 100 microns in diameter but has only a small effect on those < 100 microns. Endogenous CGRP does not modulate the tone of coronary arterial microvessels during acute myocardial ischemia in beating canine hearts.
Renin is not synthesized by cardiac and extrarenal vascular tissues. A review of experimental evidence.
Authors: von Lutterotti N , Catanzaro D F , Sealey J E , Laragh J H
Published: June 2012

A comprehensive review of physiological and molecular biological evidence refutes claims for synthesis of renin by cardiac and vascular tissues. Cardiovascular tissue renin completely disappears after binephrectomy. Residual putative reninlike activity, where investigated, has had the characteristics of lysosomal acid proteases. Occasional reports of renin or renin mRNA in vascular and cardiac tissues can be ascribed to failure to remove the kidneys 24 hours beforehand, overloading of detection systems, problems with stringency in identification, and illegitimate transcripts after more than 25 cycles of polymerase chain reaction. Others, using more stringent criteria, have failed to detect cardiac and vascular renin mRNA. Accordingly, a growing number of investigators have concluded that the kidneys are the only source of cardiovascular tissue renin. Although prorenin is secreted from extrarenal tissues as well as from the kidneys, there is no evidence that it is ever converted to renin in the circulation. The kidney is the only tissue with known capacity to convert prorenin to renin and to secrete active renin into the circulation. Accordingly, renin of renal origin determines plasma and hence, extracellular fluid renin levels. In these loci, angiotensin (Ang) I, formed by renin cleavage of circulating and interstitial fluid angiotensinogen, is in turn cleaved by angiotensin converting enzyme, located in plasma and extracellular fluids and on the luminal surface of pulmonary and systemic vascular endothelial cells, to Ang II, which perfuses and bathes the heart and vasculature. Consistent with this model, plasma renin and angiotensin and the antihypertensive action of renin inhibitors, converting enzyme inhibitor, or Ang II antagonists all disappear after binephrectomy. Thus, the plasma renin level, via Ang II formation, determines renin system vasoconstrictor activity, the antihypertensive potential of anti-renin system drugs, and the risk of heart attack in hypertensive patients. This analysis redirects renin research to renal mechanisms that create the plasma renin level, to renal prorenin biosynthesis and its processing to renin, and to their regulated secretion, extracellular distribution, and possible binding to by target tissues. In this context, it is still possible that changes in circulating and interstitial renin substrate or available converting enzyme might exert subtle modulating influences on Ang II formation. However, this analysis redefines the importance of plasma renin measurements to assess clinical situations, because plasma renin is the only known initiator driving the cardiovascular renin-angiotensin system, and its strength can be measured.
Ethinyl estradiol acutely attenuates abnormal coronary vasomotor responses to acetylcholine in postmenopausal women.
Authors: Reis S E , Gloth S T , Blumenthal R S , Resar J R , Zacur H A , Gerstenblith G , Brinker J A
Published: June 2012

BACKGROUND

Estrogen administration in postmenopausal women is associated with a 50% reduction in the clinical manifestations of coronary artery disease. The mechanisms are not known, although one potential explanation is estrogen-induced modulation of coronary vasoreactivity. Acetylcholine is an endothelium-dependent vasodilator that may be used to assess coronary vasoreactivity and elicits coronary responses that parallel those found with common daily vasomotor stimuli. Therefore, we tested whether estrogen attenuates abnormal coronary vasomotor responses to acetylcholine in postmenopausal women.

METHODS AND RESULTS

Acetylcholine-induced changes in coronary flow, resistance, and cross-sectional area were determined before and 15 minutes after intravenous administration of ethinyl estradiol (EE, 35 micrograms) in 15 postmenopausal women. The influence of estrogen on basal coronary flow, resistance, and epicardial cross-sectional area was also assessed by measuring these parameters before and after EE or placebo administration in 33 women. Estrogen altered basal coronary vasomotor tone in 22 women as manifested by an EE-induced 23.3 +/- 4.5% (mean +/- SEM) increase (P < .01) in coronary flow, a 15.0 +/- 3.2% decrease (P < .01) in resistance, and a 20.0 +/- 6.5% increase (P = .02) in epicardial cross-sectional area. Placebo administration in 11 women did not change these parameters. Estrogen also attenuated abnormal coronary vasomotor responses to acetylcholine. Seven women who exhibited a paradoxical acetylcholine-induced decrease in coronary flow (-33.5 +/- 12.3%, P < .01) and increase in resistance (38.9 +/- 14.1%, P = .05) and seven who had an abnormal acetylcholine-induced decrease in epicardial cross-sectional area (-14.2 +/- 4.4%; P = .04) did not have acetylcholine-induced changes in these parameters after EE administration. Acetylcholine-induced flow, resistance, and cross-sectional area responses before and after EE were significantly different (P < .01, P = .02, and P = .02, respectively). Normal coronary responses to acetylcholine were not affected by EE administration.

CONCLUSIONS

EE attenuates abnormal coronary vasomotor responses to acetylcholine in postmenopausal women. EE also decreases basal coronary vasomotor tone as manifested by increased coronary flow, decreased resistance, and increased epicardial cross-sectional area. These acute effects of estrogen on coronary vasoreactivity may explain, in part, the cardioprotective effects of estrogen in postmenopausal women.
Long-term prognostic importance of patency of the infarct-related coronary artery after thrombolytic therapy for acute myocardial infarction.
Authors: White H D , Cross D B , Elliott J M , Norris R M , Yee T W
Published: June 2012

BACKGROUND

After thrombolytic therapy, long-term patency of the infarct-related artery may reduce arrhythmias, limit ventricular dilatation, and provide collaterals to another infarct zone if further infarction occurs. However, independent long-term prognostic value of infarct artery patency has not been shown.

METHODS AND RESULTS

We followed 312 patients with first myocardial infarction treated < 4 hours after pain onset with thrombolysis (streptokinase [n = 188] or recombinant tissue-type plasminogen activator [n = 124]). At 28 +/- 11 days, cardiac catheterization was performed. Flow of the infarct-related artery was assessed by the TIMI scoring system, and a scoring system relating coronary stenoses and flow to the amount of myocardium supplied was also used. Follow-up was for 39 +/- 13 months. Cardiac death occurred in 5.8% of patients, and there were two noncardiac deaths. Revascularization was performed in 11.5% of patients. On univariate and multivariate analysis, ventricular function (ejection fraction, P = .006 and .02, or end-systolic volume index, P = .01 and .06) was the most important prognostic factor. Patency of the infarct-related artery measured as TIMI 3 flow was marginally significant on univariate analysis (P = .08) but not on multivariate analysis (P = .2). Patency was an independent prognostic factor in univariate and multivariate analysis when measured as an occlusion score (amount of myocardium supplied by an occluded artery, P = .01 and < .05). When the ejection fraction was > or = 50%, only occluded arteries supplying > 25% of the left ventricle affected prognosis adversely. If the ejection fraction was < 50%, occluded arteries supplying < 25% of myocardium also adversely affected prognosis. Treadmill exercise duration 4 weeks after infarction was the only other prognostic factor identified.

CONCLUSIONS

Ventricular function and infarct-related artery patency are independent prognostic factors after thrombolytic therapy for acute myocardial infarction.
Quantitative two-dimensional echocardiographic measurements are major predictors of adverse cardiovascular events after acute myocardial infarction. The protective effects of captopril.
Authors: St John Sutton M , Pfeffer M A , Plappert T , Rouleau J L , Moyé L A , Dagenais G R , Lamas G A , Klein M , Sussex B , Goldman S
Published: June 2012

BACKGROUND

Left ventricular enlargement after myocardial infarction increases the likelihood of an adverse outcome. In an echocardiographic substudy of the Survival and Ventricular Enlargement (SAVE) Trial, we assessed whether captopril would attenuate progressive left ventricular enlargement in patients with left ventricular dysfunction after acute myocardial infarction and, if so, whether this would be associated with improved clinical outcome.

METHODS AND RESULTS

Two-dimensional transthoracic echocardiograms were obtained in 512 patients at a mean of 11.1 +/- 3.2 days after infarction and were repeated at 1 year in 420 survivors. Left ventricular size was assessed as left ventricular cavity areas at end diastole and end systole and left ventricular function as percent change in cavity area from end diastole to end systole. Patients were randomly assigned to placebo or captopril, and the incidence of adverse cardiovascular events consisting of cardiovascular death, heart failure requiring either hospitalization or open-label angiotensin-converting enzyme inhibitor therapy, and recurrent infarction were determined over a follow-up period averaging 3.0 +/- 0.6 years. Irrespective of treatment assignment, baseline left ventricular systolic area and percent change in area were strong predictors of cardiovascular mortality and adverse cardiovascular events. At 1 year, left ventricular end-diastolic and end-systolic areas were larger in the placebo than in the captopril group (P = .038, P = .015, respectively), and percent change in cavity area was greater in the captopril group (P = .005). One hundred eleven of the 420 1-year survivors with 1-year echo measurements (26.4%) experienced a major adverse cardiovascular event, and these patients had more than a threefold greater increase in left ventricular cavity areas than those with an uncomplicated course. Sixty-nine patients with adverse cardiovascular events were in the placebo group compared with 42 patients in the captopril-treated group (a risk reduction of 35%, P = .010).

CONCLUSIONS

Two-dimensional echocardiography provides important and independent prognostic information in patients after infarction. Left ventricular enlargement and function after infarction are associated with the development of adverse cardiac events. Attenuation of ventricular enlargement with captopril in these patients was associated with a reduction in adverse events. This study demonstrates the linkage between attenuation of left ventricular enlargement by captopril after infarction and improved clinical outcome.
Combination antithrombotic therapy in unstable rest angina and non-Q-wave infarction in nonprior aspirin users. Primary end points analysis from the ATACS trial. Antithrombotic Therapy in Acute Coronary Syndromes Research Group.
Authors: Cohen M , Adams P C , Parry G , Xiong J , Chamberlain D , Wieczorek I , Fox K A , Chesebro J H , Strain J , Keller C
Published: June 2012

BACKGROUND

The purpose of this study was to compare combination antithrombotic therapy with aspirin plus anticoagulation versus aspirin alone, when added to conventional antianginal therapy in patients with unstable rest angina or non-Q-wave myocardial infarction who were nonprior aspirin users.

METHODS AND RESULTS

Two hundred fourteen patients were randomized; 109 were randomized to receive aspirin alone (162.5 mg daily) and 105 to receive a combination of aspirin plus anticoagulation, ie, aspirin 162.5 mg daily plus heparin (activated partial thromboplastin time, two times control) followed by aspirin 162.5 mg daily plus warfarin (international normalized ratio, 2 to 3). Trial therapy was begun by 9.5 +/- 8.8 hours of qualifying pain and was continued for 12 weeks. Primary end points were recurrent angina with ECG changes, myocardial infarction, and/or death. Analysis by intention to treat of primary events at 12 weeks was performed. At 14 days, there was a significant reduction in total ischemic events in the combination group versus aspirin alone (10.5% versus 27%, P = .004). An efficacy analysis of primary events at 12 weeks also revealed a large reduction in total ischemic events in the combination group versus aspirin alone (13% versus 25%, P = .06). Bleeding complications were slightly more common with combination therapy.

CONCLUSIONS

In nonprior aspirin users, combination antithrombotic therapy with aspirin plus anticoagulation significantly reduces recurrent ischemic events in the early phase of unstable angina.
Mitral A velocity wave transit time to the outflow tract as a measure of left ventricular diastolic stiffness. Hemodynamic correlations in patients with coronary artery disease.
Authors: Pai R G , Suzuki M , Heywood J T , Ferry D R , Shah P M
Published: June 2012

BACKGROUND: Subjects in sinus rhythm have two distinct diastolic flow velocities in the left ventricular (LV) outflow tract directed toward the aortic valve. These follow E and A waves of the transmitral flow and are referred to as Er and Ar waves, respectively. The A wave transit time from the mitral valve to the LV outflow tract is shorter than that of the E wave and is shorter in those with LV hypertrophy and the aged, suggesting its possible dependence on LV late diastolic stiffness. METHODS AND RESULTS. We measured the peak-to-peak and onset-to-onset A wave transit times from the mitral valve to the LV outflow tract (AArp and AAro intervals, respectively) using Doppler echocardiography in 20 patients undergoing left heart catheterization for evaluation of coronary artery disease. These intervals were correlated with indices of LV late diastolic stiffness obtained from high-fidelity LV pressure tracings and angiographic volume assessments. The AArp and AAro intervals correlated significantly with LV Dp/DV (conventionally dP/dV) (r = -.68 and -.83, respectively), volume stiffness, V.Dp/DV (r = -.74 and -.80, respectively) and LV (V/P) (Dp/DV) (r = -.69 and -.74, respectively). The AAro interval correlated better with the square roots of LV Dp/DV and volume stiffness (r = -.86 and -.87, respectively). CONCLUSIONS: We conclude that AArp and AAro intervals are easily obtainable Doppler parameters that reflect LV late diastolic stiffness in patients with coronary artery disease and possibly in other patients groups.
Randomized trial of a GPIIb/IIIa platelet receptor blocker in refractory unstable angina. European Cooperative Study Group.
Authors: Simoons M L , de Boer M J , van den Brand M J , van Miltenburg A J , Hoorntje J C , Heyndrickx G R , van der Wieken L R , de Bono D , Rutsch W , Schaible T F
Published: June 2012

BACKGROUND

Patients with unstable angina despite intensive medical therapy, ie, refractory angina, are at high risk for developing thrombotic complications: myocardial infarction or coronary occlusion during percutaneous transluminal coronary angioplasty (PTCA). Chimeric 7E3 (c7E3) Fab is an antibody fragment that blocks the platelet glycoprotein (GP) IIb/IIIa receptor and potently inhibits platelet aggregation.

METHODS AND RESULTS

To evaluate whether potent platelet inhibition could reduce these complications, 60 patients with dynamic ST-T changes and recurrent pain despite intensive medical therapy were randomized to c7E3 Fab or placebo. After initial angiography had demonstrated a culprit lesion suitable for PTCA, placebo or c7E3 Fab was administered as 0.25 mg/kg bolus injection followed by 10 micrograms/min for 18 to 24 hours until 1 hour after completion of second angiography and PTCA. During study drug infusion, ischemia occurred in 9 c7E3 Fab and 16 placebo patients (P = .06). During hospital stay, 12 major events occurred in 7 placebo patients (23%), including 1 death, 4 infarcts, and 7 urgent interventions. In the c7E3 Fab group, only 1 event (an infarct) occurred (3%, P = .03). Angiography showed improved TIMI flow in 4 placebo and 6 c7E3 Fab patients and worsening of flow in 3 placebo patients but in none of the c7E3 Fab patients. Quantitative analysis showed significant improvement of the lesion in the patients treated with c7E3 Fab, which was not observed in the placebo group, although the difference between the two treatment groups was not significant. Measurement of platelet function and bleeding time demonstrated > 90% blockade of GPIIb/IIIa receptors, > 90% reduction of ex vivo platelet aggregation to ADP, and a significantly prolonged bleeding time during c7E3 Fab infusion, without excess bleeding.

CONCLUSIONS

Combined therapy with c7E3 Fab, heparin, and aspirin appears safe. These pilot study results support the concept that effective blockade of the platelet GPIIb/IIIa receptors can reduce myocardial infarction and facilitate PTCA in patients with refractory unstable angina.
Thromboembolic and bleeding complications in patients with mechanical heart valve prostheses.
Authors: Cannegieter S C , Rosendaal F R , Briët E
Published: June 2012

BACKGROUND

Patients with mechanical heart valve prostheses may experience valve thrombosis and subsequent systemic embolism for which they are treated with oral anticoagulant therapy. It is essential to know reliable estimates of the risks and benefits of this therapy in order to answer a number of clinical questions rationally. We sought to obtain more precise estimates of the risks and benefits by combining the data from individual studies by using meta-analysis.

METHODS AND RESULTS

We searched for studies in which the incidences were reported of embolic or bleeding complications in patients with mechanical heart valve prostheses. They were collected from the Medline and Current Contents database and by cross-references between 1970 and 1992. Since most studies vary greatly in many respects, we used a number of inclusion criteria, thus selecting comparable studies of acceptable quality only. The influence of antithrombotic therapy, valve position, and valve type was analyzed by univariate and by multivariate analysis with Poisson regression techniques. Forty-six studies were found, including 13,088 patients studied for 53,647 patient-years. We found an incidence of major embolism in the absence of antithrombotic therapy of 4 per 100 patient-years. With antiplatelet therapy this risk was 2.2 per 100 patient-years, and with coumarin therapy it was reduced to 1 per 100 patient-years. This risk varied with the type and the site of the prosthesis. A prosthesis in mitral position increased the risk almost twice as compared with the aortic position. Tilting disc valves and bileaflet valves showed a lower incidence of major embolism than caged ball valves. An incidence of major bleeding was found in patients treated with coumarin derivatives of 1.4 per 100 patient-years. The incidence of bleeding became significantly higher with the addition of antiplatelet therapy, although this did not decrease the risk of thromboembolism any further.

CONCLUSIONS

These data provide a reference for future studies and give adequate risk estimates for clinical decision making.
Three-year outcome after balloon aortic valvuloplasty. Insights into prognosis of valvular aortic stenosis.
Authors: Otto C M , Mickel M C , Kennedy J W , Alderman E L , Bashore T M , Block P C , Brinker J A , Diver D , Ferguson J , Holmes D R
Published: June 2012

BACKGROUND

To identify predictors of long-term outcome after balloon aortic valvuloplasty, we analyzed data on 674 adults (mean age, 78 +/- 9 years; 56% were women) undergoing this procedure at 24 clinical centers who had a mean initial increase in aortic valve area of 0.3 cm2.

METHODS AND RESULTS

Baseline data included clinical, echocardiographic, and catheterization variables. Follow-up data included mortality, cause of death, rehospitalization, 6-month echocardiography, and functional status. Kaplan-Meier curves and log-rank tests were used to evaluate survival in subgroups. Multivariate Cox regression models were used to identify independent predictors of survival. Overall survival was 55% at 1 year, 35% at 2 years, and 23% at 3 years, with the majority of deaths (70%) classified as cardiac by an independent review committee. Rehospitalization was common (64%), although 61% of survivors at 2 years reported improved symptoms. Echocardiography at 6 months (n = 115) showed restenosis from the postprocedural valve area of 0.78 +/- 0.31 cm2 to 0.65 +/- 0.25 cm2 (P < .0001). With stepwise multivariate analysis, sequentially adding clinical, echocardiographic, and catheterization variables, the overall model identified independent predictors of survival as baseline functional status, baseline cardiac output, renal function, cachexia, female gender, left ventricular systolic function, and mitral regurgitation. Baseline and postprocedural variables were examined to identify which subgroup of patients has the best outcome after aortic valvuloplasty. A "lower-risk" subgroup (28% of the study population), defined by normal left ventricular systolic function and mild clinical functional limitation, had a 3-year survival of 36% compared with 17% in the remainder of the study group.

CONCLUSIONS

Long-term survival after balloon aortic valvuloplasty is poor with 1- and 3-year survival rates of 55% and 23%, respectively. Although survivors report fewer symptoms, early restenosis and recurrent hospitalization are common.
Contrasting effects of the intermittent and continuous administration of heparin in experimental restenosis.
Authors: Edelman E R , Karnovsky M J
Published: June 2012

BACKGROUND

Heparin inhibits proliferation of smooth muscle cells in culture and intimal hyperplasia in experimental animals but paradoxically exacerbates vascular injury in clinical trials. To determine whether the difference in the means by which heparin was administered explained the benefit in animals and aggravation in humans, we examined the vascular effects of a range of heparin treatments.

METHODS AND RESULTS

When laboratory rats were injected subcutaneously with heparin (55.5 IU, approximately 1.0 mg/kg) per clinical trial protocols, intimal hyperplasia after arterial injury was exacerbated rather than alleviated. The intima to media area ratio was increased 22.5% with every-other-day injections and was increased 16.8% with daily injections. When the daily dose of heparin was increased to 7.2 mg/kg or when injections were initiated a week before injury, intimal hyperplasia was made even worse (52.2% and 59.9% above control). Twice-daily heparin, 7 and 17 hours apart, had no demonstrable effect one way or the other, and it was not until the heparin was administered at 12-hour intervals that intimal hyperplasia and cell proliferation were lessened (44.6% decrease). The greatest reduction in intimal hyperplasia was obtained when the heparin was administered continuously. The continuous osmotic pump intravenous infusion of heparin inhibited 62.5% of the expected proliferation, and perivascular polymeric device release of heparin blocked the response by 74.2%. While subcutaneous injections transiently increased activated partial thromboplastin time, neither mode of continuous delivery altered coagulation.

CONCLUSIONS

We might reconsider the use of heparin in vascular diseases and not neglect this promising compound because of inappropriate extrapolation from the laboratory to clinical use.
Use of the rabbit ear artery to serially assess foreign protein secretion after site-specific arterial gene transfer in vivo. Evidence that anatomic identification of successful gene transfer may underestimate the potential magnitude of transgene expression.
Authors: Losordo D W , Pickering J G , Takeshita S , Leclerc G , Gal D , Weir L , Kearney M , Jekanowski J , Isner J M
Published: June 2012

BACKGROUND

The development of molecular strategies for the treatment of restenosis has been hindered by low efficiencies of in vivo arterial transfection. Expression of intracellular marker proteins is generally evident in < 1% of vascular smooth muscle cells after in vivo arterial transfection. Efforts to improve the efficiency of in vivo gene transfer have been further impeded by the use of transgenes encoding for intracellular marker proteins, necessitating tissue removal and limiting survey for expression to one point in time.

METHODS AND RESULTS

To study gene expression on a serial basis in vivo and determine the relation between a secreted gene product and transfection efficiency after in vivo arterial gene transfer, a method for performing and serially monitoring gene expression in vivo was developed using the central artery of the rabbit ear. Liposome-mediated transfection of plasmid DNA containing the gene for human growth hormone (hGH) was successfully performed in 18 of 23 arteries. Serum hGH levels measured 5 days after transfection ranged from 0.1 to 3.8 ng/mL (mean, 0.97 ng/mL); in contrast, serum drawn from the control arteries demonstrated no evidence of hGH production. Serial measurement of hGH from transfected arteries demonstrated maximum hGH secretion 5 days after transfection and no detectable hormone after 20 days. Despite these levels of secreted gene product documented in vivo, immunohistochemical staining of sections taken from the rabbit ear artery at necropsy disclosed only rare cells in which there was evidence of successful transfection.

CONCLUSIONS

These experiments demonstrate a useful method of performing serial in vivo analyses of gene expression after vascular transfection and that anatomic analyses of transfection efficiency may underestimate the potential magnitude of expression in the case of a secreted gene product. These findings have implications for the clinical application of somatic gene therapy because low-efficiency transfection with a gene encoding for a secreted protein may achieve therapeutic effects not realized by transfection with genes encoding for proteins that remain intracellular.