Gabriel B. Habib

Influence of coronary collateral vessels on myocardial infarct size in humans. Results of phase I thrombolysis in myocardial infarction (TIMI) trial. The TIMI Investigators.

BACKGROUND The influence of coronary collateral vessels on infarct size in humans remains controversial, partly because no previous study has examined the impact of collaterals present at the onset of acute myocardial infarction on infarct size. METHODS AND RESULTS The present study used the data base of the Thrombolysis in Myocardial Infarction (TIMI) Phase I trial to correlate the presence or absence of angiographically documented collaterals in the initial hours of myocardial infarct evolution with the size of the infarct as assessed by serial measurements of serum creatine kinase (CK). To avoid the confounding effects of reperfusion on enzymatic estimates of infarct size, this report is limited to those 125 patients who failed to recanalize at 90 minutes after administration of tissue plasminogen activator or streptokinase. Patients with angiographically documented collaterals (group A, n = 51) had significantly lower values of peak serum CK than patients without collaterals (group B, n = 74) (1,877 +/- 216 versus 2,661 +/- 212 IU/l, respectively [mean +/- SEM], p = 0.004). Similarly, CK-derived infarct size estimates were significantly lower in group A than in group B (20.6 +/- 2.5 versus 31.4 +/- 2.8 CK gram equivalents, p = 0.001). The infarct size observed in patients with collaterals was less for anterior infarctions as well as for infarctions of other locations; thus, the beneficial effects of collaterals were independent of the site of the infarct. In 65 of the 125 patients who failed to reperfuse, left ventricular ejection fraction (LVEF) was assessed by contrast ventriculography both at initial cardiac catheterization (before thrombolytic therapy) and at hospital discharge. Among the patients who had both studies, global LVEF tended to increase from pretreatment to hospital discharge in group A (from 50.6 +/- 1.8% to 53.4 +/- 1.8%, p = 0.10) but decreased in group B patients (from 50.3 +/- 1.8% to 47.8 +/- 1.7%, p = 0.02). At hospital discharge, global LVEF was greater in patients with coronary collaterals (53.5 +/- 1.7% versus 49.6 +/- 1.7%, p = 0.01). CONCLUSIONS The results demonstrate that, in patients in whom thrombolytic therapy fails to induce reperfusion, the presence of coronary collateral vessels at the onset of myocardial infarction is associated with limitation of infarct size as assessed enzymatically and with improved ventricular function on discharge as assessed by LVEF.

Diagnostic Marker Cooperative Study for the Diagnosis of Myocardial Infarction

BACKGROUND Millions of patients present annually with chest pain, but only 10% to 15% have myocardial infarction. Lack of diagnostic sensitivity and specificity of clinical and conventional markers prevents or delays treatment and leads to unnecessary costly admissions. Comparative data are lacking on the new markers, yet using all of them is inappropriate and expensive. METHODS AND RESULTS The Diagnostic Marker Cooperative Study was a prospective, multicenter, double-blind study with consecutive enrollment of patients with chest pain presenting to the emergency department. Diagnostic sensitivity and specificity and frequency of increase in patients with unstable angina were determined for creatine kinase-MB (CK-MB) subforms, myoglobin, total CK-MB (activity and mass), and troponin T and I on the basis of frequent serial sampling for </=24 hours. Of 955 patients with chest pain, 119 (12.5%) had infarction identified by use of CK-MB mass, and 203 (21%) had unstable angina. CK-MB subforms were most sensitive and specific (91% and 89%) within 6 hours of onset, followed by myoglobin (78% and 89%). For late diagnosis, total CK-MB activity (derived from subforms) was the most sensitive and specific (96% and 98%) at 10 hours from onset, followed by troponin I (96% and 93%), but not until 18 hours, and troponin T (87% and 93% at 10 hours). In unstable angina, CK-MB subforms were increased in 29.5%, myoglobin in 23.7%, troponin I in 19.7%, and troponin T in 14.8%. All markers were increased in 99 patients. With each marker as the diagnostic standard, CK-MB subforms and myoglobin remained the most sensitive for early diagnosis. CONCLUSIONS The CK-MB subform assay alone or in combination with a troponin reliably triages patients with chest pain and should lead to improved therapy and reduced cost.

More Rapid, Complete, and Stable Coronary Thrombolysis With Bolus Administration of Reteplase Compared With Alteplase Infusion in Acute Myocardial Infarction

BACKGROUND Early restoration and maintenance of normal (TIMI 3) blood flow during acute myocardial infarction is critical for optimal preservation of left ventricular function and survival. Recombinant plasminogen activator (r-PA, reteplase) is a nonglycosylated deletion mutant of wild-type tissue-type plasminogen activator (TPA) that has been shown to achieve more rapid and complete thrombolysis compared with other plasminogen activators in animal models. METHODS AND RESULTS The RAPID Trial was designed to test the hypothesis that bolus administration of one or more dosage regimens of r-PA was superior to standard-dose alteplase (TPA) in achieving infarct-related artery patency 90 minutes after initiation of treatment. Six hundred six patients with acute myocardial infarction were randomized to one of four treatment arms: (1) TPA 100 mg i.v. over 3 hours, (2) r-PA as a 15-MU single bolus, (3) r-PA as a 10-MU bolus followed by 5 MU 30 minutes later, or (4) r-PA as a 10-MU bolus followed by 10 MU 30 minutes later. Coronary arteriography was performed at 30, 60, and 90 minutes after initiation of treatment and at hospital discharge. The 10 + 10-MU r-PA group achieved better 90-minute and 5- to 14-day TIMI 3 flow (63% [CI, 55% to 71%] versus 49% [41% to 57%], P = .019, and 88% [82% to 94%] versus 71% [63% to 79%], P < .001, respectively) than the TPA group. The TIMI 3 flow in the 10 + 10-MU r-PA group at 60 minutes was equivalent to that in the TPA group at 90 minutes (51 versus 49%). Global ejection fraction and regional wall motion in the 10 + 10-MU r-PA group were superior to those of the TPA group at hospital discharge (53 +/- 1.3% versus 49 +/- 1.3%, P = .034; -2.19 +/- 0.12 versus -2.61 +/- 0.13 SD per chord, P = .02, respectively). The 15-MU and 10 + 5-MU r-PA patency and left ventricular function results were similar to those of the TPA and inferior to those of the 10 + 10-MU r-PA group. Bleeding complications were similar between the groups. CONCLUSIONS r-PA given as a double bolus of 10 + 10 MU achieves more rapid, complete, and sustained thrombolysis of the infarct-related artery than standard-dose TPA, without an apparent increased risk of complications. This was associated with improved global and regional left ventricular function at hospital discharge.

Asymptomatic Cardiac Ischemia Pilot (ACIP) study : outcome at 1 year for patients with asymptomatic cardiac ischemia randomized to medical therapy or revascularization

OBJECTIVES This report discusses the outcome at 1 year in patients in the Asymptomatic Cardiac Ischemia Pilot (ACIP) study. BACKGROUND Comparative efficacy of medical therapy versus revascularization in treatment of asymptomatic ischemia is unknown. The ACIP study assessed the ability of three treatment strategies to suppress ambulatory electrocardiographic (ECG) ischemia to determine whether a large-scale trial studying the impact of these strategies on clinical outcomes was feasible. METHODS Five hundred fifty-eight patients with coronary anatomy amenable to revascularization, at least one episode of asymptomatic ischemia on the 48-h ambulatory ECG and ischemia on treadmill exercise testing were randomized to one of three treatment strategies: 1) medication to suppress angina (angina-guided strategy, n = 183); 2) medication to suppress both angina and ambulatory ECG ischemia (ischemia-guided strategy, n = 183); or 3) revascularization strategy (angioplasty or bypass surgery, n = 192). Medication was titrated atenolol-nifedipine or diltiazem-isosorbide dinitrate. RESULTS The revascularization group received less medication and had less ischemia on serial ambulatory ECG recordings and exercise testing than those assigned to the medical strategies. The ischemia-guided group received more medication but had suppression of ischemia similar to the angina-guided group. At 1 year, the mortality rate was 4.4% in the angina-guided group (8 of 183), 1.6% in the ischemia-guided group (3 of 183) and 0% in the revascularization group (overall, p = 0.004; angina-guided vs. revascularization, p = 0.003; other pairwise comparisons, p = NS). Frequency of myocardial infarction, unstable angina, stroke and congestive heart failure was not significantly different among the three strategies. The revascularization group had significantly fewer hospital admissions and nonprotocol revascularizations at 1 year. The incidence of death, myocardial infarction, nonprotocol revascularization or hospital admissions at 1 year was 32% with the angina-guided medical strategy, 31% with the ischemia-guided medical strategy and 18% with the revascularization strategy (p = 0.003). CONCLUSIONS After 1 year, revascularization was superior to both angina-guided and ischemia-guided medical strategies in suppressing asymptomatic ischemia and was associated with better outcome. These findings require confirmation by a larger scale trial.

Doppler assessment of right ventricular filling in a normal population. Comparison with left ventricular filling dynamics.

To examine whether alterations in right ventricular filling dynamics occur with increasing age and to compare right and left ventricular filling in normal subjects, pulsed Doppler echocardiographic studies were performed at the tricuspid and mitral anuli in 50 normal volunteers (23 males and 27 females) with an age range of 5-66 years. An age-related decrease in peak early filling velocity, increase in peak late velocity, and augmentation in the late/early ratio of peak velocities at the tricuspid anulus were observed (r = -0.68, 0.63, and 0.84, respectively). Significant correlations were also found between age and first third, first half, and atrial filling fractions (r = -0.60, -0.72, and 0.69, respectively). Weaker relations were observed between heart rate and Doppler-derived diastolic parameters (r = 0.18-0.54). Right ventricular filling indexes related significantly to those of the left ventricle (r = 0.58-0.88), the best being for the late/early ratio of peak velocities. With inspiration, an increase in early and late right ventricular filling occurred, whereas a reduction in filling occurred in the left ventricle. Thus, careful consideration for age, heart rate, and respiration is necessary in examining the effect of disease states or therapeutics on the filling dynamics of either the right or left ventricle.

Transdermal Nitroglycerin Patch Therapy Improves Left Ventricular Function and Prevents Remodeling After Acute Myocardial Infarction Results of a Multicenter Prospective Randomized, Double-Blind, Placebo-Controlled Trial

BACKGROUND Nitrates are widely used in the treatment of angina in patients with acute myocardial infarction (AMI). Short-term administration prevents left ventricular (LV) dilation and infarct expansion. However, little information is available regarding their long-term effects on LV remodeling in patients surviving Q-wave AMI. METHODS AND RESULTS This was a randomized, double-blind, placebo-controlled trial designed to investigate the long-term (6-month) efficacy of intermittent transdermal nitroglycerin (NTG) patches on LV remodeling in 291 survivors of AMI. Patients meeting entry criteria had baseline gated radionuclide angiography (RNA) followed by randomization to placebo or active NTG patches delivering 0.4-, 0.8-, or 1.6-mg/h. RNA was repeated at 6 months and 6.5 days after withdrawal of double-blind medication. The primary study end point was the change in end-systolic volume index (ESVI). Both ESVI and end-diastolic volume index (EDVI) were significantly reduced with 0.4-mg/h NTG patches (-11.4 and -11.6 mL/m2, respectively, P<.03). This beneficial effect was observed primarily in patients with a baseline LV ejection fraction < or =40% (deltaESVI, -31 mL/m2; deltaEDVI, -33 mL/m2; both P<.05) and only at the 0.4-mg/h dose. After NTG patch withdrawal, ESVI significantly increased but did not reach pretreatment values. CONCLUSIONS Transdermal NTG patches prevent LV dilation in patients surviving AMI. The beneficial effects are limited to patients with depressed LV function and only at the lowest (0.4-mg/h) dose. Continued administration is necessary to maintain efficacy. Whether these remodeling effects confer a clinical or survival advantage will need to be addressed in an adequately powered cardiac event trial.

Cardiovascular outcomes using doxazosin vs. chlorthalidone for the treatment of hypertension in older adults with and without glucose disorders: a report from the ALLHAT study.

Insulin resistance underlies most glucose disorders in adults and is associated with an increased risk of cardiovascular disease. Alpha blockers decrease insulin resistance, whereas diuretics increase insulin resistance.

Normalization of cardiac structure and function after regression of cardiac hypertrophy

Previous studies have shown regression of left ventricular hypertrophy after pharmacologic treatment of hypertensive patients; however, the impact of regression of left ventricular hypertrophy on systolic function and on left and right ventricular diastolic function remains controversial and is difficult to assess because previous studies have not included concurrently studied age-matched control groups. Left ventricular mass, systolic function, and left and right ventricular diastolic function were assessed in 27 hypertensive patients, aged 43 +/- 6 years, by echocardiographic and Doppler studies before and 1, 3, 5, and 7 months after treatment. Left ventricular mass and ventricular function were concurrently evaluated in 27 age-matched normotensive subjects. Treatment with antihypertensive agents resulted in a significant (p < 0.001) reduction in diastolic blood pressure of 15 mmHg, measured at 1 month and sustained throughout the study. In response to hemodynamic unloading, left ventricular mass index decreased from 129 +/- 30 gm/m2 at baseline to 105 +/- 26 (p < 0.05) and 88 +/- 14 gm/m2 (p < 0.05) at 1 and 3 months of treatment, respectively, and remained unchanged over the subsequent 4 months. After 3 months of treatment, left ventricular mass index was similar in treated hypertensive and control subjects. Systolic function, assessed in terms of the relationship between shortening fraction and end-systolic wall stress, was unchanged throughout the treatment period and was no different from that in control subjects. However, patients with an initially depressed shortening fraction experienced a greater increase in shortening fraction during treatment compared to those with an initially normal shortening fraction (11% +/- 4% vs 5% +/- 5%, p < 0.01) and showed an improvement in the relationship between shortening fraction and end-systolic wall stress during treatment. Ventricular filling dynamics improved during the first 3 months of treatment, after which they were unchanged. Ventricular filling dynamics were similar in treated hypertensive patients and control subjects. In conclusion, sustained hemodynamic unloading of the left ventricle results in normalization of left ventricular mass, systolic function, and left and right ventricular diastolic filling dynamics, compared to those in age-matched control subjects.

Reappraisal of the importance of heart rate as a risk factor for cardiovascular morbidity and mortality

Heart rate is a key determinant of myocardial oxygen consumption. Several lines of evidence support a consistent association between heart rate and cardiovascular mortality. Increments in heart rate are positively related to cardiovascular and sudden death in patients with hypertension or previous myocardial infarction and in the elderly with heart disease. This relationship is important because a number of commonly used cardiovascular agents, such as beta-blockers and calcium antagonists (CAs), can affect heart rate. Beta-blockers decrease heart rate and reduce morbidity and mortality in post-myocardial infarction patients. The CAs are a structurally diverse group of agents with different physiologic effects. The dihydropyridine CAs are not associated with a reduction in heart rate. In fact, often they can cause reflex tachycardia as a result of potent systemic vasodilator action, which may provoke angina, especially in patients with ischemic heart disease. The nondihydropyridine CAs verapamil and diltiazem reduce heart rate but are associated with negative inotropy. Mibefradil, the first member of a new class of CAs, reduces heart rate and is not associated with negative inotropic effects. This unique pharmacologic profile may be of great value in treating hypertensive patients, particularly those with coexisting ischemic heart disease, and also patients with angina pectoris alone. However, the clinical benefit of pharmacologically reducing heart rate with mibefradil needs to be demonstrated in controlled trials.

Doppler assessment of right ventricular filling dynamics in systemic hypertension: comparison with left ventricular filling.

To assess right ventricular filling dynamics in systemic hypertension, pulsed Doppler echocardiographic studies were obtained at the tricuspid and mitral anuli in 43 untreated hypertensive patients, aged 23 to 66 years, and in 42 age-matched normotensive control subjects. In hypertensive patients, the ratio of late to early peak filling velocity and atrial filling fraction were higher, while normalized peak filling rate, one third and one half filling fractions were lower, compared with control values. Right ventricular filling dynamics correlated poorly with age in hypertensive patients, and were unrelated to left ventricular mass or left ventricular wall thickness. Weak correlations were only found between right ventricular wall thickness and right ventricular peak late inflow velocity, first half and first third filling fractions. However, right ventricular filling dynamics were closely related to left ventricular filling dynamics in both hypertensive patients (r = 0.49 to 0.82) and normal individuals (r = 0.55 to 0.86). Thus right ventricular filling dynamics are altered in hypertension, independently of left ventricular mass or blood pressure, are weakly related to right ventricular thickness, but remain closely correlated to left ventricular filling dynamics.