Calvin Eng

Prospective, Randomized Comparison of Effect of Long-Term Treatment With Metoprolol or Carvedilol on Symptoms, Exercise, Ejection Fraction, and Oxidative Stress in Heart Failure

BACKGROUND With beta-blocker use becoming more prevalent in treating chronic heart failure (CHF), the choice of drugs raises important theoretical and practical questions. Although the second-generation compound metoprolol is beta1-selective, the third-generation compound carvedilol is beta-nonselective, with ancillary pharmacological properties including alpha-blockade and antioxidant effects. A prospective comparison of these 2 agents can address the issue of optimal adrenergic blockade in selecting agents for therapy in CHF. METHODS AND RESULTS Sixty-seven patients with symptomatic stable heart failure were randomly assigned to receive either carvedilol or metoprolol in addition to standard therapy for CHF. Measured variables included symptoms, exercise, ejection fraction, and thiobarbituric acid-reactive substances (TBARS) as an indirect marker of free radical activity. Metoprolol and carvedilol were well tolerated, and both patient groups showed beneficial effects of beta-blocker therapy in each of the measured parameters, with no between-group differences. Ejection fraction increased over 6 months from 18+/-6.3% to 23+/-8.7% (P<0.005) with metoprolol and from 19+/-8.5% to 25+/-9.9% (P<0.0005) with carvedilol (P=NS between groups). With metoprolol, TBARS values decreased from 4.7+/-0.9 nmol/mL at baseline to 4.2+/-1.5 nmol/mL at month 4 to 3.9+/-1.0 nmol/mL at month 6 (P<0.0001). With carvedilol, there was a parallel decline from 4.7+/-1.4 to 4.2+/-1.3 to 4.1+/-1.2 nmol/mL over the same time frame (P<0.025), with no between-group difference in these changes. CONCLUSIONS Carvedilol and metoprolol showed parallel beneficial effects in the measured parameters over 6 months, with no relevant between-group differences in this heart failure population.

Relation between red blood cell distribution width (RDW) and all-cause mortality at two years in an unselected population referred for coronary angiography

BACKGROUND Red blood cell distribution width (RDW), a numerical measure of the variability in size of circulating erythrocytes, has recently been shown to be a strong predictor of adverse outcomes in patients with heart failure and in patients with prior myocardial infarction but no symptomatic heart failure at baseline, even after adjustment for hematocrit. However, there are no data in other cardiac populations, including patients with acute coronary syndromes (ACS). METHODS The present study investigated the long-term prognostic significance of baseline RDW in a well-characterized cohort of 389 male patients who were referred to coronary angiography for a variety of indications. All patients were followed prospectively for all-cause mortality, and data regarding this endpoint was available for 97% of the population at 24 months. RESULTS After controlling for a variety of baseline variables (including hemoglobin and the presence of heart failure), RDW (analyzed as a categorical variable comparing the upper tertile of baseline values to the lower two levels combined) was a strong and independent predictor of all-cause mortality using a Cox proportional hazards model [hazard ratio (HR) 2.69, 95% confidence interval (CI) 1.50-4.84, p=0.0008]. In addition, baseline RDW was also an independent predictor of all-cause mortality in the non-anemic (HR 4.73, 95% CI 2.06-10.86, p=0.0003) and ACS (HR 2.90, 95% CI 1.32-6.38, p=0.0082) subpopulations of patients. CONCLUSIONS These data demonstrate that elevated RDW is a strong and independent predictor of all-cause mortality in an unselected population of male patients across a broad spectrum of risk (including ACS) referred for coronary angiography.

Prognostic Implications of Normal (<0.10 ng/ml) and Borderline (0.10 to 1.49 ng/ml) Troponin Elevation Levels in Critically Ill Patients Without Acute Coronary Syndrome

Borderline increase of troponin I (cTnI) is associated with higher rates of cardiovascular events compared with normal levels in the setting of acute coronary syndrome (ACS), but the significance of borderline cTnI levels in patients without chest pain may differ. The aim of this study was to determine the prognostic implications of intermediate serum cTnI levels in patients without ACS in the intensive care unit (ICU). This was a 12-month retrospective study of 240 patients without ACS in the ICU with normal (<0.1 ng/ml) or intermediate (0.1 to 1.49 ng/ml) cTnI levels. End points included in-hospital mortality, lengths of ICU and hospital stays, and rates of postdischarge readmission and mortality. Overall in-hospital mortality was 13%, with 5% in the normal cTnI group and 28% in the intermediate cTnI group. By multivariate analysis, intermediate cTnI was independently associated with in-hospital mortality (p = 0.004) and length of ICU stay (p = 0.028). The only other independent risk factor for inpatient mortality was a standardized ICU prognostic measurement (Simplified Acute Physiology Score II score). Intermediate cTnI had no prognostic implications regarding length of hospital stay, readmission rate, or postdischarge mortality at 6 months. In conclusion, an intermediate level of cTnI in patients without ACS in the ICU is an independent prognostic marker predicting in-hospital mortality and length of ICU stay. Patients with intermediate cTnI levels who survive to discharge have equivalent out-of-hospital courses for up to 6 months compared with patients with normal cTnI levels.

Coronary collateral function during exercise.

A totally occluded coronary vessel subtending a noninfarcted, entirely collateral‐dependent myocardial region (NIECDMR) provides an opportunity to assess collateral perfusion during exercise stress. Collateral function was determined by analysis of exercise thallium‐201 myocardial perfusion images from 31 patients who had at least one NIECDMR (total 41 NIECDMRs) documented during catheterization. Twenty‐two of 41 NIECDMRs manifested exercise‐induced perfusion defects and 19 were normally perfused. The exercise‐negative NIECDMRs were further categorized: Group 1 NIECDMRs (n = 13) were associated with defects in other myocardial regions supplied by diseased vessels and were considered negative relative to other jeopardized regions; group 2 NIECDMRs (n = 6) were not associated with exercise‐induced defects in other myocardial regions, which suggests that collateral perfusion was adequate during maximal exercise. Regions supplied by a diseased left anterior descending coronary artery manifested exercise defects regardless of collaterals, possibly because these regions were larger and required more perfusion. Angiographic indexes of collateral function did not clearly predict exercise results.

Collagen loss in the stunned myocardium.

Background This study was performed to biochemically assess and quantify the previously observed ultrastructural alterations in the collagen matrix of stunned myocardium. Methods and Results The stunned myocardium was produced in 13 mongrel dogs by a series of 12 coronary artery occlusions of 5 minutes followed by 10-minute reperfusion periods, with a final reperfusion period of 90 minutes. Regional systolic function in the stunned myocardium was 17% of control. Relative end-diastolic length in the stunned region increased up to 8%. There was a nonuniform transmural loss of collagen. Hydroxyproline in the stunned endocardium was not different from control. The stunned midwall and epicardium demonstrated 12.5% (p <0.05) and 14.6% (p <0.005) decreases, respectively. All transmural layers in the stunned myocardium had significant increases in collagenase activity before procollagenase activation, averaging a 73.6% increase (p <0.025). Complete activation of all procollagenase forms with aminophenylmercuric acetate revealed no differences in fully activated collagenase between the stunned and normal regions. The lysosomal enzymes, elastase and cathepsin G, were not different between stunned and normal zone tissue. These results would tend to exclude exogenous sources of protease in the stunned myocardium at the 90-minute final reperfusion time frame. Collagen fibers were isolated from the stunned and normal zone tissue and underwent dansyl chloride reaction. Stunned collagen fibers had 9% greater dansyl labeling, suggesting greater numbers of exposed N-terminal amino acid residues on the fiber and compatible with greater enzymatic cleavage activity on the stunned collagen matrix. Tissue water content was consistently greater in the stunned region compared to the normal: a uniform transmural increase of approximately 1.7%. Conclusions The stunned myocardium is characterized by both systolic dysfunction and diastolic expansion or dilatation. Endogenous procollagenase is activated by the ischemic process leading to degradation of the extracellular matrix. The underlying mechanisms may be relevant in ischemic enlargement of the heart and cardiomyopathy.

The effects of the coronary capacitance on the interpretation of diastolic pressure-flow relationships.

The effects of coronary capacitance on instantaneous pressure-flow (P/F) relationships were analyzed using a theoretical model of coronary flow during diastole that included capacitance. The magnitude of the discrepancy between actual intramural and instantaneously derived P/F relationships was predicted to be dependent on the ratio of two natural decay constants (central aortic decay constant/intrinsic coronary decay constant). The effects of coronary capacitance are eliminated using constant pressure conditions. The instantaneous (dynamic) and constant pressure (static) P/F relationships were compared experimentally using a reservoir to provide constant pressure perfusion during prolonged diastoles in heart blocked dogs. In the presence of coronary tone, zero flow pressure intercepts (PZT) of 27.1 ± 6.6 and 11.0 ± 3.0 mm Hg were obtained under dynamic and constant pressure conditions respectively, P < 0.001. After maximal vasodilation, pzf of 14.2 ± 4.5 mmHg and 10.7 ± 2.4 mmHg were obtained under dynamic and constant pressure conditions, respectively, P = NS. Pzf derived under constant pressure conditions were independent of the state of coronary vasomotor tone with a value about 11 mmHg. The slopes of the dynamic P/ F relationships tended to be greater than those derived from constant pressure conditions. This may suggest an additional component of increasing coronary resistance during diastole that could not be readily assessed under dynamic conditions. We conclude that coronary capacitive effects and resistance changes during diastole severely limit the interpretation of instantaneous dynamic P/F relationships. Diastolic coronary perfusion ceases at about 11 mm Hg and is independent of coronary tone when capacitive effects are eliminated.

Can noninvasive exercise test criteria identify patients with left main or 3-vessel coronary disease after a first myocardial infarction?*

This study attempts to determine whether exercise treadmill testing with clinical, electrocardiographic, and thallium-201 myocardial perfusion imaging data can identify which patients have left main or 3-vessel (anatomically high-risk) coronary artery disease (CAD) after their first transmural myocardial infarct (MI). Twelve exercise test criteria for high-risk disease were compared in 40 patients referred for cardiac catheterization; 34 had a history of chest pain and 17 had angiographically defined high-risk CAD. A thallium image defect outside the vascular distribution of the MI was the most reliable criterion to distinguish patients with high-risk CAD (p = 0.00052 for Fishers exact test of discrimination). Thallium imaging was somewhat more sensitive (92 versus 65%, p = 0.108) when patients with negative thallium imaging criteria who failed to achieve 85% of the age-predicted maximal heart rate were excluded. Failure to achieve 85% of predicted heart rate was by itself a useful criterion for detecting high-risk CAD (p = 0.017), especially in patients not taking propranolol (p = 0.004). Development of positive S-T segment depression at less than 70% predicted heart rate also discriminated left main or 3-vessel disease from less extensive CAD (p = 0.016). Other criteria failed to discriminate significantly between high-risk and less extensive CAD in patients after their first MI (p greater than 0.05). S-T segment depression (p = 0.199) or chest pain (p = 0.577) during exercise testing were particularly unreliable. Further, none of the criteria for high-risk CAD were influenced by irreversible left ventricular dysfunction. It is concluded that patients with thallium imaging defects outside the region of the infarct, decreasing blood pressure during exercise, failure to achieve 85% of predicted heart rate, or S-T depression at less than 70% of predicted heart rate have a high probability of having left main or 3-vessel disease. Patients without these criteria have a very low probability of having high-risk CAD and probably do not need coronary angiography for the purpose of excluding these high-risk coronary lesions after a first MI.

The effects of acutely increased ventricular cavity pressure on intrinsic myocardial connective tissue

Studies of normal hearts have revealed a variety of intrinsic connective tissue structures that surround and interconnect myocytes and ventricular mural layers. Among these structures, springlike coiled perimysial fibers, arrayed parallel to myocytes in the interstitial space, have been described in papillary muscle and ventricle. To evaluate the role of the coiled perimysial fibers under perturbed conditions, rat ventricles were filled with barium-gelatin under different pressures and fixed, and then the myocardium was impregnated with silver to visualize the connective tissue. Ventricles were filled at 30, 70 and 100 to 120 mm Hg. The coiled perimysial fibers were studied for their orientation, stretch, integrity and relation to sarcomere length. The coils were noted to embed within the fibrous anulus and to knot into an umbilical-like mass at the apex, thus anchoring them at both ends of the ventricle. They underwent focal straightening even at 30 mm Hg, with generalized straightening and disruption at the highest pressure; changes were most pronounced in the midventricle. Sarcomeres were maintained below 2.2 micron at 30 and 70 mm Hg of cavity pressure in regions of coiled perimysial fiber stretch; only with fiber disruption at 100 to 120 mm Hg were sarcomeres significantly lengthened. Other findings included connective tissue disruption between ventricular wall layers that allowed slippage of myocytes and mural thinning. These observations suggest that coiled perimysial fibers may act as a buffer to protect myocytes from damage under the effects of high cavity pressure.

Low Plasma RANTES Levels Are an Independent Predictor of Cardiac Mortality in Patients Referred for Coronary Angiography

Objective—Our objective was to evaluate the prognostic value of baseline plasma RANTES levels in patients with known or suspected coronary artery disease. RANTES is a chemokine produced by a variety of cell types including platelets that has been implicated in atherosclerosis. Methods and Results—Baseline plasma RANTES levels were measured in 389 male patients undergoing coronary angiography at a Veterans Affairs Medical Center. The patients were followed-up prospectively for the occurrence of cardiac mortality and myocardial infarction. Follow-up data at 24 months were available for 97% of patients. In the entire cohort of patients, low baseline RANTES levels were an independent predictor of cardiac mortality. For cardiac death at 24 months, the survival rate was 87.3% in the lowest tertile of RANTES values, compared with 94% in the upper 2 tertiles combined (P=0.0298 by log rank test). Furthermore, when patients were risk-stratified into those with and without an acute coronary syndrome, RANTES was an independent predictor of both cardiac mortality and myocardial infarction in those without an acute coronary syndrome. Finally, RANTES was also an independent predictor of cardiac mortality in the diabetic subset. Conclusions—In a cohort of male patients undergoing coronary angiography, low baseline plasma RANTES levels are an independent predictor of cardiac mortality.

Relation of baseline plasma ADMA levels to cardiovascular morbidity and mortality at two years in men with diabetes mellitus referred for coronary angiography

BACKGROUND Patients with diabetes mellitus (DM) have been shown to have higher levels of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of endothelial nitric oxide (NO) synthase. Higher plasma levels of ADMA have been implicated in the pathogenesis of endothelial dysfunction and atherosclerosis by lowering NO levels. High baseline plasma levels of ADMA in patients with DM have been shown to predict diabetes related complications. However, there are limited data on the prognostic significance of baseline ADMA levels in patients with established DM. METHODS The present study investigated the long-term prognostic significance of baseline plasma ADMA levels in a well-characterized cohort of 170 high-risk diabetic men with known or suspected coronary artery disease who were referred for coronary angiography. All patients were followed prospectively for the development of vascular outcomes, including all-cause mortality. RESULTS After controlling for a variety of baseline variables (including established biomarkers such as hs-CRP and fibrinogen), plasma ADMA levels (analyzed as the upper tertile of baseline values compared with the lower two tertiles) were a strong and independent predictor of all-cause mortality (HR 2.63, 95% CI 1.13-6.11, p=0.0247) when using a Cox proportional hazards model. In addition, baseline ADMA values were also an independent predictor of the composite outcome of all-cause mortality or MI (fatal or non-fatal) (HR 2.44, 95% CI 1.26-4.72, p=0.0079), as well as the composite outcome of all-cause mortality, MI (fatal or nonfatal), or stroke (HR 2.00, 95% CI 1.10-3.62, p=0.0232). CONCLUSION These data demonstrate that elevated baseline levels of ADMA are a strong and independent predictor of cardiovascular outcomes (including all-cause mortality) in patients with DM.