Agha W. Haider

Increased left ventricular mass and hypertrophy are associated with increased risk for sudden death

OBJECTIVES This study examined the relations of echocardiographically determined left ventricular (LV) mass and hypertrophy to the risk of sudden death. BACKGROUND Echocardiographic LV hypertrophy is associated with increased risk for all-cause mortality and cardiovascular disease morbidity and mortality. However, little is known about the association of echocardiographic LV hypertrophy with sudden death. METHODS We examined the relations of LV mass and hypertrophy to the incidence of sudden death in 3,661 subjects enrolled in the Framingham Heart Study who were > or =40 years of age. The baseline examination was performed from 1979 to 1983 and LV hypertrophy was defined as LV mass (adjusted for height) > 143 g/m in men and > 102 g/m in women. During up to 14 years of follow-up there were 60 sudden deaths. Cox models examined the relations of LV mass and LV hypertrophy to sudden death risk after adjusting for known risk factors. RESULTS The prevalence of LV hypertrophy was 21.5%. The risk factor-adjusted hazard ratio (HR) for sudden death was 1.45 (95% confidence interval [CI] 1.10 to 1.92, p=0.008) for each 50-g/m increment in LV mass. For LV hypertrophy, the risk factor-adjusted HR for sudden death was 2.16 (95% CI 1.22 to 3.81, p=0.008). After excluding the first 4 years of follow-up, both increased LV mass and LV hypertrophy conferred long-term risk of sudden death (HR 1.53, 95% CI 1.01 to 2.28, p=0.047 and HR 3.28, 95% CI 1.58 to 6.83, p=0.002, respectively). CONCLUSIONS Increased LV mass and hypertrophy are associated with increased risk for sudden death after accounting for known risk factors.

Systolic Blood Pressure, Diastolic Blood Pressure, and Pulse Pressure as Predictors of Risk for Congestive Heart Failure in the Framingham Heart Study

Context Hypertension is a recognized risk factor for the development of congestive heart failure (CHF). By measuring blood pressure, however, we have not yet been able to understand the significance of pulse pressure as a contributor to CHF in middle-aged men and women. Contribution Using data from the Framingham Heart Study, the authors found that although elevations of systolic, diastolic, and pulse pressure were all related to the risk for CHF, the relation was strongest for systolic and pulse pressure. Cautions Understanding the relationships between systolic, diastolic, and pulse pressure and risk for CHF is helpful; however, they do not help determine the increased risk faced by a person with systolic hypertension who also has increased pulse pressure. The Editors Hypertension is the most common risk factor for congestive heart failure (CHF). It confers a twofold risk for the occurrence of CHF and also carries the highest population attributable risk among all risk factors for CHF (1, 2). Placebo-controlled clinical trials in patients with hypertension have demonstrated a consistent reduction in risk for CHF attributable to the lowering of elevated blood pressure (3-6). The causal role of hypertension in the pathogenesis of CHF underscores the need to identify high-risk patients because early treatment may prevent or delay the occurrence of CHF (2, 7). The prognostic significance of systolic and diastolic blood pressure in CHF has been reported. However, blood pressure may also be divided into two other components: steady (mean arterial pressure) and pulsatile (pulse arterial pressure) (8-10). Pulse pressure, a simple correlate of conduit vessel stiffness, is associated with left ventricular hypertrophy (11). Increased pulse pressure has also been implicated in the development and progression of large-vessel atherosclerosis and small-vessel disease (12-14). Accumulating evidence indicates that pulse pressure (defined as the difference between systolic and diastolic blood pressure) may be an important predictor of cardiovascular events (15-18). Pulse pressure predicts the risk for CHF in elderly persons (19, 20); however, the association of pulse pressure with CHF in middle-aged men and women has not been examined. The Framingham Heart Study provides an opportunity to examine the long-term associations of systolic, diastolic, and pulse pressure with the new onset of CHF in middle-aged and elderly men and women. Blood pressure and traditional risk factors have been measured repeatedly at serial examinations in this community-based cohort with long-term follow-up. We examined systolic blood pressure, diastolic blood pressure, and pulse pressure as predictors of risk for CHF in the Framingham Heart Study. Methods The Framingham Heart Study, which began in 1948, has followed 5209 participants (28 to 62 years of age at entry to the study) as part of a prospective epidemiologic study of cardiovascular disease. Enrollment criteria and study design have been published previously (21). Biennial follow-up visits included a medical history, physical examination, blood pressure measurements, 12-lead electrocardiography, and laboratory tests. Eligibility requirements for inclusion in our study were as follows: Participants had to be free of coronary heart disease and CHF and not be receiving antihypertensive therapy at Framingham Heart Study clinic baseline examinations 10, 11, or 12 (1968 to 1973). Participants were followed for onset of CHF through mid-1994. We obtained data for selected risk factors from the baseline examination. Methods for assessing risk factors have been published previously (21, 22). Risk factors, including age, sex, cigarette smoking, heart rate, antihypertensive medication use, and total and high-density lipoprotein cholesterol levels, were assessed. Sitting systolic and diastolic blood pressure were measured twice by the examining physician (using a mercury column sphygmomanometer) and averaged. We used body mass index (kg/m2) as a measure of obesity. Participants were categorized as smokers if they smoked cigarettes regularly within the 1-year period before the baseline examination. Electrocardiography revealed left ventricular hypertrophy when increased voltage was associated with major ST-T repolarization changes (strain pattern) (22). Diabetes mellitus was defined on the basis of a fasting blood glucose level greater than 7.77 mmol/L (>140 mg/dL), two random nonfasting blood glucose levels greater than 11.10 mmol/L (>200 mg/dL), or the use of insulin or an oral hypoglycemic agent. Diagnostic criteria for CHF have been described previously (21, 22). At each clinic examination, a history of interim hospitalizations and symptoms of CHF were obtained. Outside medical records of participants who did not attend an examination were evaluated for incident CHF. All suspected interim events were reviewed by a panel of three physicians who evaluated relevant Framingham Heart Study clinic notes, outside physician reports, and hospitalization records. Congestive heart failure was diagnosed when at least two major or one major and two minor criteria were present. Minor criteria were considered only if their presence could not be attributed to another disease process. Major criteria were paroxysmal nocturnal dyspnea, pulmonary rales, distended jugular veins, enlarging heart size on chest radiography, acute pulmonary edema, hepatojugular reflux, third heart sound, jugular venous pressure of 16 cm or greater, and weight loss of 4.5 kg or greater in response to diuresis. Major criteria also included pulmonary edema, visceral congestion, or cardiomegaly on autopsy. Minor criteria were bilateral ankle edema, nocturnal cough, shortness of breath on ordinary exertion, hepatomegaly, pleural effusion, decrease in vital capacity by one third from the previous maximum recorded value, and heart rate of 120 beats/min or more. Statistical Analysis We used multivariable Cox proportional-hazards regression models to examine the relations of systolic, diastolic, and pulse pressure with CHF. After accounting for age and sex and using a P value less than 0.15 as the selection criterion, we determined covariates by stepwise selection from the following list: body mass index, diabetes, smoking status, total cholesterol level, high-density lipoprotein (HDL) cholesterol level, totalHDL cholesterol ratio, left ventricular hypertrophy, and heart rate. Only total cholesterol level and totalHDL cholesterol ratio did not enter the model. After accounting for relevant covariates, we used Cox proportional-hazards models to obtain hazard ratio estimates with 95% CIs for standardized values of systolic, diastolic, and pulse pressure. These estimates were obtained individually and pairwise by using SAS software (SAS Institute, Inc., Cary, North Carolina) (23). We repeated analyses for participants stratified according to hypertension status and sex. Because blood pressure and age are correlated, we conducted separate analyses for participants younger than 60 years of age and 60 years of age and older. To examine constancy of effects over time, follow-up was divided into early and late periods (<10 years, 10 years), and hazard ratios were calculated separately for early and late follow-up. In addition, we analyzed blood pressure as a time-varying covariate and assessed the effect of antihypertensive treatment after the baseline blood pressure measurements. We used the KaplanMeier method to plot age- and sex-standardized cumulative incidence rates for CHF as a function of pulse pressure tertile at baseline. Descriptive data are presented as percentages or means (SD). A P value less than 0.05 was considered statistically significant. Role of the Funding Sources The funding sources had no role in the design, conduct, analyses, and reporting of the study or in the decision to submit the manuscript for publication. Results A total of 894 men and 1146 women, age 50 to 79 years, fulfilled criteria for inclusion in our study. Table 1 presents baseline clinical characteristics for these persons. During 35 497 person-years of follow-up (mean, 17.4 years [range, 0.06 to 24 years]), CHF developed in 234 (11.8%) persons. Myocardial infarction preceded CHF in 59 (25%) persons. Table 1. Baseline Clinical Characteristics of the Study Participants Increments of 1 SD in systolic pressure, pulse pressure, and diastolic pressure were associated with hazard ratios for congestive failure of 1.56, 1.55, and 1.24, respectively, after adjustment for age, sex, smoking, left ventricular hypertrophy, body mass index, diabetes mellitus, HDL cholesterol level, and heart rate (Table 2). When blood pressure tertiles were used, similar associations were observed among various components of blood pressure and CHF. No threshold effect or J-shaped association was documented (Table 2). The cumulative incidence of CHF according to tertiles of baseline pulse pressure is plotted in the Figure. Table 2. Risk FactorAdjusted Association of Blood Pressure with Congestive Heart Failure Figure. Cumulative incidence of congestive heart failure according to pulse pressure tertiles at the baseline examination. The joint influences of different blood pressure components were also examined, with adjustment for the covariates mentioned previously. Of note, correlations among the blood pressure variables ranged from modest to very high (r = 0.20 for diastolic and pulse pressure, r = 0.65 for diastolic and systolic pressure, and r = 0.88 for systolic and pulse pressure). Diastolic pressure was not significant (hazard ratio, 1.12 [CI, 0.98 to 1.29]) in conjunction with pulse pressure (hazard ratio, 1.51 [CI, 1.33 to 1.72]). Likewise, diastolic pressure was not significant (hazard ratio, 0.86 [CI, 0.72 to 1.03]) in conjunction with systolic pressure (hazard ratio, 1.71 [CI, 1.45 to 2.01]), but joint estimates were less stable than those obtained for individual pressure variables. Finally,

Effect of intracoronary serotonin on coronary vessels in patients with stable angina and patients with variant angina

BACKGROUND Serotonin, a major product of platelet activation, has potent vasoactive effects in animal models, but its role in human coronary artery disease remains largely speculative. METHODS Using quantitative coronary angiography, we compared the effects of the intracoronary infusion of graded concentrations of serotonin (10(-7) to 10(-4) mol per liter) on coronary vessels in two groups of patients with different clinical presentations of coronary disease (nine with stable angina and five with variant angina), with the effects in a control group of eight subjects with normal vessels on angiography. RESULTS Normal coronary vessels had a biphasic response to intracoronary serotonin: dilation at concentrations up to 10(-5) mol per liter, but constriction at 10(-4) mol per liter. Vessels in patients with stable angina constricted at all concentrations, with mean (+/- SEM) maximal decreases in diameter of 23.9 +/- 3.6, 33.1 +/- 3.9, and 41.7 +/- 3.1 percent from base line in proximal, middle, and distal segments at a serotonin concentration of 10(-4) mol per liter. Smooth segments constricted more than irregular segments (42.0 +/- 4.6 vs. 21.1 +/- 1.6 percent). Four patients with stable angina had a marked reduction in collateral filling. All the patients with stable angina had angina during the intracoronary infusion of serotonin, and electrocardiographic changes were noted in six. All the patients with variant angina had angina, electrocardiographic changes, and localized occlusive epicardial coronary-artery spasm at concentrations of 10(-6) (n = 2) or 10(-5) (n = 3) mol per liter. CONCLUSIONS Patients with stable coronary disease do not have the normal vasodilator response to intracoronary serotonin, but rather have progressive constriction, which is particularly intense in small distal and collateral vessels. Patients with variant angina have occlusive coronary-artery spasm at a dose that dilates normal vessels and causes only slight constriction in vessels from patients with stable angina. These findings suggest that serotonin, released after the intracoronary activation of platelets, may contribute to or cause myocardial ischemia in patients with coronary artery disease.

Preinfarction Angina as a Predictor of More Rapid Coronary Thrombolysis in Patients with Acute Myocardial Infarction

BACKGROUND When a myocardial infarction is preceded by angina, the infarct tends to be smaller than when there is no preinfarction angina. Prompt recanalization of the occluded infarct-related artery is crucial in limiting the size of the infarct. We prospectively studied the relation among preinfarction unstable angina, the speed of coronary reperfusion, and the size of the infarct in patients with acute myocardial infarction receiving thrombolytic therapy. METHODS We compared 14 patients who had unstable angina during the week before myocardial infarction with 9 patients who had no preinfarction angina. Coronary arteriograms were obtained at base line and 15, 35, 55, and 90 minutes and 24 hours after the start of thrombolytic therapy. The size of the infarct was estimated on the basis of creatine kinase and creatine kinase MB levels, which were measured every 4 hours during the first 24 hours. RESULTS Complete reperfusion (a flow of grade 3 according to the Thrombolysis in Myocardial Infarction classification) was achieved at 35 minutes in 64 percent of the patients with preinfarction angina but in none of those without preinfarction angina (P = 0.006); at 55 minutes in 86 percent and 38 percent, respectively (P = 0.05); and at 90 minutes in 86 percent and 50 percent, respectively (P = 0.14). The mean (+/- SD) time to reperfusion was 27 +/- 16 minutes in the group with preinfarction angina and 48 +/- 17 minutes in the group without preinfarction angina (P = 0.04); the peak creatine kinase levels were 1118 +/- 783 and 2395 +/- 1615 U per liter, respectively (P = 0.03); the peak creatine kinase MB levels were 102 +/- 67 and 251 +/- 186 U per liter, respectively (P = 0.009); and the 24-hour integrated creatine kinase MB levels were 1716 +/- 1171 and 4267 +/- 3252 U.liter-1 x 24 hours, respectively (P = 0.009). The time to reperfusion was positively correlated with the indexes of infarct size (r > or = 0.53, P < or = 0.02). CONCLUSIONS In patients with acute myocardial infarction preceded by unstable angina, as compared with those without preinfarction angina, thrombolytic therapy resulted in more rapid reperfusion and smaller infarcts. Earlier myocardial reperfusion may thus account for the smaller infarct size in patients with preinfarction angina.

The association of seropositivity to Helicobacter pylori, Chlamydia pneumoniae, and cytomegalovirus with risk of cardiovascular disease: A prospective study

OBJECTIVES We sought to determine whether seropositivity to Helicobacter pylori, Chlamydia pneumoniae, and cytomegalovirus (CMV) is an independent predictor of incident cardiovascular disease. BACKGROUND Recent reports have suggested that infections may contribute to risk of cardiovascular disease. However, prospective studies of these associations in a free-living population are lacking. METHODS We measured serum H. pylori IgG, C. pneumoniae IgG and IgA, and CMV IgG levels in Framingham Heart Study cohort participants. Blood samples were drawn during the 16th biennial examination cycle (1979 to 1982) from 1,187 participants free of cardiovascular disease (mean age 69 years) and stored at -20 degrees C. A pooled primary end point of myocardial infarction, atherothrombotic stroke, and coronary heart disease deaths was studied in relation to serology. Using a Cox model, hazard ratios (HR) and 95% confidence intervals (CI) were calculated, adjusting for age, gender, and established risk factors. RESULTS Seropositivity to H. pylori IgG, C. pneumoniae IgG, C. pneumoniae IgA, and CMV IgG was 60%, 45%, 11%, and 69%, respectively. During 10 years of follow-up, incident cardiovascular disease occurred in 199 participants (16.8%). In age- and gender-adjusted models, H. pylori IgG (HR 1.09, 95% CI 0.81 to 1.46), C. pneumoniae IgG (HR 0.91, 95% CI 0.68 to 1.20), C. pneumoniae IgA (HR 0.65, 95% CI 0.39 to 1.07), and CMV IgG (HR 0.84, 95% CI 0.62 to 1.12) were not associated with incident cardiovascular disease. These associations were further attenuated after adjustment for risk factors including body mass index, total and high-density lipoprotein cholesterol, diabetes mellitus, smoking, and hypertension. These estimates did not change for the individual components of cardiovascular disease, and seropositivity to more than one organism did not alter these risk estimates substantially. CONCLUSIONS In this elderly cohort, chronic H. pylori, C. pneumoniae, and CMV infections, as evidenced by seropositivity, were not associated with increased risk for cardiovascular disease. Additional studies are needed to determine the relations of chronic infections to cardiovascular disease risk in younger persons.

Antecedent Hypertension Confers Increased Risk for Adverse Outcomes After Initial Myocardial Infarction

Several studies have examined the association of blood pressure (BP) after myocardial infarction (MI) with a risk for adverse outcome; however, few studies have investigated prognosis after MI as a function of BP before MI. Our goal was to examine the relation of antecedent hypertension to risk of adverse outcomes after initial MI. From 1967 to 1990, 404 subjects followed at the Framingham Heart Study developed an initial MI. These subjects were classified on the basis of preinfarction BP into normotensive (BP<140/90 mm Hg and not receiving antihypertensive treatment; n=118), stage I-untreated hypertension (BP 140 to 159/90 to 99 mm Hg; n=89), and stage II to IV or treated hypertension (BP > or =160/100 mm Hg or treated hypertension; n=197). Cox models were used to adjust for age, sex, smoking, glucose intolerance, total cholesterol, and prior cardiovascular disease. Antecedent hypertension was related to risk of adverse outcome after MI. Compared with normotensive individuals, stage II to IV hypertensives were at increased risk for reinfarction (hazard ratio [HR], 2.20; 95% confidence interval [CI], 1.20 to 4.04). A similar but nonsignificant association was seen in stage I hypertensives (HR, 1.91; 95% CI, 0.97 to 3.77). Stage II to IV hypertensives were at increased risk for all-cause mortality compared with normotensive persons (HR, 1.45; 95% CI, 1.07 to 1.98). Thus, even after MI, a history of antecedent hypertension remains predictive of adverse outcome. These findings are consistent with beneficial effects of BP control in primary and secondary prevention settings. Effective BP control may both reduce the risk for an initial MI and improve outcome in the event that an MI occurs.

The association of chronic cough with the risk of myocardial infarction: the Framingham Heart Study

PURPOSE A persistent inflammatory response accompanying chronic infections may contribute to the risk of coronary atherothrombosis. Recent studies have reported an association between chronic respiratory infections and an increased risk of coronary heart disease; however, these reports have not accounted for important confounders such as impaired lung function. METHODS We considered chronic cough as an indicator of chronic lung infection or inflammation in the original Framingham Heart Study participants aged 47 to 89 years. Chronic cough was defined as a cough present for at least 3 months in the preceding year and was categorized as either nonproductive or productive. The association of chronic cough with myocardial infarction was examined for six consecutive examination cycles (1965 to 1979) among participants free of myocardial infarction at the baseline examination. In a secondary analysis, plasma fibrinogen levels were measured during examination cycle 10 (1965 to 1967) in a subgroup of the study sample (n = 1,288). Multivariable logistic regression analysis was performed adjusting for age, gender, smoking status, forced vital capacity, and other known risk factors. RESULTS The cross-sectional pooling method yielded 15,656 person-examinations in 3,637 subjects. During follow-up, there were 291 incident myocardial infarctions. Chronic nonproductive cough (odds ratio [OR] 1.8, 95% confidence interval [CI] 1.1 to 2.8) and chronic productive cough (OR 1.6, CI 1.1 to 2.4) were independent predictors of myocardial infarction. Results were unchanged when we further adjusted for a history of heart failure. Adjusted plasma fibrinogen levels (mean +/- SD) were greater in those with chronic nonproductive cough than among those without cough (3.2 +/- 0.6 g/L versus 2.9 +/- 0.6 g/dL, P = 0.001). CONCLUSIONS These findings provide evidence that chronic cough, a clinical manifestation of pulmonary infection or chronic inflammation, is associated with the risk of myocardial infarction. Acute phase reactants such as plasma fibrinogen may be implicated in this association. Prospective serologic studies of infections as predictors of coronary heart disease risk are warranted.

REACTIVITY OF ECCENTRIC AND CONCENTRIC CORONARY STENOSES IN PATIENTS WITH CHRONIC STABLE ANGINA

Dynamic coronary stenoses may be the cause of a variable angina threshold and rest angina in patients with chronic stable angina. It has been suggested that eccentric but not concentric coronary artery stenoses have the potential for dynamic changes of caliber in response to vasoactive stimuli. The vasomotor response of eccentric (asymmetric narrowing) and concentric (symmetric narrowing) coronary stenoses to ergonovine (20 micrograms intracoronary or 300 micrograms intravenous) and isosorbide dinitrate (1 mg intracoronary) was studied in 51 patients with chronic stable angina. Diameter of reference segments (angiographically normal segments proximal to the stenoses) and that of eccentric (n = 30) and concentric (n = 35) coronary stenoses that ranged from 50% to 90% luminal diameter reduction were measured by computerized quantitative angiography before and after ergonovine and isosorbide dinitrate. Ergonovine reduced stenosis diameter (by greater than or equal to 10%) in 80% of eccentric stenoses and 42% of concentric stenoses (p less than 0.05). Mean (+/- SEM) diameter reduction with ergonovine was 19 +/- 3% and 9.5 +/- 2% for eccentric and concentric stenoses, respectively (p less than 0.05). Isosorbide dinitrate increased coronary diameter (by greater than or equal to 10%) in 70% of eccentric and 43% of concentric stenoses (p less than 0.05). Mean diameter of eccentric stenoses increased from 1.15 +/- 0.05 to 1.35 +/- 0.06 mm after nitrate (18.6 +/- 2.5%), whereas diameter of concentric stenoses increased from 1.05 +/- 0.05 to 1.14 +/- 0.05 mm (10 +/- 2.5%) (p less than 0.05). Average dilation of reference segments with administration of isosorbide dinitrate and constriction with ergonovine were not significantly different in patients with concentric and eccentric stenoses.(ABSTRACT TRUNCATED AT 250 WORDS)

Effectiveness and safety of a single intravenous bolus injection of tissue-type plasminogen activator in acute myocardial infarction

Abstract The efficacy of multiple intravenous bolus injections of tissue-type plasminogen activator (t-PA) in inducing rapid coronary recanalization in patients with acute myocardial infarction was previously demonstrated. In this Bolus Dose-Escalation Study of Tissue-Type Plasminogen Activator (BEST), the efficacy of 3 different doses of a single rapid intravenous bolus injection of t-PA (duteplase, Wellcome Foundation, London) in inducing coronary patency (Thrombolysis In Myocardial Infarction perfusion grade 2 or 3) in 64 patients with acute myocardial infarction presenting