Jerome D. Cohen

Serum Cholesterol Levels and Six-Year Mortality from Stroke in 350,977 Men Screened for the Multiple Risk Factor Intervention Trial

We examined the relation between the serum total cholesterol level and the risk of death from stroke during six years of follow-up in 350,977 men, 35 to 57 years of age, who had no history of heart attack and were not currently being treated for diabetes mellitus. The diagnosis of stroke and the type of stroke were obtained from death certificates. Using proportional-hazards regression to control for age, cigarette smoking, diastolic blood pressure, and race or ethnic group, we found that the six-year risk of death from intracranial hemorrhage (International Classification of Diseases, ninth edition [ICD-9], categories 431 and 432) was three times higher in men with serum cholesterol levels under 4.14 mmol per liter (160 mg per deciliter) than in those with higher cholesterol levels (P = 0.05 by omnibus test across five cholesterol levels). On the other hand, a positive association was observed between the serum cholesterol level and death from nonhemorrhagic stroke (P = 0.007). The inverse association of the serum cholesterol level with the risk of death from intracranial hemorrhage was confined to men with diastolic blood pressure greater than or equal to 90 mm Hg, in whom death from intracranial hemorrhage is relatively common. We conclude that there is an inverse relation between the serum cholesterol level and the risk of death from hemorrhagic stroke in middle-aged American men, but that its public health impact is overwhelmed by the positive association of higher serum cholesterol levels with death from nonhemorrhagic stroke and total cardiovascular disease (ICD-9 categories 390 through 459).

Long-Term Weight Loss and Changes in Blood Pressure: Results of the Trials of Hypertension Prevention, Phase II

Approximately one fourth of the U.S. adult populationnearly 50 million peoplehas hypertension (1, 2). Taking a broader perspective, more than half of the adult population has higher than optimal blood pressure (1), defined as systolic blood pressure greater than 120 mm Hg and diastolic blood pressure greater than 80 mm Hg (2). These persons are at significantly increased risk for cardiovascular disease and stroke (3). Although pharmacologic treatment for hypertension significantly reduces morbidity and mortality from cardiovascular diseases (4, 5), long-term pharmacologic therapy can have undesirable side effects and requires the expense of continuing medical supervision. Furthermore, pharmacologic therapy is not usually initiated when blood pressure is higher than optimal yet below diagnostic thresholds for hypertension. Thus, lifestyle interventions for primary prevention and initial treatment of high blood pressure remain a vital strategy for controlling this highly prevalent condition (2). Weight loss has been shown to reduce blood pressure in overweight hypertensive patients (6-9) and in overweight persons with high-normal blood pressure (10-12). Two reviews of randomized trials of weight reduction to reduce blood pressure examined the results of nine studies (13, 14). Most of these trials were small, only one had more than 500 participants (11), and most had short-term follow-up (1 year or less). Only three studies had follow-up of 3 to 5 years (8, 10, 11). Compared with controls, weight loss averaged nearly 7 kg in the short-term trials and approximately 3 kg in the three longer-term trials. In almost all trials, systolic blood pressure and diastolic blood pressure were reduced in the intervention groups. Since these reviews were published, the Trials of Hypertension Prevention (TOHP) Phase I reported mean weight reduction of 3.9 kg at 18 months in 564 overweight participants with high-normal blood pressure, resulting in significant decreases in systolic blood pressure and diastolic blood pressure compared with a usual care control group (12, 15). To investigate whether nonpharmacologic interventions can prevent hypertension over the long term, TOHP II was initiated. This was a randomized, controlled trial examining the effects of weight loss and dietary sodium reduction, alone and in combination, in reducing blood pressure in overweight adults with high-normal diastolic blood pressure (16). This target population is at high risk for hypertension as they age. The primary outcome paper from this trial (17) provided only a brief overview of the effects of weight loss on blood pressure. Here, we provide more detailed analysis of weight loss and blood pressure in TOHP II. Of special interest are the long-term effects of weight loss on blood pressure, the magnitude of the doseresponse relationship at 36 months, the effect of patterns of weight loss on blood pressure, and the predictors of weight loss and blood pressure response. Methods Participants Participants in TOHP II were overweight adults with nonmedicated diastolic blood pressure of 83 to 89 mm Hg and systolic blood pressure less than 140 mm Hg. Other eligibility criteria included age 30 to 54 years and a body mass index of 26.1 to 37.4 kg/m2 for men and 24.4 to 37.4 kg/m2 for women, approximately 110% to 165% of ideal weight (18). Principal exclusion criteria were current treatment with medications that might affect blood pressure, clinical or laboratory evidence of cardiovascular disease, diabetes mellitus, renal insufficiency (serum creatinine concentration 150 mol/L [ 1.7 mg/dL] for men and 132 mol/L [ 1.5 mg/dL] for women), and current or planned pregnancy. Detailed descriptions of recruitment and participant characteristics have been published elsewhere (19, 20). The study was reviewed and approved by the institutional review boards at all nine TOHP centers and the coordinating center, and all participants signed informed consent forms. Design Eligible participants were randomly assigned with equal probability to one of four groups: weight loss only, sodium reduction only, combined weight loss and sodium reduction, or usual care (controls). Measurements Age, sex, ethnicity, and years of education were obtained by questionnaire. Baseline blood pressure measurements were taken at three screening visits, each separated by 7 to 45 days. At each visit, three readings of systolic blood pressure and diastolic blood pressure were obtained and averaged. Certified staff obtained measurements in seated participants by using a Hawksley random-zero sphygmomanometer (21). Body weight was measured to the nearest 0.2 kg (0.5 lb) by using a calibrated balance-beam scale; participants wore indoor clothing (without shoes). Blood pressure and weight were measured every 6 months after randomization to the end of follow-up at 36, 42, or 48 months, depending on randomization date. Clinic staff who were blinded to study group assignment made these assessments. Blood pressure measurements were obtained during a single visit at all follow-up points except for 18 and 36 months, when measurements were taken at a series of three visits approximately 1 week apart. Multiple measurements were taken at 18 and 36 months to provide a more precise assessment of average blood pressures at these primary outcome points. Dietary intake was assessed by 24-hour recall, and physical activity was assessed by questionnaire. Intervention Participants assigned to the weight loss intervention group sought to lose at least 4.5 kg (10 lb) during the first 6 months of the intervention and to maintain their weight loss for the remainder of the trial. A brief description of the intervention methods is presented here; a more detailed description has been published elsewhere (22). The intervention started with an individual counseling session, followed by 14 weekly group meetings led by dietitians or health educators. After this 14-week intensive phase, participants attended six biweekly group meetings and then monthly group meetings. Beginning in the 18th month, participants were offered a variety of options to keep them involved in the intervention, including individual counseling sessions and special group sessions focused on selected weight loss topics. The intervention focused on self-directed behavior change (behavioral self-management), nutrition education, information on physical activity, and social support for making and maintaining behavior changes. Specific behavior change techniques included self-monitoring (food diaries and graphs of minutes of physical activity per day), setting explicit short-term goals and developing specific action plans to achieve those objectives, and developing alternative strategies for situations that trigger problem eating. The dietary intervention focused on reducing caloric intake by decreasing consumption of excess fat, sugar, and alcohol. Keeping daily food diaries was emphasized for monitoring intake and assessing progress. With experience, the participants determined the caloric intake that produced moderate weight loss for them. It was suggested that men not consume less than 1500 kcal/d and women not less than 1200 kcal/d. Weight loss of more than 0.9 kg (2 lb) per week was discouraged. The physical activity goal was to gradually increase activity to 30 to 45 minutes per day, four to five days per week. Exercise intensity was moderate, approximately 40% to 55% of heart rate reserve, and consisted primarily of brisk walking. Statistical Analysis Baseline characteristics of the weight loss and usual care groups were compared overall and by sex by using t-tests for means and chi-square tests for proportions. Although weight and blood pressure data were collected every 6 months, special efforts were made to achieve high follow-up rates at 18 and 36 months; at each of these two time points, nine blood pressure readings were collected over three visits and were averaged. For participants prescribed antihypertensive medication, follow-up blood pressure for all subsequent visits was taken to be the last study blood pressure before therapy was started. Participants receiving medications that affect blood pressure for reasons other than hypertension or who became pregnant were treated as missing at that visit. We used two-sample t-tests to compare changes in weight and blood pressure from baseline in the weight loss intervention and usual care groups overall, by sex, by ethnicity, and by sex and ethnicity. The effects of the intervention in terms of changes in weight and blood pressure were examined overall and in subgroups defined by sex, ethnicity, and sex and ethnicity. Subgroup differences were tested by using terms for the interaction of treatment group with sex and with ethnicity in multiple linear regression models. Regression analyses were also used to analyze the doseresponse relationship between change in weight and change in blood pressure, overall and within sex and ethnicity subgroups. Differences in dose response were tested by using interaction terms in linear regression models. All regressions were adjusted for age and baseline weight. We also adjusted for baseline blood pressure in the blood pressure regression models. Change in blood pressure was also examined in relation to quintile of weight loss. Quintiles were computed by using the distribution of weight change in the weight loss intervention group. Additional multiple regression analyses were performed in which weight loss participants were categorized according to patterns of weight loss at 6 and 36 months. The PROC MIXED function of SAS software (SAS Institute, Inc., Cary, North Carolina) was used to perform repeated-measures analyses that tested differences over time by pattern of weight loss. Cox proportional-hazards models were used for survival analyses, with onset of hypertension as the outcome. Results Baseline Findings The baseline characteristics of participants assigned to th

The relevance of tissue angiotensin-converting enzyme: manifestations in mechanistic and endpoint data

Angiotensin-converting enzyme (ACE) is primarily localized (>90%) in various tissues and organs, most notably on the endothelium but also within parenchyma and inflammatory cells. Tissue ACE is now recognized as a key factor in cardiovascular and renal diseases. Endothelial dysfunction, in response to a number of risk factors or injury such as hypertension, diabetes mellitus, hypercholesteremia, and cigarette smoking, disrupts the balance of vasodilation and vasoconstriction, vascular smooth muscle cell growth, the inflammatory and oxidative state of the vessel wall, and is associated with activation of tissue ACE. Pathologic activation of local ACE can have deleterious effects on the heart, vasculature, and the kidneys. The imbalance resulting from increased local formation of angiotensin II and increased bradykinin degradation favors cardiovascular disease. Indeed, ACE inhibitors effectively reduce high blood pressure and exert cardio- and renoprotective actions. Recent evidence suggests that a principal target of ACE inhibitor action is at the tissue sites. Pharmacokinetic properties of various ACE inhibitors indicate that there are differences in their binding characteristics for tissue ACE. Clinical studies comparing the effects of antihypertensives (especially ACE inhibitors) on endothelial function suggest differences. More comparative experimental and clinical studies should address the significance of these drug differences and their impact on clinical events.

Ischemic, Hemodynamic, and Neurohormonal Responses to Mental and Exercise Stress Experience From the Psychophysiological Investigations of Myocardial Ischemia Study (PIMI)

BACKGROUND The pathophysiology of mental stress-induced myocardial ischemia, which occurs at lower heart rates than during physical stress, is not well understood. METHODS AND RESULTS The Psychophysiological Investigations of Myocardial Ischemia Study (PIMI) evaluated the physiological and neuroendocrine functioning in unmedicated patients with stable coronary artery disease and exercise-induced ischemia. Hemodynamic and neurohormonal responses to bicycle exercise, public speaking, and the Stroop test were measured by radionuclide ventriculography, ECG, and blood pressure and catecholamine monitoring. With mental stress, there were increases in heart rate, systolic blood pressure, cardiac output, and systemic vascular resistance that were correlated with increases in plasma epinephrine. During exercise, systemic vascular resistance fell, and there was no relationship between the hemodynamic changes and epinephrine levels. The fall in ejection fraction was greater with mental stress than exercise. During mental stress, the changes in ejection fraction were inversely correlated with the changes in systemic vascular resistance. Evidence for myocardial ischemia was present in 92% of patients during bicycle exercise and in 58% of patients during mental stress. Greater increases in plasma epinephrine and norepinephrine occurred with ischemia during exercise, and greater increases in systemic vascular resistance occurred with ischemia during mental stress. CONCLUSIONS Mental stress-induced myocardial ischemia is associated with a significant increase in systemic vascular resistance and a relatively minor increase in heart rate and rate-pressure product compared with ischemia induced by exercise. These hemodynamic responses to mental stress can be mediated by the adrenal secretion of epinephrine. The pathophysiological mechanism involved are important in the understanding of the etiology of myocardial ischemia and perhaps in the selection of appropriate anti-ischemic therapy.

Understanding Statin Use in America and Gaps in Patient Education (USAGE): An internet-based survey of 10,138 current and former statin users

BACKGROUND Statins substantially reduce the risk of cardiovascular disease and are generally well-tolerated. Despite this, many patients discontinue therapy. A better understanding of the characteristics of current and former statin users may be helpful for formulating strategies to improve long-term adherence. OBJECTIVE The Understanding Statin Use in America and Gaps in Education (USAGE) survey assessed the attitudes, beliefs, practices, and behavior of current and former statin users. METHODS Individuals 18 years or older who reported a history of high cholesterol and current or former statin use were identified within a registered consumer panel cohort in the United States and invited to participate in an Internet survey. RESULTS Of the 10,138 respondents, 8918 (88%) were current statin users and 1220 (12%) were former users. Participants (mean age 61 years) were predominantly white (92%), female (61%), of middle income (median

Mental Stress-Induced Ischemia and All-Cause Mortality in Patients With Coronary Artery Disease Results From the Psychophysiological Investigations of Myocardial Ischemia Study

44,504/yr), and had health insurance (93%). Among current users, 95% took a statin alone, and 70% had not missed a dose in the past month. Although ∼70% reported that their physicians had explained the importance of cholesterol levels for their heart health former users were less satisfied with the discussions (65% vs. 83%, P < .05). Muscle-related side effects were reported by 60% and 25% of former and current users, respectively (P < .05). Nearly half of all respondents switched statins at least once. The primary reason for switching by current users was cost (32%) and the primary reason for discontinuation was side effects (62%). CONCLUSIONS This survey provides important insights into behavior and attitudes among current and former statin users and the results suggest that more effective dialogue between healthcare providers and patients may increase persistence of statin use, particularly when the patient has concerns about side effects and drug costs.

Left Ventricular, Peripheral Vascular, and Neurohumoral Responses to Mental Stress in Normal Middle-Aged Men and Women Reference Group for the Psychophysiological Investigations of Myocardial Ischemia (PIMI) Study

Background—Ischemia during laboratory mental stress tests has been linked to significantly higher rates of adverse cardiac events. Previous studies have not been designed to detect differences in mortality rates. Methods and Results—To determine whether mental stress–induced ischemia predicts death, we evaluated 196 patients from the Psychophysiological Investigations of Myocardial Ischemia (PIMI) study who had documented coronary artery disease and exercise-induced ischemia. Participants underwent bicycle exercise and psychological stress testing with radionuclide imaging. Cardiac function data and psychological test results were collected. Vital status was ascertained by telephone and by querying Social Security records 3.5±0.4 years and 5.2±0.4 years later. Of the 17 participants who had died, new or worsened wall motion abnormalities during the speech test were present in 40% compared with 19% of survivors (P =0.04) and significantly predicted death (rate ratio=3.0; 95% CI, 1.04 to 8.36;P =0.04). Ejection fraction changes during the speech test were similar in patients who died and in survivors (P =0.9) and did not predict death even after adjusting for resting ejection fraction (P =0.63), which was similar in both groups (mean, 56.4 versus 59.7;P =0.24). Other indicators of ischemia during the speech test (ST-segment depression, chest pain) did not predict death, nor did psychological traits, hemodynamic responses to the speech test, or markers of the presence and severity of ischemia during daily life and exercise. Conclusions—In patients with coronary artery disease and exercise-induced ischemia, the presence of mental stress–induced ischemia predicts subsequent death.

Pathophysiologic and Therapeutic Importance of Tissue ACE: A Consensus Report

BACKGROUND The normal cardiovascular response to mental stress in middle-aged and older people has not been well characterized. METHODS AND RESULTS We studied 29 individuals 45 to 73 years old (15 women, 14 men) who had no coronary risk factors, no history of coronary artery disease, and a negative exercise test. Left ventricular (LV) volumes and global and regional function were assessed by radionuclide ventriculography at rest and during two 5-minute standardized mental stress tasks (simulated public speaking and the Stroop Color-Word Test), administered in random order. A substantial sympathetic response occurred with both mental stress tests, characterized by increases in blood pressure, heart rate, rate-pressure product, cardiac index, and stroke work index and rises in plasma levels of epinephrine and norepinephrine but not beta-endorphin or cortisol. Despite this sympathetic response, LV volume increased and ejection fraction (EF) decreased secondary to an increase in afterload. The change in EF during mental stress-varied among individuals but was associated positively with changes in LV contractility and negatively with baseline EF and changes in afterload. EF decreased > 5% during mental stress in 12 individuals and > 8% in 5; 3 developed regional wall motion abnormalities. CONCLUSIONS Mental stress in the laboratory results in a substantial sympathetic response in normal middle-aged and older men and women, but EF commonly falls because of a concomitant rise in afterload. These results provide essential age- and sex-matched reference data for studies of mental stress-induced ischemia in patients with coronary artery disease.

Echocardiographic evaluation of cardiac structure and function in elderly subjects with isolated systolic hypertension

Angiotensin-converting enzyme (ACE) activation and the de novo production of angiotensin II contribute to cardiovascular disease through direct pathological tissue effects, including vascular remodeling and inflammation, as well as indirect action on nitric oxide bioavailability and its consequences. The endothelium plays a pivotal role in both vascular function and structure; thus, the predominant localization of ACE to the endothelium has implications for the pathobiology of vascular disease, such as coronary artery disease. Numerous experimental studies and clinical trials support the emerging realization that tissue ACE is a vital therapeutic target, and that its inhibition may restore endothelial function or prevent endothelial dysfunction. These effects exceed those attributable to blood pressure reduction alone; hence, ACE inhibitors may exert an important part of their effects through direct tissue action. Pharmacologic studies show that while ACE inhibitors may differ according to their binding affinity for tissue ACE the clinical significance remains to be determined.

Influence of Race and Dietary Salt on the Antihypertensive Efficacy of an Angiotensin-Converting Enzyme Inhibitor or a Calcium Channel Antagonist in Salt-Sensitive Hypertensives

One hundred four participants in the Systolic Hypertension in the Elderly Program (SHEP) trial (mean age 71 +/- 6 years) were examined by Doppler echocardiography to gain information on the cardiac structural and functional alterations in isolated systolic hypertension. Participants had a systolic blood pressure greater than 160 mm Hg with diastolic blood pressure less than 90 mm Hg and were compared with 55 age-matched normotensive control subjects. Left ventricular mass index was significantly higher in the participants than in the normotensive subjects (103 +/- 28 versus 87 +/- 23 g/m2, p = 0.0014) and 26% of the participants met echocardiographic criteria for left ventricular hypertrophy compared with 10% of normotensive subjects. Left atrial index was also greater in participants than in normotensive subjects (2.26 +/- 0.32 versus 2.11 +/- 0.24 cm/m2, p = 0.005) and 51% of participants had left atrial enlargement. Doppler measures of diastolic filling were significantly different between the two groups, with peak atrial velocity higher (76 +/- 17 versus 69 +/- 17 cm/s, p = 0.02) and ratio of peak early to atrial velocity lower (0.76 +/- 0.23 versus 0.86 +/- 0.22, p = 0.0124) in participants. There was no correlation between left ventricular mass index and Doppler measures of diastolic function, but relative wall thickness correlated significantly with peak atrial velocity (r = 0.22, p = 0.016) and peak early to peak atrial velocity ratio (r = 0.24, p = 0.007). There was no difference in M-mode ejection phase indexes of systolic performance (shortening fraction and peak velocity of circumferential fiber shortening) between the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)