The TPA controversy and the drug approval process. The view of the Cardiovascular and Renal Drugs Advisory Committee.
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Cerebral Hemorrhage↗
Biomedical subjects
F H Messerli
Publications and source records attributed to F H Messerli.
Myocardial contractility and left ventricular function in obese patients with essential hypertension.
Although the risk of developing congestive heart failure increases in parallel with the degree of obesity, load-dependent indexes of left ventricular function are found to be reduced in patients with morbid obesity only. We used the ratio of end-systolic wall stress to end-systolic volume index, which is load-independent, to assess myocardial contractility in 23 nonobese, 28 mildly obese and 26 moderately obese patients with mild to moderate essential hypertension. Although load-dependent indexes (i.e., ejection fraction, fractional fiber shortening and velocity of circumferential fiber shortening) were similar in the 3 groups, end-systolic wall stress to end-systolic volume index was lower in the moderately obese group (2.63 +/- 0.4, p less than 0.002) and even in the mildly obese group (2.88 +/- 0.8, p less than 0.05) than in the nonobese group (3.27 +/- 0.7). Further, there was a significant inverse relation between end-systolic wall stress to end-systolic volume index and body mass index (r = -0.34, p less than 0.005), diastolic diameter (r = -0.56, p less than 0.001) and left ventricular mass index (r = -0.55, p less than 0.001). Some obese patients have depressed myocardial contractility when compared with lean patients despite well-preserved pump function.
Adult↗
Does the renin-angiotensin-aldosterone system modify cardiac structure and function in essential hypertension?
To determine the impact of the renin-angiotensin-aldosterone system on left ventricular function and structure, 36 untreated patients with essential hypertension (WHO class I and II) were examined. Posterior wall thickness, relative wall thickness, and left ventricular mass were determined by M-mode echocardiography. Plasma renin activity, aldosterone, angiotensin I, and angiotensin II levels were measured by radioimmunoassay. Plasma renin activity was related to 24-hour urinary sodium excretion. Of all the endocrine parameters, only the angiotensin II level correlated with posterior wall thickness (r = 0.50, p less than 0.05) and relative wall thickness (r = 0.46, p less than 0.05). This relationship was confirmed by stepwise multiple regression analysis taking arterial pressure, obesity, and sodium excretion into account (p less than 0.05). Plasma renin activity but not the angiotensin II level correlated positively with the ejection fraction (r = 0.42, p less than 0.05) and velocity of circumferential fiber shortening (r = 0.57, p less than 0.01). Thus, angiotensin II emerged as a determinant of left ventricular structural adaptation in essential hypertension.
Aldosterone↗
Ambulatory blood pressure monitoring: practical considerations.
Ambulatory blood pressure monitoring (ABPM) allows one to evaluate the blood pressure (BP) profile over a 24-hour period in the patient's natural environment. Casual pressure measurements in the physician's office can be affected by alarm reactions, thus causing "white coat" hypertension. ABPM allows one to evaluate these reactions and determine the average pressure and variability of BP along with the effects of physical activity and emotional arousal on BP patterns while at work, at home, and during sleep. Average pressures determined by ABPM are more predictive of target organ involvement and cardiovascular complications of hypertension than casual monitoring of BP in the clinic. The absence of physiologic decline in arterial pressure during sleep is associated with increased prevalence of atherosclerotic complications and left ventricular hypertrophy as well as impairment of the autonomic nervous system. Although further prospective studies are needed to confirm the benefits of home pressure readings and ABPM, ABPM can be helpful in the diagnosis and determination of prognosis and therapeutic responses in a select group of patients.
Blood Pressure↗
The heterogeneity of essential hypertension: hemodynamic aspects.
Numerous studies over the past few years have indicated that mechanisms of pressure elevation are not uniform in all patients with essential hypertension. Simple clinical findings such as age, sex, body habitus, and race often allow us to define the predominant pathogenetic mechanism. Not only is the hemodynamic and biochemical pattern of essential hypertension different in patient subgroups, but manifestations of target organs and therefore the risk of cardiovascular disease also vary distinctly from one group to another. Identifying the predominant hemodynamic, biochemical, and target organ disease pattern in a given patient will help the physician to select more specific antihypertensive therapy and thereby, it is hoped, prevent or reverse target organ disease and improve the quality of life.
Hemodynamics↗
Angiotensin converting enzyme inhibitors. Disparities in the mechanism of their antihypertensive effect.
Systemic and renal hemodynamics were studied by invasive and noninvasive techniques in 30 patients with mild to moderate essential hypertension before and after antihypertensive therapy with captopril (12 patients), enalapril (8 patients), and lisinopril (10 patients). All three angiotensin-converting enzyme (ACE) inhibitors reduced arterial pressure to about the same extent: captopril by 14%, enalapril by 18%, and lisinopril by 13%. However, lisinopril produced a significant fall (14%, P less than 0.001) in cardiac output that was not seen with captopril or enalapril therapy. Moreover, lisinopril elicited an increase in renal blood flow (22%, P less than 0.05) that was more marked than that with enalapril (12%) or captopril (4%). Although left ventricular mass was reduced (P less than 0.05) with all three agents, enalapril induced a twofold greater reduction (29%) than captopril (14%) or lisinopril (12%). These findings suggest that systemic and renal hemodynamic effects may be drug specific and not uniform for all ACE inhibitors.
Adult↗
Sodium intake modulates left ventricular hypertrophy in essential hypertension.
In order to assess the impact of dietary sodium intake on the degree of left ventricular hypertrophy, we determined posterior wall thickness, relative wall thickness and left ventricular mass by two-dimensionally guided M-mode echocardiography, and related these parameters to sodium excretion over 24 h. There was no restriction on sodium intake. The first cohort comprised 43 subjects (residents of New Orleans) with mild to moderate essential hypertension who had not been treated for at least 4 weeks; in this cohort sodium excretion correlated with posterior wall thickness (r = 0.64, P less than 0.001), relative wall thickness (r = 0.67, P less than 0.001) and left ventricular mass (r = 0.37, P less than 0.02). A stepwise multiple regression analysis confirmed that sodium excretion was a determinant of posterior wall thickness (P less than 0.02) and relative wall thickness (P less than 0.05) independently of age, arterial pressure and body weight. The second cohort comprised 60 white male patients (residents of Bonn) with mild essential hypertension who had never been treated in the past; in this cohort sodium excretion correlated with diastolic diameter (r = 0.36, P less than 0.001) and with left ventricular mass (r = 0.35, P less than 0.001). Sodium excretion and systolic pressure emerged as independent variables (P less than 0.02) for left ventricular mass as evaluated by multiple regression analysis. These results identify dietary sodium intake as an independent powerful determinant of left ventricular hypertrophy in two disparate patient cohorts. Thus, for a similar haemodynamic load, sodium intake might accelerate, and conversely salt restriction mitigate, cardiac structural adaptation in patients with essential hypertension.
Cardiomegaly↗
Effects of calcium channel blockade on cardiac repercussions of long-standing hypertension.
Left ventricular hypertrophy (LVH) is a common sequela of long-standing hypertension. However, LVH can no longer be considered as an adaptive process serving to normalize wall stress. The occurrence of LVH in a given patient significantly increases the risk of sudden death, myocardial ischemia, congestive heart failure, and other cardiovascular morbidity and mortality. Patients with LVH often exhibit increased ventricular ectopic activity, myocardial ischemia, and diminished ventricular compliance even in the absence of coronary artery disease. LVH has been shown to regress in parallel with arterial pressure when specific antihypertensive agents are given. Recent evidence indicates that calcium channel blockers cannot only lower pressure and reduce LVH but will suppress ectopic impulse generation, improve ventricular compliance, and alleviate myocardial ischemia in susceptible patients as well. However, whether such a promising therapeutic approach will ultimately diminish the risk of the well-documented increased cardiovascular morbidity and mortality associated with LVH remains to be documented.
Calcium Channel Blockers↗
Hypertensive concentric left ventricular hypertrophy: when is ventricular ectopic activity increased?
The Framingham Study has indicated that patients with left ventricular hypertrophy (LVH) have a greater risk of cardiovascular complications and sudden death than subjects with a normal heart. We have previously demonstrated that ventricular ectopy was more prevalent and complex in hypertensive patients with LVH by electrocardiographic (ECG) criteria than in those without ECG evidence of LVH. The present study was designed to detect and quantify ventricular dysrhythmias in hypertensive patients with early concentric LVH by echocardiography but without LVH by ECG criteria. Continuous ambulatory ECG tracings were recorded for 24 hours in 94 patients with essential hypertension: 37 without LVH, 26 with concentric LVH by echocardiographic but not ECG criteria, and 31 with LVH on both echocardiography and ECG. Patients with LVH by ECG criteria had significantly more premature ventricular contractions (P less than .001) and more complex (higher Lown's class) ventricular ectopy (P less than .001) than hypertensives without LVH or with LVH only by echocardiographic criteria. Prevalence and complexity of ventricular ectopic activity, however, was not affected by mild to moderate concentric cardiac hypertrophy detected echocardiographically. We conclude that unlike LVH shown by ECG, early hypertensive concentric LVH detected echocardiographically is not associated with increased electrical irritability of the myocardium.
Adult↗
Dietary salt intake. A determinant of cardiac involvement in essential hypertension.
Because a given increase in afterload does not consistently produce the same degree of left ventricular hypertrophy, we evaluated several clinical, hemodynamic, and endocrine factors that are prone to modify the adaptation of left ventricular structure in patients with mild essential hypertension (World Health Organization stages I or II). Dietary salt intake assessed by sodium excretion over 24 hours was a powerful determinant of posterior wall thickness (r = 0.64, p less than 0.001), relative wall thickness (r = 0.67, p less than 0.001), and left ventricular mass (r = 0.37, p less than 0.05). In contrast, diastolic pressure, body mass index, hematocrit, and epinephrine were found to be weaker determinants of left ventricular structure (r = 0.31-0.40, p less than 0.05). A stepwise multiple regression analysis revealed that sodium excretion was the strongest predictor for posterior wall thickness (p less than 0.02) and relative wall thickness (p less than 0.05) independent of the other examined variables. These results identify dietary salt intake as a strong determinant of cardiac structural adaptation to a persistent increase in arterial pressure. Consequently, a high salt intake might aggravate and, conversely, dietary salt restriction might prevent (or at least mitigate) the development of left ventricular hypertrophy in patients with essential hypertension.
Blood Pressure↗
Systemic and regional hemodynamic and humoral effects of nitrendipine in essential hypertension.
The hemodynamic effects of 3 months of nitrendipine therapy were evaluated in 14 patients with mild to moderate essential hypertension. Nitrendipine reduced systolic and diastolic pressures from 145 +/- 4/95 +/- 3 to 119 +/- 3/78 +/- 2 mm Hg, respectively, (p less than 0.001) through a fall in total peripheral resistance index (46 +/- 4 to 34 +/- 3 units/m2, p less than 0.001) without associated reflex cardiac stimulation. This antihypertensive effect was related directly to the height of pretreatment arterial pressure (r = -0.67, p = 0.006) but not to age or pretreatment plasma renin activity. Renal and forearm blood flow increased, vascular resistance decreased, and glomerular filtration rate remained stable. In addition, nitrendipine reduced left ventricular mass index (133 +/- 7 to 116 +/- 5 g/m2, p = 0.003) and wall thickness, changes that were accompanied by improvement in diastolic as well as systolic (ejection fraction and fractional fiber shortening rate) left ventricular functions. Intravascular volume did not expand with reduction in pressure. This study provides new information concerning the long-term hemodynamic effects and associated echocardiographic changes with nitrendipine. It also provides the first regional hemodynamic data in essential hypertensive patients detailing forearm and splanchnic changes and renal blood flow increase during prolonged treatment.
Aged↗
Left ventricular hypertrophy and antihypertensive therapy.
Cardiac adaptation to long-standing arterial hypertension consists of left ventricular hypertrophy (LVH), usually of the concentric type, i.e. an increase in wall thickness at the expense of chamber volume. LVH can no longer be considered only as a simple adaptive myocardial process; it drastically increases the risk of sudden death and cardiovascular morbidity and mortality, irrespective of the levels of arterial pressure. Patients with LVH have more premature ventricular contractions than patients without LVH or normotensive subjects, which indicates that LVH per se increases ventricular ectopic activity. Antihypertensive therapy should not only lower blood pressure, but also prevent or improve end-organ damage and therefore allow left ventricular mass to regress. Although they lower blood pressure, certain antihypertensive agents such as the thiazide diuretics and arteriolar dilators (hydralazine, minoxidil) have little or even a detrimental effect on LVH. In contrast, other agents such as angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, antiadrenergic drugs, and certain calcium antagonists decrease left ventricular mass in parallel with arterial pressure. Recent evidence has shown that a decrease in left ventricular mass induced by certain antihypertensive drugs suppresses ventricular ectopic activity by 85%. In contrast, left ventricular mass and ventricular ectopic activity remain unchanged or may even increase in patients treated with diuretics. It is not known whether the risk of sudden death can be decreased and the ominous prognosis of LVH altered by such specific antihypertensive therapy.
Antihypertensive Agents↗
Haemodynamic effects of urapidil in arterial hypertension and congestive heart failure.
An elevated total peripheral resistance is the haemodynamic hallmark of both arterial hypertension and congestive heart failure. In essential hypertension it is the main pathogenetic abnormality, whereas in congestive heart failure it is the result of vasoconstriction serving to compensate for the fall in cardiac output and arterial pressure. Any drug that lowers total peripheral resistance can, therefore, potentially favourably influence established hypertension as well as unload the left ventricle in congestive failure. In essential hypertension, urapidil lowers arterial pressure acutely by a fall in total peripheral resistance with a small compensatory increase in cardiac output. Concomitantly, renal and splanchnic blood flow increase and the resistance in these vascular beds falls. In congestive heart failure, the acute administration of urapidil increases cardiac index and lowers mean pulmonary artery wedge pressure and systemic vascular resistance by about 30%. At the same time, a mild fall in mean arterial pressure is observed. Long term non-invasive studies document that these acute haemodynamic effects remain preserved in both arterial hypertension and congestive heart failure. Urapidil seems, therefore, to be a promising agent for the treatment of haemodynamic disorders that are characterised by an elevation of total peripheral resistance, such as established essential hypertension and congestive heart failure.
Antihypertensive Agents↗
High blood pressure: side effects of drugs, poisons, and food.
A number of therapeutic agents, foods, chemicals, and poisons have been associated with the development or exacerbation of hypertension. This review discusses those identified in recent years.
Drug-Related Side Effects and Adverse Reactions↗
[Risks in the development of hypertension].
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Alcohol Drinking↗
Antihypertensive therapy and cardiovascular reactivity during isometric stress.
The cardiovascular reactivity to isometric stress test before and after antihypertensive therapy was evaluated by invasive haemodynamic techniques in 23 patients with mild to moderate essential hypertension. A beta-blocking agent (atenolol 50 to 100 mg daily) was given to 11 patients; 12 patients received calcium entry blockers (diltiazem 240 to 360 mg daily or verapamil 240 to 480 mg per day). The pressor response to isometric stress before therapy consisted of an increase in systolic, diastolic, and mean arterial pressure (all P less than 0.01) that was similar in both treatment groups. The rise in arterial pressure was mainly due to an increase in cardiac output (P less than 0.01), as total peripheral resistance did not change significantly. After treatment with the beta-blocker, the increase in total peripheral resistance during isometric stress was exaggerated (P less than 0.01), and, conversely, the increase in cardiac output was attenuated (P less than 0.01). In contrast, treatment with calcium entry blockers preserved the haemodynamic reactivity pattern of the untreated state: arterial pressure increased during isometric stress through an increase in cardiac output, while total peripheral resistance remained unchanged. Since the haemodynamic culprit of essential hypertension is an elevated peripheral resistance, a drug that numerically increases this culprit under conditions of resting and isometric stress becomes less attractive than one that lowers peripheral resistance and preserves the physiologic response pattern.
Adult↗
Essential hypertension. Matching pathophysiology and pharmacology.
The underlying pathophysiologic mechanisms that elevate arterial pressure differ according to the patient's age, adipose body mass, and race. However, these mechanisms represent the extremes of a continuum, and overlap among them can be encountered in some patients. A few simple clinical clues allow the physician to identify whether an increase in cardiac output, total peripheral resistance, or both is the predominant mechanism in a given patient. Antihypertensive therapy should be aimed not only at lowering arterial pressure but also, more importantly, at ameliorating the concomitant pathophysiologic abnormality. A beta-adrenoreceptor blocker is the initial drug of choice in young patients with "cardiogenic hypertension." In middle-aged patients, cardiac output is usually normal and elevated total peripheral resistance becomes the hemodynamic culprit. In these patients, an angiotensin-converting enzyme (ACE) inhibitor, antiadrenergic drug, or calcium channel blocker should be given to lower total peripheral resistance without affecting cardiac output. In elderly patients, the burden on the heart should be lessened by use of an agent that lowers preload and afterload, such as an ACE inhibitor or certain of the calcium blockers. In obese patients in whom intravascular volume is expanded and in most black patients, the initial antihypertensive agent of choice remains a thiazide diuretic unless left ventricular hypertrophy is present.
Adolescent↗
Overweight and sudden death. Increased ventricular ectopy in cardiopathy of obesity.
Obesity has been documented to be an independent risk factor for sudden death and other cardiovascular mortality. The present study was designed to monitor and quantify cardiac arrhythmias in obese subjects with and without eccentric left ventricular hypertrophy, who were matched with regard to arterial pressure, age, sex, and height with lean subjects. Prevalence of premature ventricular (but not atrial) contractions was 30 times higher in obese patients with eccentric left ventricular hypertrophy compared with lean subjects. Similarly, obese patients with left ventricular hypertrophy scored higher with regard to the classification of Lown and Wolf than those without left ventricular hypertrophy and lean subjects having the same level of arterial pressure. Patients' class in the Lown and Wolf system correlated with ventricular diastolic diameter and left ventricular mass. Thus, heart enlargement of the eccentric type as a consequence of obesity predisposes to excessive ventricular ectopy. Echocardiographic assessment and electrocardiographic monitoring allow us to identify the patients who are at highest risk of more serious arrhythmias or possibly sudden death and to subject them to the most specific preventive and therapeutic measures.
Adult↗