Timothy C. Fagan

The Cardiovascular Dysmetabolic Syndrome

Aclustering of metabolic abnormalities associated with cardiovascular disease has been recognized since at least 1988. This clustering has been given many names including Syndrome X, The Deadly Quartet, and The Insulin Resistance Syndrome. For various reasons each of these names is unsatisfactory. The Western Working Group believes that cardiovascular dysmetabolic syndrome (CDS) is the name that best describes this group of abnormalities, because it emphasizes the cardiovascular consequences of these abnormalities, recognizes that they are distinguishable abnormalities, and indicates that any given patient may have some or all of the components of the syndrome. The CDS is summarized in Table 1. The mnemonic D-R-O-P stands for Dyslipidemia, insulin Resistance, Obesity, and high blood Pressure. Other abnormalities that may be associated include elevated serum uric acid and elevated plasminogen activator inhibitor-1 (PAI-1) levels. Insulin resistance is thought to be central to the metabolic abnormalities, but all of the mechanisms are not established and other etiologies are possible. A diagnosis of CDS requires the presence of criteria for at least 2 of the first 3 components (dyslipidemia, insulin resistance, and obesity). Any component is a risk factor for macrovascular (coronary, cerebral, or peripheral vascular) disease. Additional components confer additional risk, although some, such as diabetes mellitus, confer more risk than others. These risk factors are in addition to, but not necessarily completely independent of, other traditional risk factors, such as established vascular disease, smoking, age, gender, elevated LDL cholesterol, sedentary lifestyle, and positive family history of vascular disease. All risk factors do not convey equal risk of atherosclerotic cardiovascular disease. Existing vascular disease increases risk of a subsequent event 5-fold compared to a patient without pre-existing vascular disease. Diabetes mellitus increases the risk of macrovascular disease 2-fold in men and 4 –5-fold in women. Thus, women with diabetes lose the protective effect of their gender and are at equally high risk of coronary artery disease (CAD) as men of the same age with the same additional risk factors. Hyperinsulinemia has been shown to be associated with CAD in multiple studies in nondiabetic men, but most studies in women have not shown a significant relationship. Recently, the Atherosclerosis Risk in Communities study has shown a significant relationship between plasma insulin levels and CAD in women. The relationship between CAD risk and increased plasma insulin levels is stronger in younger compared to older individuals. Whether hyperinsulinemia is a marker for insulin resistance and/or causative of atherosclerosis is unclear. Insulin resistance (which is harder to document than frank diabetes mellitus) is more highly correlated with atherosclerotic cardiovascular disease than is elevated insulin, per se. This may be because insulin levels are affected by many factors and elevated plasma insulin is only a surrogate for insulin resistance, and/or because insulin resistance impairs insulin-dependent production of nitric oxide (NO), which is anti-atherogenic, without affecting insulin-dependent vascular smooth muscle cell growth and migration, which are pro-atherogenic. Insulin resistance, rather than hyperglycemia, appears to be the primary factor in endothelial dysfunction in type 2 diabetes. Furthermore, insulin potentiates angiotensin II–stimulated production of PAI-1, which may contribute to a prothrombotic effect. Adequate studies are lacking regarding whether different insulin regimens—and specifically the 4 classes of oral hypoglycemic agents— have different effects on morbidity and mortality due to cardiovascular disease. Insulin resistance is difficult to detect clinically, although the extreme of type 2 diabetes mellitus is well defined. Fasting plasma glucose

Effects of ketorolac tromethamine on hemostasis in volunteers

110 mg/dL identifies persons who have insulin resistance. Diabetes mellitus affects approximately 6% of the US population, yet only 50% of those individuals have been diagnosed. These patients have predominantly type 2 diabetes mellitus. Significant sequelae often develop prior to diagnosis; at the time of diagnosis of type 2 diabetes, 20% of patients have retinopathy, 8% have nephropathy, and 9% have neuropathy. In addition to these microvascular complications, the prevalence of macrovascular complications is similar to that in diagnosed type 2 diabetes. The new classification promulgated by the American Diabetes Association (ADA) divides diabetes mellitus into type 1 (absolute insulin deficiency) and type 2 (insulin resistance with inadequate compensatory insulin secretory response), as well as gestational diabetes and From the Departments of Medicine and Pharmacology, University of Arizona College of Medicine, Tucson, Arizona; Cardiology Division, Department of Medicine, University of California, San Francisco, San Francisco, California; Stanford University Medical Center, Palo Alto, California. Requests for reprints should be addressed to Timothy C. Fagan, MD, University Health Care at Ventana Vista, 5620 North Kolb Road, Suite 166, Tucson, Arizona 85750.

Application of ambulatory blood pressure monitoring in differentiating between antihypertensive agents

Ketorolac tromethamine, an analgesic agent with prostaglandin synthetase–inhibiting activity, is more active than aspirin in vitro in inhibiting collagen– or arachidonic acid–induced platelet aggregation. In this randomized, double‐blind study, 26 volunteers received ketorolac, 30 mg intramuscularly four times a day for 5 days, and placebo, two capsules orally four times a day for at the last 2 study days. The effects of this treatment were compared with those of intramuscular placebo and oral aspirin, two 325 mg capsules, given on the same schedule to eight volunteers. Aspirin at a mean serum concentration of 84 μg/ml did not affect prothrombin time, partial thromboplastin time, platelet count, or bleeding time. Ketorolac produced a modest prolongation of the bleeding time, from 4.9 ±1.1 minutes (mean ± SD) to 7.8 ± 4.0 minutes (p < 0.005). Ketorolac did not affect the prothrombin time or partial thromboplastin time but was associated with clinically insignificant change in the platelet count from 303 ± 57 × 103/m3 to 277 ± 56 × 103/mm3.

Effects of candesartan cilexetil in patients with severe systemic hypertension

PURPOSE This multicenter, double-blind, parallel group study assessed the usefulness of the ambulatory blood pressure monitoring (ABPM) technique in differentiating between the once-daily administration of the beta blockers bisoprolol (10 to 20 mg) and atenolol (50 to 100 mg) in terms of efficacy and duration of action. PATIENTS AND METHODS The study population consisted of 659 patients with essential hypertension and an average office diastolic blood pressure (BP) between 95 and 115 mm Hg after 4 weeks of placebo treatment. Office BPs were recorded at the end of the 24-hour dosing interval (trough). ABPM was performed in 11 of the 28 institutions participating in this study in a total of 203 patients. These procedures were performed at the end of the placebo phase and again after 8 weeks of active treatment. RESULTS With the use of conventionally measured office BPs, the two drugs significantly (p < 0.001) decreased trough systolic and diastolic BPs to a similar extent. By 24-hour monitoring, bisoprolol demonstrated a 33% greater reduction in whole-day average diastolic BP than did atenolol (11.6 +/- 0.7 mm Hg versus 8.7 +/- 0.8 mm Hg, p < 0.01). Significant treatment differences in systolic (p < 0.05) and diastolic (p < 0.01) BPs were also noted for bisoprolol compared with atenolol during the final 4 hours of the dosing interval (-13.2 +/- 1.5/-10.9 +/- 1.0 mm Hg versus -8.9 +/- 1.6/-7.3 +/- 1.1 mm Hg, respectively), and over the time period 6:00 AM to noon (-14.2 +/- 1.3/-11.5 +/- 0.9 mm Hg versus -9.9 +/- 1.4/-7.7 +/- 0.9 mm Hg). CONCLUSIONS Whereas conventional BP measurements did not detect differences in the antihypertensive effects of the beta blockers bisoprolol and atenolol, ABPM revealed significant treatment differences in both the efficacy and duration of action of these two agents. These findings indicate the power of this technique to discriminate potentially important differences between apparently similar antihypertensive drugs.

Effects of meals on hemodynamics: Implications for antihypertensive drug studies

The efficacy, tolerability, and safety of the potent angiotensin II receptor blocker candesartan cilexetil were evaluated in 217 adult patients (68% men, 41% black) with severe systemic hypertension on background therapy with hydrochlorothiazide (HCTZ) in a 4-week, multicenter, randomized, double-blind, placebo-controlled study. Patients with sitting diastolic blood pressure (BP) > or =110 mm Hg during the placebo run-in received HCTZ 12.5 mg once daily for 1 week. Those with sitting diastolic BP >95 mm Hg after the HCTZ run-in were randomized (2:1) to receive candesartan cilexetil 8 mg once daily (n = 141) or placebo (n = 76), plus HCTZ 12.5 mg. After 1 week of double-blind treatment, patients with sitting diastolic BP > or =90 mm Hg were uptitrated to candesartan cilexetil 16 mg once daily or matching placebo, plus HCTZ 12.5 mg; 84% required uptitration. Primary efficacy measurement was a change in trough (24+/-3 hours after treatment) sitting diastolic BP from the end of the HCTZ run-in to double-blind week 4. Mean changes in systolic and diastolic BP were significantly greater with candesartan cilexetil than with placebo, -11.3/-9.1 mm Hg versus -4.1/-3.1 mm Hg, p <0.001/p <0.001, respectively. Patients with higher sitting diastolic BP at the end of the HCTZ run-in tended to have greater decreases in BP (p <0.05). Most patients (53%) receiving candesartan cilexetil were responders (diastolic BP <90 mm Hg or > or =10 mm Hg decrease) and 32% were controlled (diastolic BP <90 mm Hg). Tolerability and safety profiles were similar in the candesartan and placebo groups. In conclusion, candesartan cilexetil 8 to 16 mg once daily was an effective and well-tolerated therapy for lowering BP when added to HCTZ 12.5 mg in a diverse population of patients with severe systemic hypertension in the United States.

Cardiovascular safety of sublingual apomorphine in patients on stable doses of oral antihypertensive agents and nitrates.

The ingestion of food is known to affect blood pressure and heart rate, but food is often allowed in patients under observation for antihypertensive drug effects. Seventy‐seven patients with essential hypertension were observed for 8 hours after a 16‐hour fast. Thirty‐six continued to fast, 20 ate a high‐carbohydrate meal, and 21 ate a meal of their own choice. Blood pressure and heart rate did not change during fasting, but both meals lowered mean supine and standing diastolic blood pressures during the subsequent 4 hours by 3 to 7 mm Hg (P < 0.001). The high‐carbohydrate meal reduced supine systolic blood pressure by 6 mm Hg (P < 0.0001). Both meals increased supine and standing heart rates by 5 to 8 bpm (P < 0.001). After the self‐selected meal, standing systolic blood pressure increased in younger patients but decreased in older patients. Food ingestion during antihypertensive drug studies may interfere with the interpretation of results and should be avoided whenever possible.

A comparative trial of controlled-onset, extended-release verapamil, enalapril, and losartan on blood pressure and heart rate changes.

Sublingual (SL) apomorphine (2 to 6 mg) has been shown to be effective for treatment of male erectile dysfunction. Many patients with erectile dysfunction are also being treated for systemic hypertension and/or cardiovascular disease. In a double-blind, randomized, placebo-controlled, crossover trial, SL apomorphine 5 mg and placebo were administered on alternate days to 162 men who were on long-term therapy (> or =4 weeks) with angiotensin-converting enzyme inhibitors, beta blockers, diuretics, calcium channel blockers, alpha(1) blockers, or short- or long-acting nitrates. Blood pressure and heart rate were measured before and after dosing; cardiac rhythm was recorded by 4-hour Holter monitoring. The only potentially clinically significant interactions between SL apomorphine and the antihypertensive agents or short-acting nitrates were greater orthostatic decreases in systolic blood pressure in the alpha-blocker and calcium channel blocker groups (-10 and -6 mm Hg vs placebo, respectively). Administration of SL apomorphine after dosing with long-acting nitrates resulted in significant decreases in blood pressure when patients were standing (mean systolic change, -5 to -9 mm Hg 30 to 60 minutes postdose, p <0.05; mean diastolic change, -3 to -4 mm Hg 50 to 60 minutes postdose, p <0.05). The most common adverse events with SL apomorphine were dizziness, nausea, and headache. Syncope occurred in 1 patient in the beta-blocker group; symptomatic hypotension occurred in 2 patients each in the short- and long-acting nitrate groups. Thus, in patients receiving common antihypertensive agents and short-acting nitrates, as well as in most patients receiving long-acting nitrates, SL apomorphine at higher than recommended doses produced no clinically significant changes in heart rate or blood pressure greater than changes seen with SL apomorphine alone.

Doxazosin in patients with hypertension

BACKGROUND The excess morning risk of myocardial infarction and stroke may be attributable to the rapid rise in blood pressure (BP) and heart rate in the hours after awakening. The aim of this randomized, double-blinded, placebo-controlled, multicenter study was to compare once-daily, controlled-onset, extended-release (COER-24) verapamil to enalapril and losartan on BP and heart rate during the postawakening morning phase as well as throughout the 24-h period. METHODS A total of 406 patients were randomized to an 8-week forced-titration period with one of the following: 1) COER-24 verapamil 240 mg/day titrated to 360 mg/day; 2) enalapril 10 mg/day titrated to 20 mg/day, 3) losartan 50 mg/day titrated to 100 mg/day, or 4) placebo. Office BP and heart rate and ambulatory 24-h BP monitoring was performed at baseline, 4 weeks, and 8 weeks. RESULTS Each active treatment, as compared with placebo, lowered BP both during the morning hours as well as the entire 24-h period. COER-24 verapamil was more effective in lowering morning systolic (-16.6 mm Hg) and diastolic (-11.9 mm Hg) BP than either enalapril or losartan (P < .001). For the entire 24-h period, the effects of COER-24 verapamil (-11.6/-8.4 mm Hg) were comparable to enalapril (- 13.4/-8.3 mm Hg; P = NS). Losartan achieved a similar 24-h effect on systolic pressure (-9.3 mm Hg) but was less effective on diastolic pressure (-5.4 mm Hg; P = .004 v COER-verapamil). Unlike losartan or enalapril, COER-24 verapamil was the only treatment to lower the heart rate over both the 24-h period (-4.6 beats/min; P < .001) and during waking hours (-4.6 beats/min; P < .001). A blunted rate of rise in BP, heart rate, and rate-pressure product occurred during the postawakening period with COER-verapamil (P = .03) but not with either of the other treatment arms. Lastly, the decline in BP at night was similar for COER-verapamil and losartan and greater with enalapril (P = .014) CONCLUSIONS COER-24 verapamil produces changes in BP and pulse that more closely match the normal circadian hemodynamic rhythms than either do enalapril or losartan.

Single versus triplicate measurements of blood pressure and heart rate.

SummaryThe antihypertensive effects and steady-state pharmacokinetics of doxazosin, as well as the bioequivalence of four dosage forms, were studied in 25 hypertensive patients.For an 8 mg daily dose mean Cmax at steady-state for all patients was 108 ng/ml; the mean tmax was 1.8 h. The mean terminal elimination half-life was 22 h. The four tablets containing 1, 2, 4, or 8 mg of doxazosin were bioequivalent in delivering the 8 mg dose.In patients with mild to moderate hypertension, 26-day treatment with doxazosin resulted in blood pressure reduction of 10/7 mm Hg in the supine and 13/18 mm Hg in the standing position. Adverse effects were generally mild and of brief duration.

Efficacy and safety comparison of nitrendipine and hydralazine as antihypertensive monotherapy.

The mean of rapidly repeated duplicate or triplicate measurements is often used in studies of antihypertensive drugs. Forty patients with hypertension had triplicate measurements of blood pressure and heart rate on two occasions, 1 week apart, during placebo treatment. The average difference between the first measurement and the mean of the triplicate measurements was -0.3 mm Hg. The average coefficient of variation for supine and standing, systolic and diastolic blood pressures was 8.4% for the single measurements and 8.0% for the mean of triplicate measurements. The correlations between the first measurements and the mean of triplicate measurements ranged from 0.90 to 0.98 (all p less than 0.01). The average difference between the two visits for all four blood pressure parameters was -0.6 mm Hg for the single measurements and -0.5 mm Hg for the mean of triplicate measurements (all p = NS). These results indicate that 1) blood pressure does not change further after 1 week of placebo treatment, and 2) use of the mean of triplicate measurements of blood pressure and heart rate gives the same result as use of single measurements, and the results are no less variable.