Richard I. Ogilvie

Aortic Diameter, Wall Stiffness, and Wave Reflection in Systolic Hypertension

Systolic hypertension is associated with increased pulse pressure (PP) and increased risk for adverse cardiovascular outcomes. However the pathogenesis of increased PP remains controversial. One hypothesis suggests that aortic dilatation, wall stiffening and increased pulse wave velocity result from elastin fragmentation, leading to a premature reflected pressure wave that contributes to elevated PP. An alternative hypothesis suggests that increased proximal aortic stiffness and reduced aortic diameter leads to mismatch between pressure and flow, giving rise to an increased forward pressure wave and increased PP. To evaluate these two hypotheses, we measured pulsatile hemodynamics and proximal aortic diameter directly using tonometry, ultrasound imaging, and Doppler in 167 individuals with systolic hypertension. Antihypertensive medications were withdrawn for at least 1 week before study. Patients with PP above the median (75 mm Hg) had lower aortic diameter (2.94±0.36 versus 3.13±0.28 cm, P<0.001) and higher aortic wall stiffness (elastance-wall stiffness product: 16.1±0.7 versus 15.7±0.7 ln[dyne/cm], P<0.001) with no difference in augmentation index (19.9±10.4 versus 17.5±10.0%, P=0.12). Aortic diameter and wall stiffness both increased with advancing age (P<0.001). However, an inverse relation between PP and aortic diameter remained significant (P<0.001) in models that adjusted for age, sex, height, and weight and then further adjusted for aortic wall stiffness, augmentation index, and mean arterial pressure. Among individuals with systolic hypertension, increased PP is primarily attributable to increased wall stiffness and reduced aortic diameter rather than premature wave reflection.

Pharmacokinetic and pharmacodynamic interactions between nisoldipine and propranolol

The pharmacokinetic and pharmacodynamic effects of nisoldipine, a 1,4‐dihydropyridine calcium entry blocker, and the lipophilic β‐adrenoceptor blocker propranolol were assessed alone and in combination in 12 healthy men. Oral nisoldipine, 20 mg, or placebo was followed 1 hour later by propranolol, 40 mg, or placebo using a randomized, crossover, double‐blind design. Nisoldipine significantly increased the AUC (+ 43%) and peak plasma drug concentration (Cmax) (+ 68%) of propranolol resulting in a higher degree of β‐adrenoceptor blockade (as assessed by isoproterenol). Conversely, nisoldipines AUC (+ 30%) and Cmax (+ 57%) were increased with concomitant administration of propranolol. Nisoldipine did not affect blood pressure but caused significant decreases in total peripheral resistance (TPR) and increases in plasma catecholamines and cardiac index. Forearm vascular resistance and blood flow changed more markedly than did TPR and cardiac index. In contrast, propranolol had little effect on forearm hemodynamics despite significant decreases in cardiac index and increases in TPR. The data are compatible with changes in hepatic blood flow, accounting for the pharmacokinetic interaction of nisoldipine and propranolol. Different vascular beds appear to contribute to the effects of nisoldipine vs. propranolol on peripheral resistance.

Determinants of left ventricular mass in early hypertension

One hundred seventy-six unmedicated mildly hypertensive subjects (113 men, 63 women) underwent M-mode echocardiography to determine left ventricular mass (LVM) and relative wall thickness (RWT), 24-h ambulatory blood pressure monitoring, and completed standardized questionnaires measuring marital and job stress. Subjects were aged 46 +/- 9 years old; 45.4% had daytime diastolic blood pressure < 90 mm Hg; 96.1% of LVM results were in the normal range. We found that neither marital distress nor job strain was a determinant of LVM. However, a segmental regression approach revealed inflection points of 131 mm Hg systolic daytime blood pressure and 83 and 87 mm Hg nighttime diastolic blood pressure in the relation between LVM and RWT, respectively, and ambulatory BP. In addition, we found that the variability of LVM was best explained by indexing LVM by height, rather than body surface area.

The Effects of Cardiac Transplantation and Cyclosporine Therapy on Digoxin Pharmacokinetics

Most patients needing cardiac transplantation are treated with digoxin for heart failure. Because of its narrow therapeutic range, even recommended doses of digoxin may cause severe toxicity. Several drugs, including quinidine, amiodarone, verapamil, and propafenone can interact with digoxin, leading to toxic accumulation of the glycoside. The authors have recently reported two cases of severe digitalis toxicity after the initiation of cyclosporine treatment in patients awaiting cardiac transplantation. A preliminary study on two additional patients suggested that cyclosporine reduced the plasma clearance and volume of distribution of digoxin. To assess the mechanism of this interaction, the authors studied digoxin pharmacokinetics in patients awaiting cardiac transplantation and again after the surgery, during chronic cyclosporine therapy. To separate the effects of transplantation and cyclosporine on digoxin pharmacokinetics, pharmacokinetic studies were subsequently performed in dogs to allow controlled experimental conditions for evaluation of the digoxin‐cyclosporine interaction.

Perindopril for control of blood pressure in patients with hypertension and other cardiovascular risk factors: an open-label, observational, multicentre, general practice-based study.

AbstractBackground and objectives: Hypertension, one of the major treatable cardiovascular (CV) risk factors, usually occurs in association with other major risk factors. As well as providing rapid blood pressure (BP) goal attainment, antihypertensive therapy should also provide reductions in CV events and mortality in a wide range of patients. For this, higher dosages and combinations of antihypertensive agents are often required. ACE inhibitors are recommended as first-line agents for control of hypertension in patients with additional CV risk factors. The PEACH (Perindopril’s Effect At Controlling Hypertension) study was a community-based study performed to evaluate the effectiveness and safety of highdose perindopril in patients with mild-to-moderate hypertension and additional risk factors for CV disease.n Methods: This was an open-label, multicentre observational study conducted in Canadian general practice clinics. The study assessed the efficacy and tolerability of perindopril given once daily for 10 weeks uptitrated to the maximal recommended dose of perindopril as required for BP control in newly diagnosed or previously treated patients with uncontrolled mild to moderate hypertension and ≥1 additional risk factor. Patients not achieving target BP after 2 weeks of therapy were uptitrated from perindopril 4 mg to perindopril 8 mg once daily. Efficacy endpoints included reduction in systolic (SBP) and diastolic (DBP) BP and BP control. Tolerability assessments included adverse effects and physicians’ assessment of tolerability. The number of missed doses was also recorded.n Results: Overall, 2220 patients with hypertension and ≥1 other risk factor were prescribed perindopril at 291 centres; 51.9% were male, 78.3% Caucasian, 12.8% Asian, 36.2% ≥65 years of age and 34.5% had uncontrolled BP despite previous antihypertensive treatment. Compared with previously treated patients, treatment-naive patients had fewer risk factors, and a higher proportion were Asian (p < 0.05 for all comparisons). Most patients (76%) had 1–2 risk factors. Perindopril produced significant SBP/DBP reductions at 2 and 10 weeks (−15.8/−8.0 and −21.1/−11.0 mmHg, respectively). Overall, at week 10, BP control rate was 53.6%, better than at week 2 in the overall cohort and in all subgroups. Uptitration to high-dose perindopril to achieve BP control was required in 46% of patients with one additional risk factor compared with 64% of patients with ≥4 additional risk factors. These results demonstrate that the more risk factors the patient has, the greater the need for high-dose perindopril to achieve BP control. Perindopril was well tolerated as indicated by the high proportion of physicians (95.9%) reporting ‘good’ to ‘excellent’ tolerability at week 10.n Conclusion: In this community-based clinical practice trial, up to 10 weeks’ perindopril therapy, uptitrated to the maximal recommended dose as required for BP control, significantly reduced SBP/DBP in patients with mild-to-moderate hypertension and additional CV risk factors. Patients with more risk factors were more likely to require high-dose perindopril.

Adverse events: past and future

The article by Alan Forster and associates[1][1] on adverse events among patients admitted to a Canadian teaching hospital might suggest that this aspect of patient safety is of only recent interest and concern. However, CMAJ readers may be interested to learn of a study with similar findings that

Cardiovascular effects of enprofylline and theophylline

The cardiovascular effects of enprofylline (with no adenosine receptor antagonism) and of theophylline (with adenosine receptor antagonism) were compared in six normal subjects in a double‐blind trial at steady‐state concentrations of theophylline (12.5 ± 1.6 mg/L) and enprofylline (2.7 ± 0.3 mg/L). The mean (± SD) recumbent heart rate (HR) was higher (P < 0.04) after enprofylline (70 ± 14 bpm) than after theophylline (58 ± 13 bpm) or saline solution (57 ± 10 bpm). Forearm arterial resistance determined by plethysmography was lowered (P < 0.01) by theophylline (− 37% ± 14%) and enprofylline (—43% ± 24%) but not by saline solution (−6% ± 16%). In the semiupright position, the mean arterial pressure was lower (P < 0.01) after enprofylline (93 ±15 mm Hg) than after theophylline (108 ± 16 mm Hg). The cardiac index (CI) and left ventricular ejection fraction (LVEF) determined by radionuclide angiocardiography and the left ventricular end‐systolic pressure/volume ratio were not different for any regimen. During maximal exercise, HR was higher (P < 0.01) after both enprofylline (176 bpm) and theophylline (175 bpm) than after saline solution (161 bpm), but the increases in mean arterial pressure (18% to 32%), CI (153% to 167%), and LVEF (34% to 74%) were similar for all three regimens. Both theophylline and enprofylline lowered forearm arterial resistance without an increase in CI, LVEF, or cardiac inotropy, although enprofylline tended to cause a lower blood pressure and higher HR than did theophylline.

Response to Wave Reflection in Systolic Hypertension: Smaller Stature, Shorter Aorta: Higher Pulse Pressure? and Questions Regarding the Aortic Measurements of Mitchell et al

We thank Richart et al1 and Roman and Devereux2 for their careful reading of our article3 and thoughtful feedback. Richart et al1 raise 3 points, described below.nnFirst, dichotomization of the sample at the overall median pulse pressure led to overrepresentation of women, who are shorter, in the high pulse pressure group. Wave reflection may have contributed substantially to higher pulse pressure in these shorter individuals. Second, in our Figure 3, women and men are pooled without any evidence that the slopes of the regression lines are the same in men and women. Third, peak wall tension seems to be higher in the proximal aorta in the high pulse pressure group and may have contributed to premature mechanical wear and consequent wall stiffening.nnThey conclude that contributions of smaller diameter and increased wave reflection to increased pulse pressure may not be mutually exclusive and add that only properly conducted, longitudinal studies, not the analysis of an arbitrarily subdivided cross-sectional study, can inform a definite conclusion.nnRegarding dichotomization of the sample at the median pulse pressure, we wish to point out that the primary pulse pressure model, presented in our Table 3 and Figure 3, considered pulse pressure as a continuous variable. Furthermore, as noted in the article, the models …

Hypertension in the elderly: Therapeutic recommendations developed from controlled trials

Several clincal trials of anti-hypertensive treatment of the older patient have demonstrated significant reductions in cardiovascular morbidity and mortality as well as hospitalisation. Therapeutic recommendations have been developed from the results of these trials. The threshold for treatment comes from the recognition of benefit being related to absolute risk for patients with isolated systolic pressure > 160 mm Hg or combined systolic/diastolic hypertension with a pressure > 160/100 mm Hg. The treatment goal is a normal pressure < 140/90 mm Hg without adverse effects. Low-dose diuretic therapy is recommended as initial treatment along with non-drug measures.