Abstract-In hypertensive heart disease, no data are available on the repair of coronary resistance vessels in patients after long-term ACE inhibitor treatment. Fourteen patients with essential hypertension were studied with coronary flow reserve and with transvenous endomyocardial biopsy before and after 12 months of antihypertensive treatment with perindopril (4 to 8 mg/d, mean 5.9Ϯ2.3 mg/d). Left ventricular muscle mass index decreased by 11% (from 145Ϯ41 to 128Ϯ36 g/m 2 , Pϭ0.04). Maximal coronary blood flow was increased by 54% (from 170Ϯ46 to 263Ϯ142 mL ⅐ min Ϫ1 ⅐ 100 g Ϫ1 , Pϭ0.001), and minimal coronary vascular resistance was diminished by 33% (from 0.67Ϯ0.21 to 0.45Ϯ0.19 mm Hg ⅐ min ⅐ 100 g ⅐ mL Ϫ1 , Pϭ0.001); consequently, coronary reserve increased by 67% from 2.1Ϯ0.6 to 3.5Ϯ1.9 (Pϭ0.001). Structural analysis revealed regression of periarteriolar collagen area by 54% (from 558Ϯ270 to 260Ϯ173 m 2 , Pϭ0.04) and of total interstitial collagen volume density by 22% (from 5.5Ϯ3.8 Vv% to 4.3Ϯ3.2 Vv%, Pϭ0.04), whereas arteriolar wall area was slightly but not significantly reduced. Long-term therapy with the ACE inhibitor perindopril induces structural repair of coronary arterioles that is mainly characterized by the regression of periarteriolar fibrosis and associated with a marked improvement in coronary reserve. These findings indicate the beneficial reparative effects of ACE inhibition on coronary microcirculation in hypertensive heart disease. (Hypertension. 2000;36:220-225.) Key Words: arterioles Ⅲ collagen Ⅲ hypertension, arterial Ⅲ angiotensin-converting enzyme inhibitors Ⅲ coronary reserve A rterial hypertension is the most common cause of pressure overload of the left ventricle, and left ventricular (LV) hypertrophy (LVH) is its common sequelae. Furthermore, LVH is a strong independent risk factor for cardiovascular morbidity and mortality. 1 Potential mechanisms that might account for this observation include increased vulnerability of the hypertrophied myocardium to ischemic damage and enhanced arrhythmogenesis. 2 Moreover, it is increasingly recognized that patients with arterial hypertension and LVH have symptoms and signs of myocardial ischemia despite angiographically normal coronary arteries, and this was found to be related to impaired coronary flow reserve. 3 Functional and structural abnormalities of the coronary microcirculation have been described in hypertensive heart disease. 4 -6 Thus, an adequate increase in myocardial blood flow may be prevented in response to increased metabolic demand and may precipitate myocardial ischemia in these patients. 7 Important structural components of impaired coronary reserve are thickening of the media wall with reduced lumen size and accumulation of collagen in the periarteriolar region. 4,5 The thickening and hardening of arterioles have been called arteriolosclerosis and are characteristic of pathological hypertensive hypertrophy. 8,9 Antihypertensive treatment has been shown to normalize blood pressure and to reverse LVH in hypertensive patients...

Left ventricular hypertrophy is a risk factor for cardiovascular morbidity and mortality. In arterial hypertension and in hypertrophic cardiomyopathy it may be accompanied by clinical signs of myocardial ischaemia resulting from microcirculatory dysfunction in the absence of coronary macroangiopathy. Structural changes of the vascular and interstitial compartment of the heart are involved in the pathogenesis of impaired microcirculation. We investigated patients with hypertensive heart disease (HHD; n = 12) and hypertrophic cardiomyopathy (HCM; n = 19) without coronary macroangiopathy but with signs of myocardial ischaemia. Right septal endomyocardial biopsies were evaluated to quantify the structure of intramyocardial arterioles, collagen content and myocytic diameter by morphometric rules. Nine normotensive subjects served as controls. The groups differed significantly (P < 0.05) in myocytic diameter and total collagen content. The myocytic diameter correlated with the thickness of the interventricular septum. Arterioles in HHD showed a significant increase in cross-sectional medial area and in HHD patients the periarteriolar collagen area increased both in absolute terms and when standardized to medial area. Arteriolar density was significantly reduced in HCM. In a multivariate discriminant analysis the positive predictive value for differentiation of the groups by non-myocytic variables was 72.5% (P = 0.013). HHD and HCM differ in the structural alterations in the arteriolar bed. Medial hypertrophy and periarteriolar fibrosis prevail in HHD, and reduced arteriolar density is found in HCM. Different microvascular remodelling at the level of arterioles indicates distinct pathophysiologic processes that may contribute to the clinically observed disturbance of coronary microperfusion in these two diseases.

Myocytic hypertrophy and increased perimyocytic fibrosis accompany intraventricular pressure overload (hypertension and aortic stenosis) in human hearts. Myocardial structure as a result of arterial hypertension, but not aortic stenosis, is also characterized by intramyocardial arteriole wall-thickening and increased perivascular fibrosis. Thus, distinct structural reaction patterns are noted in the cardiac hypertrophy associated with hypertension and aortic stenosis.

The non–vitamin K antagonist oral anticoagulant rivaroxaban is used in several thromboembolic disorders. Rivaroxaban is eliminated via both metabolic degradation and renal elimination as unchanged drug. Therefore, renal and hepatic impairment may reduce rivaroxaban clearance, and medications inhibiting these clearance pathways could lead to drug‐drug interactions. This physiologically based pharmacokinetic (PBPK) study investigated the pharmacokinetic behavior of rivaroxaban in clinical situations where drug clearance is impaired. A PBPK model was developed using mass balance and bioavailability data from adults and qualified using clinically observed data. Renal and hepatic impairment were simulated by adjusting disease‐specific parameters, and concomitant drug use was simulated by varying enzyme activity in virtual populations (n = 1000) and compared with pharmacokinetic predictions in virtual healthy populations and clinical observations. Rivaroxaban doses of 10 mg or 20 mg were used. Mild to moderate renal impairment had a minor effect on area under the concentration‐time curve and maximum plasma concentration of rivaroxaban, whereas severe renal impairment caused a more pronounced increase in these parameters vs normal renal function. Area under the concentration‐time curve and maximum plasma concentration increased with severity of hepatic impairment. These effects were smaller in the simulations compared with clinical observations. AUC and Cmax increased with the strength of cytochrome P450 3A4 and P‐glycoprotein inhibitors in simulations and clinical observations. This PBPK model can be useful for estimating the effects of impaired drug clearance on rivaroxaban pharmacokinetics. Identifying other factors that affect the pharmacokinetics of rivaroxaban could facilitate the development of models that approximate real‐world pharmacokinetics more accurately.