Improvement of impaired coronary vasodilator reserve in hypertensive patients by low-dose ACE inhibitor/diuretic therapy: a pilot PET study

JRAAS 2003;4:94-5 The importance of microvascular abnormalities associated with hypertension is increasingly recognised, and these may be central to the development of hypertensive end-organ damage in the heart, as well as in the kidney and elsewhere. Clinical and experimental studies suggest that different classes of antihypertensive agents differ in their ability to reduce or reverse microvascular abnormalities. Positron emission tomography (PET) allows reproducible, non-invasive measurements of absolute myocardial blood flow (MBF) in man. The ratio of MBF measured during near maximal vasodilatation (with drugs such as adenosine or dipyridamole) to resting MBF gives the coronary vasodilator reserve (CVR), which is an integrated index of the function of the coronary circulation. In patients with coronary artery disease, CVR gives information on the functional significance of coronary stenoses; in the absence of coronary artery stenosis, CVR is primarily an indicator of the status of the coronary microcirculation. In this study, we used PET to investigate the effects on the coronary microcirculation of six months of antihypertensive treatment with a very low-dose combination of the angiotensin-converting enzyme (ACE) inhibitor, perindopril, and the diuretic, indapamide (Preterax, Servier). Six newly-diagnosed, never-treated patients (mean [SD] age 57.2 [10.0] years; five male), with uncomplicated moderate essential hypertension (systolic blood pressure [SBP] 160–179 mmHg and/or diastolic blood pressure [DBP] 95–109 mmHg),and without clinical history or symptoms of coronary artery disease (confirmed by negative ECG during maximal exercise test at selection visit),were included.All patients gave informed written consent, and the protocol was approved by the local Consultative Committee for the Protection of Persons Engaged in Biomedical Research. Patients underwent 2-D echocardiography and PET at baseline (M0), and after six months of therapy (M6) with perindopril 2.0 mg/indapamide 0.625 mg once-daily (o.d.). Resting MBF and maximal MBF after vasodilatation with dipyridamole (0.80 mg/kg i.v.) were measured by PET with H2O as tracer, as previously described. The short-term reproducibility of this method has been established by repeated measurements in healthy volunteers. Reproducibility coefficients (accounting for methodological and physiological variability) for resting MBF, maximal MBF and CVR were 0.17 ml/minute/g, 0.90 ml/minute/g, and 1.32, respectively. PET data analyses for MBF quantifications were performed at the end of the study, in random order, by a ‘blinded’ investigator. One patient was not evaluable for changes in blood pressure (BP) (because of instability in BP between selection and M0), and one other patient was not evaluable for PET (because of movement during scanning). Thus, four patients completed the study ‘per-protocol’ (PP). Values are quoted as mean (+SD), and significance was assessed by paired Student t-test. No treatment-related adverse events were reported during the study. After six months of therapy,BP had normalised to SBP < 140 and/or DBP < 80 mmHg in all six patients. For the PP patients, SBP decreased from 160.3 (+12.0) mmHg at M0 to 133.8 (+3.8) mmHg at M6 (p=0.040), and DBP from 100.3 (+9.5) to 83.5 (+3.7) mmHg (p=0.053). One patient had left ventricular (LV) hypertrophy at baseline (LV mass index by echocardiography 131 g/m), which normalised after treatment (118 g/m). CVR in normal subjects,measured by this technique, is 4.0 (+0.67). As in a previous study, CVR in our hypertensive patients was impaired at baseline, with a mean of 2.05 (+0.41) for the PP patients (Table 1). After six months of therapy, CVR increased to 5.49 (+2.55) (p=0.0498); the corresponding change for the five evaluable patients was 2.09 (+0.36) at M0 to 4.89 (+2.58) at M6 (p=0.0562). Every patient showed an improvement in CVR after treatment; however, inspection of absolute MBF values revealed clear differences between patients. In some patients, the improvement in CVR was primarily due to an increase in maximal MBF (patients one, two, and five; see Table 1), while in others the main change was a reduction of initially high resting MBF values (patients three and four). There are several plausible mechanisms by which perindopril/indapamide might improve CVR in hypertensive patients. Long-term ACE inhibition can reverse changes in small vessel structure and microvascular rarefaction, and improve endothelial function. Perindopril treatment also reduces periarteriolar fibrosis in hypertensive patients. Recent Research letter