Silvana Cicala

Nebivolol improves coronary flow reserve in hypertensive patients without coronary heart disease.

Objective To examine the effects of nebivolol, a β-blocker with nitroxide-mediated vasodilating properties, on coronary flow reserve (CFR) in patients with uncomplicated arterial hypertension. Design, setting and patients Fourteen newly diagnosed, never-treated, World Health Organization grade I–II hypertensive patients (male/female, 10/4; mean age, 47 years), free of coronary heart disease, underwent standard Doppler echocardiography and determination of CFR in the distal left anterior descending artery by low-dose dipyridamole (0.56 mg/kg intravenously in 4 min) at baseline and after 4 weeks of treatment with 5 mg nebivolol once daily. Results At baseline, nine patients had left ventricular (LV) hypertrophy (LV mass index ⩾ 51 g/m2.7). After 4 weeks of therapy, the blood pressure was decreased from 148 ± 8.1/101.4 ± 4.6 mmHg to 140.7 ± 7.0/91.1 ± 7.4 mmHg and end-systolic stress was also significantly reduced. Heart rate was reduced (P < 0.01), whereas LV end-diastolic diameter and stroke volume tended to increase (P = 0.07 and P = 0.09, respectively). No changes were detected in the LV mass index, relative wall thickness, fractional shortening and LV diastolic properties. Both resting and dipyridamole rate–pressure products were lower after nebivolol but dipyridamole-induced changes were not influenced by the therapy. In contrast, nebivolol therapy did not alter coronary velocities at rest, but caused a greater increase in coronary velocities after dipyridamole (P < 0.03), leading to a greater CFR (2.12 ± 0.33 versus 1.89 ± 0.31, P < 0.0001). Nebivolol induced an absolute increase of 8% in the CFR in nine of 14 patients (64.3%). Conclusions In hypertensive patients free of coronary artery disease, 4-week nebivolol therapy induces a significant increase of the CFR. Nebivolol preserves coronary flow at rest despite the reduction of metabolic (O2 consumption) and hemodynamic (diastolic blood pressure) determinants. The increase of hyperemic coronary velocities appears due to the reduction of coronary resistance.

Positive association between circulating free insulin-like growth factor-1 levels and coronary flow reserve in arterial systemic hypertension.

BACKGROUND The reduction of coronary flow reserve (CFR) found in arterial hypertension may be due to changes in afterload, left ventricular (LV) structure, and metabolic factors. Also, insulin-like growth factor-1 (IGF-1) may be associated with the magnitude of CFR in relation to its modulating action on cardiac and endothelial function. METHODS A total of 44 newly diagnosed, untreated hypertensive patients, who were free of diabetes mellitus and coronary artery disease, underwent M-mode analysis, second-harmonic Doppler echocardiographic assessment of CFR (dipyridamole infusion 0.56 mg/kg intravenously in four patients), determination of circulating free IGF-1, and insulin resistance. Based on CFR levels, hypertensive subjects were divided into two groups: 18 with normal CFR (> or = 2) and 26 with impaired CFR (<2). RESULTS Patients with normal CFR had lower diastolic blood pressure, heart rate, and LV mass index but higher free circulating IGF-I than patients with reduced CFR (P < .001). Insulin resistance was not significantly different between the two groups. In a first multilinear regression analysis that included demographic and echocardiographic variables, insulin resistance was independently associated with CFR (standardized beta coefficient = -0.31, P < .05) in the overall population. However, in a subsequent model which included also IGF-1, the relationship between insulin resistance and CFR disappeared, whereas IGF-1 was the main independent determinant of CFR (beta = 0.51, P < .0002). CONCLUSIONS Free IGF-1 circulating levels are independently associated with CFR in hypertensive individuals free of overt coronary artery disease. A possible beneficial effect exerted by IGF-1 on coronary blood flow may be supposed in arterial hypertension.

Clinical impact of 'in-treatment' wall motion abnormalities in hypertensive patients with left ventricular hypertrophy: the LIFE study.

Objectives Left ventricular systolic wall motion abnormalities have prognostic value. Whether wall motion detected by serial echocardiographic examinations predicts prognosis in hypertensive patients with left ventricular hypertrophy (LVH) without clinically recognized atherosclerotic disease has, however, never been investigated. We examined whether ‘in-treatment’ wall motion abnormalities predicted outcome in the Losartan Intervention For Endpoint (LIFE) reduction in hypertension echocardiographic substudy. Methods We studied 749 patients without coronary artery disease, myocardial infarction (MI), or stroke history. Echocardiographic segmental wall motion abnormalities at baseline and annual re-evaluations (‘as time-varying covariate’) were examined in relation to endpoints (cardiovascular mortality, MI, stroke, and hospitalized heart failure). Adjusted Cox regression was used to analyze the primary composite endpoint of cardiovascular death, MI, or stroke and, separately, for fatal and nonfatal MI and hospitalized heart failure. Results During a mean follow-up of 4.8 years, an event was recorded in 67 (9%) patients. In Cox models after adjusting for age, gender, treatment, blood pressure lowering, and serial change of left ventricular mass index, ‘in-treatment’ segmental wall motion abnormalities were associated with subsequent composite endpoint [hazard ratio = 2.1, 95% confidence interval (CI) 1.1–3.8; P = 0.019] and MI [hazard ratio = 3.7 (1.5–8.9); P = 0.004]. Conclusion In hypertensive patients with LVH and no history of cardiovascular disease, ‘in-treatment’ left ventricular wall motion abnormalities are associated with increased likelihood of subsequent cardiovascular events independent of age, gender, blood pressure lowering, treatment modality, and in-treatment left ventricular mass index.

Are coronary revascularization and myocardial infarction a homogeneous combined endpoint in hypertension trials? The Losartan intervention for endpoint reduction in hypertension study

Objective Construction of prognostically relevant endpoints for clinical trials in hypertension has increasingly included coronary revascularization with myocardial infarction (MI) as manifestations of coronary artery disease. However, whether coronary revascularization and MI predict other cardiovascular events similarly is unknown. Methods We examined risks of cardiovascular death, all-cause death, and stroke following MI or coronary revascularization in hypertensive patients with left ventricular hypertrophy (LVH) enrolled in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE). We studied 9113 patients after excluding those who died within 7 days after MI or underwent coronary revascularization within 24 h after MI. Results In multivariate Cox regression adjusting for participating countries, time-varying systolic blood pressure, and Framingham risk score, hazard ratios for cardiovascular death, all-cause death, and stroke were, respectively, 4.5 (P < 0.0001), 2.9 (P < 0.0001), and 1.9 (P = 0.003) in 321 patients with MI as first event. In similar models, coronary revascularization as first event (n = 202) was not associated with increased risks of cardiovascular death, all-cause death, and stroke (P = 0.06–0.86). Conclusion During follow-up of hypertensive patients with LVH, occurrence of MI but not coronary revascularization as first cardiovascular event significantly increased risk of subsequent cardiovascular death, all-cause death, and stroke. In view of differences in prognostic implications, when the goal is to have a prognostically relevant composite endpoint for trials in hypertensive patients, caution should be used in combining coronary revascularization with MI.

Transthoracic coronary flow reserve and dobutamine derived myocardial function: a 6-month evaluation after successful coronary angioplasty

After percutaneous transluminal coronary angioplasty (PTCA), stress-echocardiography and gated single photon emission computerized tomography (g-SPECT) are usually performed but both tools have technical limitations. The present study evaluated results of PTCA of left anterior descending artery (LAD) six months after PTCA, by combining transthoracic Doppler coronary flow reserve (CFR) and color Tissue Doppler (C-TD) dobutamine stress.Six months after PTCA of LAD, 24 men, free of angiographic evidence of restenosis, underwent standard Doppler-echocardiography, transthoracic CFR of distal LAD (hyperemic to basal diastolic coronary flow ratio) and C-TD at rest and during dobutamine stress to quantify myocardial systolic (Sm) and diastolic (Em and Am, Em/Am ratio) peak velocities in middle posterior septum. Patients with myocardial infarction, coronary stenosis of non-LAD territory and heart failure were excluded. According to dipyridamole g-SPECT, 13 patients had normal perfusion and 11 with perfusion defects. The 2 groups were comparable for age, wall motion score index (WMSI) and C-TD at rest. However, patients with perfusion defects had lower CFR (2.11 ± 0.4 versus 2.87 ± 0.6, p < 0.002) and septal Sm at high-dose dobutamine (p < 0.01), with higher WMSI (p < 0.05) and stress-echo positivity of LAD territory in 5/11 patients. In the overall population, CFR was related negatively to high-dobutamine WMSI (r = -0.50, p < 0.01) and positively to high-dobutamine Sm of middle septum (r = 0.55, p < 0.005).In conclusion, even in absence of epicardial coronary restenosis, stress perfusion imaging reflects a physiologic impairment in coronary microcirculation function whose magnitude is associated with the degree of regional functional impairment detectable by C-TD.

383 The impact of cholesterol on coronary flow reserve in hypertensive patients without evidence of coronary heart disease

Background: It has been demonstrated that the maximal oxygen uptake (VO2max) is strictly related to functional status (NYHA Class) in patients with idiopathic dilative cardiomyopathy (IDC) and therefore represents an important clinical predictor. The VO2max is the physiological trigger to increase the coronary flow reserve (CFR). At present it is possible noninvasively evaluate the CFR by transthoracic echocardiography on left anterior descending (LAD) coronary artery. Methods: We have consecutively enrolled 26 patients (pts), 16 Male mean age 64±b12 years, all affected with IDC confirmed by normal coronary artery with angiography. Each of them underwent TTE, evaluating the standard parameters such as LVEDV, LVESV (ml), EF (%) and Stress-Echo with Dipirydamole (0,84 mg/Kg over 6 m’) evaluating the LV contractility (WMSI) and simultaneously the CFR on LAD, calculated as the maximum peak-rest diastolic flow velocity (LADDFVDp-r) ratio, using a high frequency probe in 2ˆ harmonic (7 MHz). We utilized an off axis apical approach under the guide of color-Doppler and when necessary we injected a contrast agent (Sonovue 2ml in bolus) to improve the signal-noise coronary flow ratio. All pts underwent within 24 hour the effort test (treadmill) with gas analysis evaluating particularly the VO2max (ml/kg/m’) and anaerobic threshold. We considered as clinical parameter the NYHA Class. Results: We found the following mean values: EDV = 226 ± 63ml, ESV = 144 ± 52ml, EF = 36 ± 6%, WMSIb = 1,8 ± 0,3, LADDFVr 31 ± 4cm/s, LADDFVp = 59 ± O8cm/s, CFR = 1,9 ± 0,2, VO2max = 19 ± O6, NYHA Class = 2,3 ± 0,8 The parameters that demonstrated a significance linear statistical relationship were: NYHA Class vs MVO2: r = 0,70 p = 0.002 NYHA Class vs RC: r = 0.92 p = 0.001 VO2max vs CFR: r = 0.60 p = 0.016 VO2max vs LADDFVDr: r = 0.60 p = 0.020 The feasibility of CFR study in pts affected with IDC was excellent: 27/27 pts (100%) Conclusion: The excellent relationship between the NYHA Class and VO2max and between CFR and VO2max suggest us to consider the CFR of LAD in daily practice as an important functional predictor: this, in the next future could have a relevant therapeutic and prognostic impact in pts with IDC.