CLINICS 2009;64(4): Endothelial and non-endothelial coronary blood flow reserve and left ventricular dysfunction in systemic hypertension R2 이홍주

M Acethylcholine

Introduction LVH in systemic HTN : independent risk factor for sudden death, ventricular arrhythmia, MI, HF pathophysiological mechanisms : compensated LVH → ventricular dysfx : reductions in coronary blood flow reserve (CBFR) Coronary microcirculation alterations in HTN - J Am Coll Cardiol 2000;35: – CBFR was low in HTN patients both with and without LVH → following 1 year of antiHTN treatment → CBFR became normal in the non-LVH patients : HTN treatment may normalize compromised coronary blood flow. - J Am Coll Cardiol 1993;.22:

Introduction Endothelial dysfunction in HTN has been shown in peripheral and coronary vasculature in patients without LV systolic dysfunction endothelium-dependent coronary vasodilatation capacity : one of the mechanisms responsible for inadequate myocardial flow ? : contributes to ventricular maladaptation before the development of morphological alterations that affect the capacity of endothelium- independent vasodilatation ? normal endothelium- independent CBFR coronary vasculature endothelial dysfunction LV maladaptation

Introduction Goals of this study to evaluate (1) endothelium-dependent and independent coronary artery vasodilatation compromise in HTN patients with reduced or preserved fractional shortening (2) whether an association exists between LV dysfunction progression and endothelium-dependent and independent coronary reserve decrease (3) influence of clinical, structural, and functional factors to LV maladaptation in HTN patients.

Methods - Study population and groups NYHA functional class I or II conventional antiHTN medication Inclusion criteria BP > 140X90 mm Hg ≥ 3 occasions in a sitting position after resting for ≥ 5 minutes Exclusion criteria serum Cr >2.0 mg/dL coronary artery stenosis >30% contraindication for adenosine (previous COPD, use of xanthine, bradyarrhythmia) or femoral access catheterization iodate contrast allergy use of ASA - interfere with the behavior of coronary blood flow any other systemic or heart disease.

33 : diagnosed with HTN ≥ 4 years prior to our study receiving initial antiHTN treatment for ≥ 3.5 years. 12 : significant coronary artery disease 3 : inability to obtain an adequate coronary flow curve 18 : studied Methods - Study population and groups Group 1Group 2 preserved ventricular function LVFS ≥ 25% ventricular dysfunction LVFS < 25% 8 patients (3 male, ± years) 10 patients (7 male, 48.7 ± years) hydrochlorothiazide (50 mg/day) methyldopa ( mg/day) ACEI (captopril mg/day or enalapril 40 mg/day) or ARB(losartan mg/day) amlodipine (10 mg/day) ACEI (captopril 150 mg/day or enalapril mg/day) clonidine (0.2 mg/day) nifedipine (60 mg/day) digoxin (0.25 mg/day) furosemide (40-80 mg/day) spironolactone ( mg/day)

Methods - Echocardiography study LV structure and function LV end-diastolic diameter (LVDD) LV end-systolic diameter (LVSD) interventricular septum (IVS) systolic and diastolic thickness posterior wall (PW) systolic and diastolic thickness LV mass index (LVM) : LV mass corrected by BSA LVEF relative wall thickness (RWT) and LV end-systolic stress (LVFSS)

Methods - Hemodynamic study right cardiac catheterization : thermodilution method using a Swan-Ganz catheter : pressure, CO left cardiac catheterization : cinecoronariography using non-ionic iopamidol iodated contrast and intracoronary Doppler blood flow study : LV aorta pressure

Methods - Coronary arterial flow study in the proximal third of the anterior descending artery epicardial luminal cross-sectional area (CSA) coronary blood flow (CBF) endothelium-independent : induction with adenosine -18μg (AD1) and 36μg (AD2) IV bolus CBFRei = CBFRm ad CBFRb coronary blood flow (CBF) endothelium-dependent : induction with acetylcholine : 5 mL/min for 2 minutes target concentrations = (AC1), (AC2), M (AC3) CBFRed = CBFRm ac CBFRb

Methods - Coronary arterial flow study endothelium-dependent coronary vasodilation = highest CBF obtained with acetylcholine (CBFRm ac) highest CBF obtained with adenosine (CBFRm ad) Minimal coronary vascular resistance (RESISTmin) = mean blood pressure using adenosine (MBP ad) maximum CBF using adenosine endothelium-independent vasodilation capacity : 300μg nitroglycerin IV bolus → 2 minutes later → cross-sectional diameter

Methods - Statistical analysis Student t test or Wilcoxon’s test Fisher’s exact test profile analysis covariance analysis. Pearson’s correlation coefficient and multiple linear regression stepwise method : entry significance level equal to 0.10 exit equal to means and standard deviations p < 0.05 : significant.

Results - Demographic and lab. variables Table 1 - Baseline characteristics of the two groups of patients < <

Results – LV structure and function p <0.05 Group 1Group 2 LVDD54.2 ± 5.9 mm69.0 ± 10.7 mm LVSD38.3 ± 4.4 mm57.4 ± 9.6 mm LVM201.5 ± 65.7 g/m ± 99.1 g/m 2 LVFSS81.0 ± dyn/cm ± dyn/cm 2 RWT0.44 ± ± 0.1 IVSNo differences PW thicknessNo differences < < < < >

Results – Hemodynamic study Group 1Group 2 Aorta root BP (p < 0.05) systolic168.1 ± 28.5 mm Hg136.6 ± 31.0 mm Hg diastolic90.6 ± 11.5 mm Hg75.0 ± 12.3 mm Hg mean117.4 ± 13.7 mm Hg95.9 ± 15.6 mm Hg Cardiac index p = ± 0.6 L/min.m ± 0.5 L/min.m 2 LV pulmonary capillary pressurenot statistically different central venous pressurenot statistically different final diastolic pressurenot statistically different pulmonary blood pressure (systolic, diastolic, and median) not statistically different systemic and pulmonary vascular resistance rates not statistically different > > > >

Results – Coronary blood flow Saline solution infusion (p=0.9136) Group 1Group 2 anterior descending coronary artery diameter (p=0.2913) 2.98±0.58 → 3.00±0.50mm 3.49±0.34 → 3.54±0.30mm coronary blood flow velocity (p=0.0850) 23.88±8.01 → 25.00±8.77cm/sec 21.10±4.98 → 22.30±6.62 cm/sec heart rate (p=0.1712)73.88±8.97 → 72.88±10.22bpm 68.40±9.77 → 67.70±10.24 bpm SBP (p=0.2464)164.88±25.39 → ±26.04 mmHg ±26.81 → ±27.22 mmHg MBP (p=0.1551)121.75±14.87 → ± mmHg 97.10±14.41 → 97.70±15.38 mmHg DBP (p=0.0176)91.38±10.98 → 88.88±10.20mm Hg 77.40±11.47 → 75.10±12.02 mm = = = = = =

Results – Adenosine coronary blood flow Table 2 Hemodynamic variables, coronary blood flow velocity, and anterior descending coronary artery diameter with the use of adenosine > > = = = <

Results – Coronary blood flow Figure 1 - Effect of intracoronary administration of adenosine (AD1=18 μg. AD2=36 μg) on coronary blood flow in Groups 1 and 2

Results – Ach coronary blood flow Table 3 - Hemodynamic variables, coronary blood flow velocity, and anterior descending coronary artery diameter with the use of acetylcholine = > > >= =

Results – Ach coronary blood flow Figure 2 - Effect of intracoronary administration of acetylcholine (AC1=10-7 M. AC2=10-6 M. AC3=10-5 M) on coronary blood flow in Groups 1 and 2

Results – Endothelium-independent CBFR No endothelium-independent CBFR difference was seen between groups (p=0.4652) Results – Endothelium-dependent CBFR No endothelium-dependent CBFR difference occurred between groups (p=0.0772)

Results– Minimal coronary blood resistance Results– NG epicardial ant coronary a vasodilatation Group 1Group 2 RESISTmin (p=0.0874) 0.48 ± 0.21 mm Hg/mL/min0.34 ± 0.12 mm Hg/mL/min anterior descending coronary artery diameter Group 1Group 2 Baseline (p=0.0253)2.98 ± 0.58 mm3.49 ± 0.34 mm NG (p=0.0002)3.35 ± 0.60 mm3.91 ± 0.36 mm heart rateincreased (p=0.0244), SBP with NG administrationDecreased (p=0.0122) MBP with NG administrationDecreased (p=0.0035) DBP with NG administrationDecreased (p=0.0118) <

Results – LV fractional shortening and predictive factors Table 4 - Pearson’s linear correlation between LVFS and study variables

Conclusion In our HTN patients, endothelium-dependent and endothelium- independent coronary blood flow reserve vasodilator administrations had similar effects in patients with either normal or decreased left ventricular systolic function.