AJH
2004; 17:433– 438
Myocardial Blood Flow and Efficiency in Concentric and Eccentric Left Ventricular Hypertrophy Olakunle O. Akinboboye, Ru-Ling Chou, and Steven R. Bergmann Background: It is not clearly understood why concentric left ventricular hypertrophy (increased left ventricular mass and relative wall thickness) is associated with higher cardiovascular risk than eccentric hypertrophy (increased left ventricular mass but normal relative wall thickness). Possible reasons include lower myocardial efficiency or perfusion reserve in concentric than in eccentric hypertrophy. We compared myocardial perfusion reserve and efficiency in normotensive controls and in hypertensive patients with concentric and with eccentric hypertrophy.
However, myocardial perfusion reserve in both patient groups were lower than in controls. Although myocardial efficiency in patients with eccentric hypertrophy and in controls were not different, both values were higher than measurements in patients with concentric hypertrophy (18% ⫾ 6% v 16% ⫾ 3% v 13% ⫾ 4%, eccentric hypertrophy versus controls versus concentric hypertrophy, respectively, P ⫽ .04 for both eccentric versus concentric hypertrophy and for controls versus concentric hypertrophy).
Methods: Study subjects comprised 16 patients with hypertension-induced left ventricular hypertrophy and 10 normotensive controls. We measured myocardial perfusion reserve and oxygen consumption by positron emission tomography. We calculated myocardial efficiency by dividing left ventricular minute work by myocardial oxygen consumption.
Conclusions: Myocardial efficiency but not perfusion reserve is lower in hearts with concentric compared with eccentric left ventricular hypertrophy. This might be an explanation for the higher cardiovascular morbidity and mortality associated with concentric left ventricular hypertrophy. Am J Hypertens 2004;17:433– 438 © 2004 American Journal of Hypertension, Ltd.
Results: There was no significant difference in myocardial perfusion reserve between patients with concentric (n ⫽ 9) as compared to eccentric (n ⫽ 7) hypertrophy.
Key Words: Myocardial perfusion reserve, left ventricular hypertrophy, myocardial oxygen demand, myocardial blood flow, positron emission tomography.
eft ventricular hypertrophy (LVH) is an important independent predictor of cardiovascular morbidity and mortality.1,2 The increased cardiovascular morbidity and mortality is related to the fact that MVO2 is increased,3 whereas myocardial perfusion reserve is decreased4 – 6 in the hypertrophied ventricle. Consequently, myocardial efficiency, the ratio of external work performed by the myocardium to oxygen consumed, is an important concept in hypertensive heart disease. In concentric left ventricular hypertrophy (CLVH), although left ventricular (LV) mass is increased, cavity volume is normal; consequently, relative wall thickness is increased. Conversely, in eccentric left ventricular hypertrophy (ELVH), both LV mass and cavity volume are
L
increased; consequently, relative wall thickness is normal. Due to the larger cavity volume in ELVH than in CLVH, wall stress tends to be higher in the former. Consequently, one would expect ELVH to be associated with higher cardiovascular risk than CLVH. However, studies have shown that CLVH is associated with higher cardiovascular risk than ELVH.1,7 It is not clearly understood why CLVH is associated with higher cardiovascular morbidity and mortality than ELVH. Possible reasons include lower myocardial efficiency or perfusion reserve in CLVH than ELVH. We hypothesized that myocardial efficiency is less in hearts with CLVH than in those with ELVH. Hence, the objective of this study was to compare myocardial perfusion reserve and efficiency using positron emission tomog-
Received August 22, 2003. First decision December 16, 2003. Accepted February 3, 2004. From the Saint Francis Hospital, Roslyn, State University of New York at StonyBrook (OOA), StonyBrook; Division of Cardiology, Columbia University (R-LC, SRB), New York; and Division of Cardiology, Beth-Israel Medical Center (SRB), New York, New York.
This study was supported by research grant RR00645 from the National Center for Research Resources, National Institutes of Health. Address correspondence and reprint requests to Dr. Olakunle O. Akinboboye, Non-Invasive Laboratory, Saint Francis Hospital, 100 Port Washington Blvd., Roslyn, NY 11576; e-mail:
[email protected]
© 2004 by the American Journal of Hypertension, Ltd. Published by Elsevier Inc.
0895-7061/04/$30.00 doi:10.1016/j.amjhyper.2004.02.006
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raphy and echocardiography in normotensive controls and in hypertensive patients with CLVH or with ELVH.
Methods Patient Population The Institutional Review Board of Columbia University approved the study. Informed consent was obtained. Participants with pre-existing hypertension and increased LV mass by screening M-mode echocardiography (⬎125 g/m2)1 were recruited from the patient population at New York Presbyterian Hospital–Columbia Campus in New York City. The normotensive controls were recruited from the surrounding community. Pre-existing hypertension was validated by BP measurement on entry and by the patient’s medical history. Exclusion criteria for patients with hypertension and LVH included echocardiographic evidence of significant cardiac abnormality other than hypertrophy; significant cardiovascular disease other than hypertension or left ventricular hypertrophy; pregnancy; malignant, accelerated, or secondary hypertension; bronchospastic lung disease; regional variance in myocardial perfusion reserve by positron emission tomography (PET), that was suggestive of coronary artery disease; diabetes mellitus; smoking; hyperlipidemia; and secondary hypertension. Additional exclusion criteria for normotensive controls included hypertension and left ventricular hypertrophy. Blood specimens were drawn and tested to check for occult diabetes and hyperlipidemia. Using these criteria, 16 hypertensive patients with LVH and 10 normotensive controls were enrolled. Of the 16 patients with high BP, 10 were treated but uncontrolled. Of those who were on treatment, 6 patients were taking an angiotensin-converting enzyme inhibitor and 4 were taking a calcium channel blocker. Echocardiography Two-dimensional-guided M-mode Echocardiography for the Measurement of Relative Wall Thickness Left ventricular posterior wall thickness and internal diameter were measured at end-diastole using two-dimensional (2D) -guided M-mode echocardiography according to the guidelines of the American Society of Echocardiography.8 Relative wall thickness was calculated as follows: (2 ⫻ LV posterior wall thickness)/LV internal diameter. A partition value of 0.45 was used to classify patients with LV mass-to-height2.7 ⬎51 g/m2 into CLVH (ⱖ0.45) or ELVH (⬍0.45) subsets.9,10 Measurement of Stroke Volume and LV Mass by 3D Echocardiography The 3D echocardiographic system (K3 Systems, Inc., Darien, CT) comprises an acoustic spatial locater (model GP 8-3D, Science Accessories Corp., Stratford, CT) and personal computer (model 4DX33V, Gateway 2000, North Sioux City, SD).11,12 These components are linked to a conventional 2D echocardiograph interfaced with an acoustic spatial locater. Left
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ventricular volume was computed from a series of guided six to eight real-time parasternal short-axis images. These images were stored along with their XYZ Cartesian coordinates in the personal computer. End-diastolic and endsystolic video frames from each acquired cine-loop were selected for off-line endocardial and epicardial boundary tracing. Epicardial and endocardial volumes in diastole and in systole were calculated from their corresponding boundaries using a polyhedral surface reconstruction algorithm.12,13 End-systolic endocardial volume was subtracted from end-diastolic endocardial volume to yield stroke volume and calculate ejection fraction. Endocardial volume was subtracted from epicardial volume to yield myocardial volume, which was multiplied by myocardial density to yield left ventricular mass. Measurement of Myocardial Work Myocardial minute work was calculated from the product of stroke volume by 3D echocardiography, mean arterial pressure, and heart rate. All measurements were taken simultaneously. Positron Emission Tomography All medications were held for at least five half-lives before the PET studies. Studies were performed on an ECAT EXACT-47 PET scanner (Siemens Inc., Iselin, NJ), which provides 47 contiguous transaxial slices and has a postprocessing spatial resolution of 9 to 10 mm in plane and 4 to 5 mm in the axial direction. Subjects were studied after an overnight fast and abstinence from methyl-xanthines including caffeine for 24 h. After inserting a large bore catheter in the antecubital vein, subjects were placed supine in the PET scanner and localization of the heart within the axial field of view of the scanner was confirmed by performing a 2-min “positioning” scan using a rotating 68 Ge/ 68Ga-rod source. A 20-min transmission scan with the rotating 68Ge/ 68Ga-rod source was performed to generate an attenuation correction map for correction of the emission sonogram. Measurement of MVO2 Positron emission tomography with 11C-acetate enables noninvasive quantification of MVO2 under resting conditions.13–15 Approximately 0.2 mCi/kg of 11C-acetate was injected intravenously as a bolus. A 30-min dynamic data acquisition was performed using multiple frames with progressively increasing scan lengths (10-sec frames ⫻ 12, 60-sec frames ⫻ 5, 90-sec frames ⫻ 10, 120-sec frames ⫻ 4). Emission sinograms were corrected for attenuation and radioactivity decay and reconstructed into transaxial slices. Transaxial slices were reoriented into six short axis slices using standard system software. Each short axis slice was divided into eight equal myocardial sectors, and count data in each sector used to generate myocardial time activity curves describing the clearance of 11C-acetate activity from the myocardium. A monoexponential fit for the myocardial time activity curve of 11C-acetate clearance was performed. The monoexponential myocardial turnover rate constant, kmono, which
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Table 1. Clinical characteristics Controls CLVH (n ⴝ 9) ELVH (n ⴝ 7) (n ⴝ 10) (P versus controls) (P versus controls) Age (yr) 46 ⫾ 11 Females (n, %) 7 Duration of hypertension African American (n) 0 Latino (n) 5 White 5 Body mass index (kg/m2) 25 ⫾ 2 Systolic blood pressure (mm Hg) 117 ⫾ 15 Diastolic blood pressure (mm Hg) 65 ⫾ 12 Mean arterial pressure (mm Hg) 82 ⫾ 12
54 ⫾ 7 (0.01) 2 (22) 5⫾1 6 3 0 31 ⫾ 4 (.02) 160 ⫾ 20 (⬍ .001) 91 ⫾ 12 (⬍ .001) 113 ⫾ 8 (⬍ .001)
CLVH versus ELVH P
53 ⫾ 14 (NS) 5 (71) 7⫾2 6 1 0 32 ⫾ 5 (.02) 160 ⫾ 14 (⬍ .001) 90 ⫾ 10 (⬍ .001) 114 ⫾ 14 (⬍ .001)
NS
NS NS NS NS
CLVH ⫽ concentric left ventricular hypertrophy; ELVH ⫽ eccentric left ventricular hypertrophy.
describes the clearance of 11C-acetate activity from the myocardium, correlates closely with MVO2 under resting conditions.12,16 Thus, regional MVO2 (rMVO2) was determined from a regression equation that converts kmono (in units of min⫺1) to rMVO2 (in units of mL/g/min).17 Variations in rMVO2 were evaluated by calculating regional variance. Because there was no significant difference in regional variance, rMVO2 was averaged MVO2 to yield average MVO2 for the entire ventricle.
⫻ Stroke volume (in milliliters)
structed into transaxial slices, and reoriented into shortaxis tomograms. The short axis tomograms were divided into four equal myocardial sectors, and count data in each sector used to generate myocardial tissue time activity curves. The arterial input function was obtained from the time-activity curve generated from a 1.5-cm3 region of interest placed in the center of mid-to-basal short axis tomograms. Regional myocardial blood flow was quantified using a one-compartment model.19 This parameter optimization approach incorporates corrections for both partial volume effects and blood to myocardial spillover. Because no regional differences were identified, regional myocardial blood flow values were averaged to yield average flow values for the entire heart. Myocardial perfusion reserve was expressed as the ratio of global maximal to resting myocardial blood flow values.
⫻ 0.0136/(MVO 2 [in milliliters]
Statistical Analysis
Calculation of Left Ventricular Myocardial Efficiency (%) The percentage of left ventricular myocardial efficiency is 100 ⫻ Minute work/Oxygen consumption18: 100 ⫻ Mean arterial pressure (in mm Hg)
⫻ Energy equivalent per milliliter of O 2 consumed [2059 g · m ⫺1 · mL ⫺1 ]) The number 0.0136 represents the conversion factor from units of pressure and volume (mm Hg and cm3) to work (g · m⫺1). Measurement of Myocardial Perfusion Reserve After allowing enough time for 11C activity to decay to background level, myocardial perfusion reserve was determined by evaluating myocardial blood flow at rest and after maximal coronary vasodilatation with intravenous dipyridamole using 15O-water as the flow tracer. A bolus administration of 0.20 mCi/kg of 15O-water was given with simultaneous initiation of dynamic data acquisition for 300 sec. After completion of the rest perfusion scans, 0.56 mg/kg of dipyridamole were administered during 4 min. An additional 4 min was allowed to achieve peak flow response and 0.20 mCi/kg of 15O-water were readministered. Dynamic data acquisition was initiated for 300 sec. The initial 20 sec of the two dynamic datasets were summed to identify the blood pool. The emission sinograms were corrected for radioactivity decay, recon-
The results are expressed as the mean ⫾ SD. Differences among group means were assessed by ANOVA for continuous variables and by 2 analysis for categorical variables. Linear regression analysis was performed to examine the relationship between parameters. A two-tailed P value ⬍ .05 was considered statistically significant.
Results Clinical Characteristics There was no difference between the CLVH and ELVH groups in terms of age, gender, ethnic distribution, resting BP, and duration of hypertension. Patients with CLVH were significantly older than the controls (Table 1). Echocardiographic Measurements Expectedly, BP and left ventricular mass were significantly higher in the patients than in the controls, but not different between patient groups (Tables 1 and 2). In addition, left ventricular ejection fraction was significantly higher in the controls than in the patients, but similar between patient groups (Table 2). Left ventricular enddiastolic and stroke volumes were significantly higher in
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Table 2. Clinical and echocardiographic indices Controls (n ⴝ 10) LV mass (g) Relative wall thickness Heart rate (beats/min) LV end-diastolic volume (mL) LV stroke volume (mL) Ejection fraction (%) LV minute work (kg/m)
129 0.34 69 97 61 62 4.8
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
25 0.1 8 19 9 3 1
CLVH (n ⴝ 9) (P versus controls) 203 0.55 67 113 60 53 6.3
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
43 (⬍ .001) 0.04 (⬍ .001) 7 (NS) 21 (⬍ .001) 10 (NS) 3 (⬍ .001) 1 (⬍ .001)
ELVH (n ⴝ 7) (P versus controls) 201 0.42 64 148 76 51 7.4
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
CLVH versus ELVH P
48 (⬍ .001) 0.02 (⬍ .001) 8 (NS) 31 (⬍ .001) 10 (.01) 8 (⬍ .001) 1 (⬍ .001)
NS ⬍ .001 NS .02 .01 NS .09
LV ⫽ left ventricular; other abbreviations as in Table 1.
the patients than in controls and in the ELVH compared with the CLVH group (Table 2). Hemodynamic Response to Dipyridamole Administration The response to dipyridamole infusion was not significantly different between the two patient groups. Heart rate increased and systolic BP decreased by 18 ⫾ 4 beats/min and 8 ⫾ 2 mm Hg, respectively, with dipyridamole infusion. No patient had anginal chest pain or ST depression with dipyridamole administration. Myocardial Blood Flow Measurements Resting myocardial blood flow was not different between the three groups; however, hyperemic myocardial blood flow and myocardial perfusion reserve were significantly lower in the patients than in the controls (Table 3). There was no significant difference between the CLVH and ELVH groups in terms of their hyperemic myocardial blood flow and myocardial perfusion reserve (Table 3). In addition, resting myocardial blood flow correlated significantly with myocardial oxygen consumption in both CLVH (r ⫽ 0.8, P ⫽ .04) and ELVH (r ⫽ 0.85, P ⫽ .02) groups. The correlation between resting myocardial blood flow and myocardial oxygen consumption did not differ between the two patient groups.
Myocardial Efficiency Myocardial oxygen consumption per gram of cardiac tissue was not different between the three groups (Table 3). However, myocardial oxygen consumption for the entire left ventricle was significantly higher in the patients than in the controls (Table 3). There was no difference in myocardial oxygen consumption between the CLVH and ELVH groups (Table 3). Left ventricular minute work was significantly higher in both patient groups than in controls (Table 2). In addition, left ventricular minute work tended to be higher in ELVH than CLVH (Table 2). Myocardial efficiency was significantly higher in ELVH than CLVH (18% ⫾ 6% v 13% ⫾ 4%, P ⫽ .04) (Table 3). Furthermore, myocardial efficiency was significantly higher in the controls than in CLVH group (16% ⫾ 3% v 13% ⫾ 4%, P ⫽ .04) (Table 3). There was no difference between myocardial efficiency in controls compared with the ELVH group (Table 3 and Fig. 1).
Discussion In this study we compared myocardial efficiency and perfusion reserve between controls, patients with CLVH, and patients with ELVH. There was no difference in myocardial blood flow and myocardial perfusion reserve between the two patient groups. However, hyperemic myocardial
Table 3. Myocardial blood flow and efficiency
Controls Resting myocardial blood flow (mL/g/min) Hyperemic myocardial blood flow (mL/g/min) Myocardial perfusion reserve Myocardial oxygen consumption (mL/g/min) Myocardial oxygen consumption (whole left ventricle) (mL/min) Myocardial efficiency (%) Abbreviations as in Table 1.
CLVH (P versus control)
ELVH (P versus control)
ELVH versus CLVH
1 ⫾ 0.3
1 ⫾ 0.3
1 ⫾ 0.3
NS
4 ⫾ 0.8 4 ⫾ 0.4
3 ⫾ 0.3 (.05) 3 ⫾ 0.3 (.004)
3 ⫾ 0.9 (.05) 3 ⫾ 0.3 (.008)
NS NS
0.11 ⫾ 0.03 (NS)
NS
22 ⫾ 10 (.04) 18 ⫾ 6 (NS)
NS .04
0.11 ⫾ 0.01 15 ⫾ 4 16 ⫾ 3
0.13 ⫾ .03 (NS) 26 ⫾ 7 (⬍ .001) 13 ⫾ 4 (.04)
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FIG. 1. Myocardial efficiency (%) in controls, patients with left ventricular hypertrophy (CLVH), and patients with eccentric left ventricular hypertrophy (ELVH). Myocardial efficiency was significantly lower in the CLVH group than in the ELVH group. There was no difference in myocardial efficiency between patients with ELVH and controls.
blood flow and myocardial perfusion reserve were significantly lower in both patient groups than in controls. Impairment in flow reserve in hypertrophied ventricles has been demonstrated by several investigators.20 –23 It is believed to be primarily due to reduced intramyocardial capillary density as a result of increased interstitial fibrosis in the hypertrophied left ventricle.19 –21 Myocardial oxygen consumption per gram of tissue was not different between the three groups. However, oxygen consumption for the entire ventricle was significantly higher in both patient groups than in controls. In the ELVH group, there was a proportionate increase in left ventricular minute work, such that myocardial efficiency was not significantly different between patients with ELVH and controls. However, the relative increase in left ventricular minute work in patients with CLVH, compared with controls, was less than the increase in myocardial oxygen consumption. Consequently, myocardial efficiency was significantly less in patients with CLVH than in controls. Although there was no difference in myocardial oxygen consumption per gram of cardiac tissue between patients with ELVH and with CLVH, left ventricular minute work tended to be higher in patients with ELVH than with CLVH. Consequently, myocardial efficiency was significantly higher in the former. Although a few studies have reported on the efficiency of hypertrophied ventricles,3,24 to the best of our knowledge, ours is the first to report on myocardial efficiency in geometric subtypes of left ventricle hypertrophy. The observed myocardial efficiency of 13% in the CLVH group is consistent with the study of Laine et al,3 in which a myocardial efficiency of 13.5% was found in patients with hypertension-induced LVH. However, the geometric subtype of LVH in the latter study was not reported. The few available studies on the myocardial efficiency in hypertrophied ventricles have yielded conflicting results. Laine et al3 reported reduced myocardial efficiency compared to normotensive controls. Another study demonstrated no difference in pump efficiency between patients with hypertension studies induced LVH and normotensive controls.18 The geometric pattern of LVH was not reported in both studies. A possible reason for the conflicting findings is that the geometric pattern of LVH differed between the two studies.
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Although CLVH is associated with lower wall stress than ELVH due to the LaPlace effect, it appears that the reduction in wall stress occurs at the expense of the efficiency of oxygen utilization. Impairment in the efficiency of oxygen utilization in the hypertrophied ventricle has been attributed to increased interstitial fibrosis in the hypertrophied ventricle,3,25 which can increase myocardial oxygen consumption, but not contribute to left ventricular minute work. Thus, myocardial efficiency is reduced. It has been shown in animal studies that there is more interstitial fibrosis in hearts with CLVH than in those with ELVH.26 This might explain the lower myocardial efficiency in the former. An alternate hypothesis might be an alteration in substrate utilization and mechanoenergetics in hypertrophied left ventricular myocytes.27 It is well recognized that myocardial oxygen demand is increased in hypertrophied ventricles under resting conditions. The combination of a reduced myocardial perfusion reserve and impaired efficiency of oxygen utilization would predispose patients with CLVH to myocardial ischemia even with a relatively modest increase in cardiac workload. This might be an explanation for the relatively higher cardiovascular risk in patients with CLVH. Conversely, in patients with ELVH, although myocardial perfusion reserve is reduced, myocardial efficiency is normal, which might explain the relatively lower coronary artery disease (CAD) morbidity and mortality in these patients compared with those with CLVH. Limitations The limitations of this study should be recognized. First, our sample size is small. Thus, the absence of a difference in myocardial perfusion reserve between patients with concentric and eccentric left ventricular hypertrophy might potentially be due to a type II error. Second, the fact that the percentage of women is higher in the eccentric than in the concentric LVH group might potentially confound our results because women with LVH have been shown to have a higher mortality than men with LVH.28 Consequently, the effects of LVH on myocardial function might be worse in women than in men. However this would not invalidate our results, because mechanical efficiency is higher in the eccentric LVH group despite having a larger population of women. In conclusion, myocardial efficiency but not myocardial perfusion reserve is lower in hearts with CLVH than with ELVH, which might explain the higher risk in patients with CLVH. Clinical Implication The clinical implication of our study is that patients with concentric left ventricle hypertrophy may require a different treatment strategy from patients with eccentric left ventricle hypertrophy. Patients with eccentric ventricle hypertrophy benefit from treatment strategies that reduce
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wall stress, whereas patients with concentric left ventricle hypertrophy may require treatment strategies that not only reduce wall stress but also improve the efficiency of oxygen utilization in the myocardium. Angiotensin-converting enzyme inhibitors have been shown to decrease the magnitude of interstitial fibrosis in hypertrophied myocardium,29 which potentially can lead to an improvement in myocardial efficiency. Further studies are needed to examine the impact of treatment with angiotensin-converting enzyme inhibitors on the efficiency of energy utilization in the hypertrophied ventricle.
Acknowledgments
13.
14.
15.
16.
We thank Karen Ngai and Tina Farmer for their assistance with the preparation of this manuscript. 17.
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