International Journal of Cardiology 187 (2015) 411–413
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Impact of left ventricular hypertrophy on impaired coronary microvascular dysfunction Kenichi Tsujita a,⁎, Kenshi Yamanaga a, Naohiro Komura a, Kenji Sakamoto a, Takashi Miyazaki a, Masanobu Ishii a, Noriaki Tabata a, Tomonori Akasaka a, Daisuke Sueta a, Yuichiro Arima a, Sunao Kojima a, Eiichiro Yamamoto a, Megumi Yamamuro a, Tomoko Tanaka a, Yasuhiro Izumiya a, Shinji Tayama a, Sunao Nakamura a,b, Koichi Kaikita a, Seiji Hokimoto a, Hisao Ogawa a a b
Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan Divison of Cardiology, New Tokyo Hospital, Matsudo, Japan
a r t i c l e
i n f o
Article history: Received 15 February 2015 Accepted 25 March 2015 Available online 26 March 2015 Keywords: Microcirculation Vascular resistance Hypertrophy Catheterization Pressure
Left ventricular hypertrophy (LVH) has been recognized as a marker of hypertension-related target organ damage, and a strong independent risk factor for adverse cardiovascular (CV) outcomes. CV risk increases with increasing LV mass, and decreases with regression of LVH in response to antihypertensive treatment [1]. However, the exact mechanisms underlying the CV events in patients with LVH have not yet been elucidated. Although coronary microvascular (MV) dysfunction (CMD) with structural abnormalities has been pathologically recognized as a possible cause of adverse outcomes in patients with hypertrophic cardiomyopathy (HCM) and in those with arterial hypertension [2], there has been no clinically-available technique that enables direct measurement of coronary microcirculation in vivo in humans. Whereas coronary flow velocity reserve (CFVR) appears to be affected by baseline systemic hemodynamic parameters [3], direct coronary MV resistance measurements, such as the index of MV resistance or hyperemic MV resistance (hMR), are newly developed, specific, quantitative indices of CMD. These modalities might have provided further insight into the pathophysiological aspect of pathologic LVH. The aim of this study was to measure hMR using a dual-sensor-equipped guidewire in order ⁎ Corresponding author at: Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan. E-mail address: [email protected] (K. Tsujita).
http://dx.doi.org/10.1016/j.ijcard.2015.03.367 0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.
to directly evaluate coronary microcirculation in patients with LVH in vivo. We recruited consecutive patients with suspected stable coronary artery disease who were admitted to Kumamoto University Hospital from June 2011 to September 2013. During this period, comprehensive hemodynamic parameters of the coronary circulation were quantitated using a 0.014-inch guidewire, which was equipped with a Doppler velocity probe and a pressure sensor (Combowire, Volcano, San Diego, CA, USA) in 104 patients. Excluding 63 patients with possible heart failure or obstructive coronary artery disease, finally, 41 patients were enrolled in the current study. Among them, patients were divided into 2 groups; LVH (n = 17) and non-LVH (n = 24). LVH was defined either interventricular septal thickness (IVST) or left ventricular posterior wall thickness (LVPW) thicker N 11 mm on the transthoracic echocardiography. Written informed consent was obtained from each study patient. This study was approved by the ethics committee of our institution and fully complied with the Declaration of Helsinki. After administration of intracoronary isosorbide dinitrate (ISDN) and post-ISDN CAG, the Combowire was inserted into the proximal site of the LAD and adenosine triphosphate (150 μg/kg/min) was administered via the central vein until maximal hyperemia was achieved for the calculation of hemodynamic parameters. Aortic pressure was measured via a guiding catheter that was placed at the left coronary ostium. Mean coronary arterial distal pressure and average peak velocity were measured using dual sensors of the Combowire. Fractional flow reserve (FFR), CFVR, hyperemic stenosis resistance, and hMR were measured as described previously at the time of coronary maximal hyperemia [4]. As CV risk is associated with severity of LVH, we generated linear model in order to assess the relationship between the degree of CMD and several severity parameters of LVH on echocardiography, including IVST, LVPW, and LV mass index. Also, as glomerular filtration rate (GFR) may in part reflect the integrity of the renal MV bed, correlation between hMR and estimated GFR (eGFR) excretion was analyzed to evaluate systemic MV function in the study patients. Finally, in order to elucidate the predictors of CMD among all patients, logistic regression analysis was employed. Regarding the baseline characteristics of the study patients (Table 1A), higher incidence of male gender, greater body surface area, and higher prevalence of HCM were observed in the LVH group compared with the non-LVH group. In terms of echocardiographic parameters, IVST, LVPW,
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K. Tsujita et al. / International Journal of Cardiology 187 (2015) 411–413
Table 1A Clinical characteristics between patients with and without LVH.
Age, mean y (SD) Male sex, n (%) Body mass index (kg/m2) Body surface area (m2) Hypertension, n (%) Dyslipidemia, n (%) Diabetes mellitus, n (%) Impaired glucose tolerance, n (%) Chronic kidney disease, n (%) Current smoking, n (%) Hypertrophic cardiomyopathy, n (%) Concomitant medication ACE inhibitor or ARB, n (%) Beta-blocker, n (%) Calcium blocker, n (%) Nitrate, n (%) Statin, n (%) Echocardiographic data Left ventricular ejection fraction, % LVDd, mm LVDs, mm IVSTd, mm LVPWs, mm E/e′ Left ventricular mass index, g/m2 B-type natriuretic peptide, pg/mL Mean pulmonary wedge pressure, mm Hg Reactive hyperemic peripheral arterial tonometry
Table 1C Predictors of higher hyperemic microvascular resistance.
LVH group (n = 17)
Non-LVH group (n = 24)
62.9 ± 10.0 13 (77) 24.1 ± 3.6 1.69 ± 0.19 12 (71) 10 (59) 5 (29) 4 (24) 5 (29) 3 (18) 4 (24)
60.8 ± 13.4 10 (42) 22.4 ± 2.9 1.56 ± 0.21 11 (46) 14 (58) 3 (13) 5 (21) 3 (13) 4 (17) 0 (0)
0.8 0.03 0.11 0.03 0.12 1.0 0.2 1.0 0.2 1.0 0.02
6 (35) 2 (12) 7 (41) 1 (6) 9 (53)
6 (25) 2 (8) 12 (50) 7 (29) 8 (33)
0.5 1.0 0.6 0.11 0.2
63.7 ± 6.3 46.8 ± 6.5 28.6 ± 7.5 11.4 ± 2.3 10.9 ± 1.0 11.2 ± 3.7 135.5 ± 37.4 46.0 ± 79.8 9.9 ± 4.7 2.00 ± 0.52
64.0 ± 5.4 43.4 ± 5.7 27.6 ± 5.1 8.8 ± 0.8 8.5 ± 0.9 9.9 ± 2.4 88.2 ± 20.1 19.4 ± 16.5 8.2 ± 3.4 2.13 ± 0.75
P value
Variable
Univariate analysis Odds ratio (95% CI)
0.9 0.10 0.9 b0.0001 b0.0001 0.4 b0.0001 0.5 0.17 0.8
Data are presented as mean ± 1SD or number (%). LVH = left ventricular hypertrophy, ACE = angiotensin-converting enzyme, ARB = angiotensin receptor blocker, LVDd = left ventricular end-diastolic diameter, LVDs = left ventricular end-systolic diameter, IVSTd = interventricular septal thickness at diastole, LVPWs = left ventricular posterior wall thickness at systole.
Clinical factor Age Male BMI BSA Current smoking Hypertension Dyslipidemia Diabetes mellitus Chronic kidney disease Estimated GFR Medication ACEi or ARB Beta-blocker Calcium blocker Nitrate Statin Ultrasonic cardiographic parameters LVEF LVDd LVDs IVSTd LVPWs LV mass index E/e′ B-type natriuretic peptide Mean pulmonary wedge pressure
Multivariate analysis P value
Odds ratio (95% CI)
P value
1.10 (1.015–1.098)
0.02
0.15
1.44 (0.38–5.57) 1.08 (0.85–1.36) 0.30 (0.012–7.203) 0.77 (0.13–4.43) 2.39 (0.62–9.20) 0.73 (0.19–2.81) 1.00 (0.19–5.33) 6.43 (0.69–60.33) 0.94 (0.89–0.99)
0.6 0.5 0.9 0.8 0.2 0.7 1.0 0.10 0.01
1.07 (0.97–1.19) – – – – – – – – 0.95 (0.90–1.02)
1.62 (0.38–6.94) 1.67 (0.14–20.24) 1.00 (0.27–3.72) 0.75 (0.16–3.62) 1.80 (0.46–7.13)
0.5 0.7 N0.99 0.7 0.4
– – – – –
– – – – –
0.95 (0.84–1.07) 1.03 (0.92–1.14) 1.04 (0.92–1.16) 2.04 (1.09–3.81) 1.78 (1.03–3.08) 1.032 (1.003–1.062)
0.4 0.6 0.5 0.03 0.04 0.03
– – – – – 0.10
1.42 (1.05–1.91) 1.02 (0.99–1.06) 1.16 (0.96–1.40)
0.02 0.18 0.12
– – – – – 1.03 (1.00–1.06) – – –
– – – – – – – – 0.14
– – –
Data are presented as odds ratio (95% confidence interval). CI = confidence interval, BMI = body mass index, BSA = body surface area, GFR = glomerular filtration rate, ACEi =
and LV mass index were significantly greater in the LVH group than in the non-LVH group naturally, whereas other hemodynamic and endothelial parameters were comparable between the groups. Table 1B summarizes the Combowire-derived coronary hemodynamic parameters. Although there was no significance between-group difference in FFR within the clinically-nonsignificant levels, CFVR was significantly impaired, and hMR was pathologically increased in the LVH group than in the nonLVH group. Based on logistic regression analysis (Table 1C), older age, worse eGFR, and LVH were significantly associated with CMD (defined as ≥median value of hMR [1.6]) in univariate analysis, and LV mass index tended to predict CMD in multivariate analysis. Finally, scatter plots showed weak but positive association between hMR values and all echocardiographic LVH parameters (Fig. 1A). Also, there was significant negative correlation between hMR and eGFR, suggesting that the exacerbated “coronary” MV function might be associated with “systemic” concurrent development of MV dysfunction in patients with LVH (Fig. 1B).
Table 1B Coronary hemodynamic parameters in patients with and without LVH at hyperemia.
Fractional flow reserve (FFR) Coronary flow reserve (CFR): 3.0–4.0 (healthy), b2.0 (diseased) FFR/CFR Hyperemic stenosis resistance (hSR) Hyperemic microvascular resistance (hMR)
LVH group (n = 17)
Non-LVH group (n = 24)
P value
0.89 ± 0.10 1.96 ± 0.79
0.91 ± 0.04 2.55 ± 0.89
0.9 0.04
0.56 ± 0.23 0.19 ± 0.16 2.09 ± 0.79
0.41 ± 0.16 0.12 ± 0.09 1.60 ± 0.50
0.07 0.4 0.04
Data are presented as mean ± 1SD. LVH = left ventricular hypertrophy, FFR = fractional flow reserve, CFVR = coronary flow velocity reserve, hSR = hyperemic stenosis resistance, hMR = hyperemic microvascular resistance.
angiotensin-converting enzyme inhibitor, ARB = angiotensin receptor blocker, LVEF = left ventricular ejection fraction, LVDd = left ventricular end-diastolic diameter, LVDs = left ventricular end-systolic diameter, IVSTd = interventricular septal thickness at diastole, LVPWs = left ventricular posterior wall thickness at systole.
The coronary arterial system is composed of 3 compartments (conductive artery, prearteriole, and arteriole). Their main function is to dilate coronary artery to increase myocardial blood flow according to myocardium oxygen demand [5]. Epicardial coronary obstruction is usually the cause of myocardial ischemia, whereas CMD has also been ascertained as another cause of myocardial ischemia, and the importance of CMD has been recognized because patients who might have CMD have a worse outcome compared with those with normal MV function [6–8]. On the other hand, the exact pathogenic mechanisms underlying the adverse CV events in patients with LVH are still unclear. Pathologically, structural abnormalities have been presumed responsible for CMD in patients with LVH [2]. In such condition, morphologic changes are characterized by an adverse remodeling of intramural coronary arterioles consisting of vessel wall thickening, mainly due to hypertrophy of smooth muscle cells and increased collagen deposition in the tunica media, with variable degrees of intimal thickening [2,5]. In the absence of epicardial obstruction, therefore, the abnormal coronary circulation appeared to be mainly based on CMD in patients with pathologic LVH. Our results suggest that impaired MV function might be one of the underlying mechanisms of LV dysfunction in patients with LVH. In terms of indices of CMD, our current study demonstrated that direct estimation of MV resistance might be more reliable than relative approaches that are dependent on baseline measurements, as several studies have previously reported on the intrinsic reliability and reproducibility of nonrelative microcirculatory resistance obtained with a
K. Tsujita et al. / International Journal of Cardiology 187 (2015) 411–413
413
Fig. 1. A. Correlation between hMR and severity of LVH. Scatter plots showed weak but positive association between hyperemic microvascular resistance (hMR) values and all echocardiographic left ventricular hypertrophy (LVH) parameters. B. Correlation between hMR and eGFR. There was significant negative correlation between hyperemic microvascular resistance (hMR) and estimated glomerular filtration ratio (eGFR), suggesting that the exacerbated coronary microvascular (MV) function might be associated with “systemic” concurrent development of MV dysfunction in patients with left ventricular hypertrophy.
combination of flow and pressure [9,10]. In conclusion, hMR was increased in patients with LVH, in association with the severity of LVH. Conflict of interest There are no conflicts of interest to disclose concerning this research project. Funding/support This work was supported by a Grant-in-Aid for Young Scientists B (24790769) and a Scientific Research C grant (26461075) from the Ministry of Education, Science, and Culture, Japan (to K. Tsujita) and the Smoking Research Foundation (SRF-46). Acknowledgments The authors thank Michiyo Saito, MT, Satomi Iwashita, MT, Daisuke Obara, BMET, Taiki Harada, BMET, Kosuke Mizuno, BMET, Takayuki Miyagawa, BMET, Yumie Harada, RT, Shuichi Tochihara, RT, and Koichi Ashimura, BMET for their dedicated assistance with measurement of hemodynamic parameters and data administration. References [1] L.M. Ruilope, R.E. Schmieder, Left ventricular hypertrophy and clinical outcomes in hypertensive patients, Am. J. Hypertens. 21 (2008) 500–508.
[2] P.G. Camici, I. Olivotto, O.E. Rimoldi, The coronary circulation and blood flow in left ventricular hypertrophy, J. Mol. Cell. Cardiol. 52 (2012) 857–864. [3] M.J. Kern, A. Lerman, J.W. Bech, B. De Bruyne, E. Eeckhout, W.F. Fearon, et al., Physiological assessment of coronary artery disease in the cardiac catheterization laboratory: a scientific statement from the American Heart Association Committee on Diagnostic and Interventional Cardiac Catheterization, Council on Clinical Cardiology, Circulation 114 (2006) 1321–1341. [4] M. Meuwissen, S.A. Chamuleau, M. Siebes, C.E. Schotborgh, K.T. Koch, R.J. de Winter, et al., Role of variability in microvascular resistance on fractional flow reserve and coronary blood flow velocity reserve in intermediate coronary lesions, Circulation 103 (2001) 184–187. [5] P.G. Camici, F. Crea, Coronary microvascular dysfunction, N. Engl. J. Med. 356 (2007) 830–840. [6] B.D. Johnson, L.J. Shaw, C.J. Pepine, S.E. Reis, S.F. Kelsey, G. Sopko, et al., Persistent chest pain predicts cardiovascular events in women without obstructive coronary artery disease: results from the NIH–NHLBI-sponsored Women's Ischaemia Syndrome Evaluation (WISE) study, Eur. Heart J. 27 (2006) 1408–1415. [7] G.A. Lanza, F. Crea, Primary coronary microvascular dysfunction: clinical presentation, pathophysiology, and management, Circulation 121 (2010) 2317–2325. [8] A.R. Pries, H. Habazettl, G. Ambrosio, P.R. Hansen, J.C. Kaski, V. Schachinger, et al., A review of methods for assessment of coronary microvascular disease in both clinical and experimental settings, Cardiovasc. Res. 80 (2008) 165–174. [9] N. Meneveau, C. Di Mario, R. Gil, P. de Jaegere, P.J. de Feyter, J. Roelandt, et al., Instantaneous pressure–velocity relationship of the coronary flow, alternative to coronary reserve measurement: a feasibility study and reproducibility of the method, Arch. Mal. Coeur Vaiss. 86 (1993) 975–985. [10] M.K. Ng, A.C. Yeung, W.F. Fearon, Invasive assessment of the coronary microcirculation: superior reproducibility and less hemodynamic dependence of index of microcirculatory resistance compared with coronary flow reserve, Circulation 113 (2006) 2054–2061.
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Impact of left ventricular hypertrophy on impaired coronary microvascular dysfunction Kenichi Tsujita a,⁎, Kenshi Yamanaga a, Naohiro Komura a, Kenji Sakamoto a, Takashi Miyazaki a, Masanobu Ishii a, Noriaki Tabata a, Tomonori Akasaka a, Daisuke Sueta a, Yuichiro Arima a, Sunao Kojima a, Eiichiro Yamamoto a, Megumi Yamamuro a, Tomoko Tanaka a, Yasuhiro Izumiya a, Shinji Tayama a, Sunao Nakamura a,b, Koichi Kaikita a, Seiji Hokimoto a, Hisao Ogawa a a b
Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan Divison of Cardiology, New Tokyo Hospital, Matsudo, Japan
a r t i c l e
i n f o
Article history: Received 15 February 2015 Accepted 25 March 2015 Available online 26 March 2015 Keywords: Microcirculation Vascular resistance Hypertrophy Catheterization Pressure
Left ventricular hypertrophy (LVH) has been recognized as a marker of hypertension-related target organ damage, and a strong independent risk factor for adverse cardiovascular (CV) outcomes. CV risk increases with increasing LV mass, and decreases with regression of LVH in response to antihypertensive treatment [1]. However, the exact mechanisms underlying the CV events in patients with LVH have not yet been elucidated. Although coronary microvascular (MV) dysfunction (CMD) with structural abnormalities has been pathologically recognized as a possible cause of adverse outcomes in patients with hypertrophic cardiomyopathy (HCM) and in those with arterial hypertension [2], there has been no clinically-available technique that enables direct measurement of coronary microcirculation in vivo in humans. Whereas coronary flow velocity reserve (CFVR) appears to be affected by baseline systemic hemodynamic parameters [3], direct coronary MV resistance measurements, such as the index of MV resistance or hyperemic MV resistance (hMR), are newly developed, specific, quantitative indices of CMD. These modalities might have provided further insight into the pathophysiological aspect of pathologic LVH. The aim of this study was to measure hMR using a dual-sensor-equipped guidewire in order ⁎ Corresponding author at: Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan. E-mail address: [email protected] (K. Tsujita).
http://dx.doi.org/10.1016/j.ijcard.2015.03.367 0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.
to directly evaluate coronary microcirculation in patients with LVH in vivo. We recruited consecutive patients with suspected stable coronary artery disease who were admitted to Kumamoto University Hospital from June 2011 to September 2013. During this period, comprehensive hemodynamic parameters of the coronary circulation were quantitated using a 0.014-inch guidewire, which was equipped with a Doppler velocity probe and a pressure sensor (Combowire, Volcano, San Diego, CA, USA) in 104 patients. Excluding 63 patients with possible heart failure or obstructive coronary artery disease, finally, 41 patients were enrolled in the current study. Among them, patients were divided into 2 groups; LVH (n = 17) and non-LVH (n = 24). LVH was defined either interventricular septal thickness (IVST) or left ventricular posterior wall thickness (LVPW) thicker N 11 mm on the transthoracic echocardiography. Written informed consent was obtained from each study patient. This study was approved by the ethics committee of our institution and fully complied with the Declaration of Helsinki. After administration of intracoronary isosorbide dinitrate (ISDN) and post-ISDN CAG, the Combowire was inserted into the proximal site of the LAD and adenosine triphosphate (150 μg/kg/min) was administered via the central vein until maximal hyperemia was achieved for the calculation of hemodynamic parameters. Aortic pressure was measured via a guiding catheter that was placed at the left coronary ostium. Mean coronary arterial distal pressure and average peak velocity were measured using dual sensors of the Combowire. Fractional flow reserve (FFR), CFVR, hyperemic stenosis resistance, and hMR were measured as described previously at the time of coronary maximal hyperemia [4]. As CV risk is associated with severity of LVH, we generated linear model in order to assess the relationship between the degree of CMD and several severity parameters of LVH on echocardiography, including IVST, LVPW, and LV mass index. Also, as glomerular filtration rate (GFR) may in part reflect the integrity of the renal MV bed, correlation between hMR and estimated GFR (eGFR) excretion was analyzed to evaluate systemic MV function in the study patients. Finally, in order to elucidate the predictors of CMD among all patients, logistic regression analysis was employed. Regarding the baseline characteristics of the study patients (Table 1A), higher incidence of male gender, greater body surface area, and higher prevalence of HCM were observed in the LVH group compared with the non-LVH group. In terms of echocardiographic parameters, IVST, LVPW,
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K. Tsujita et al. / International Journal of Cardiology 187 (2015) 411–413
Table 1A Clinical characteristics between patients with and without LVH.
Age, mean y (SD) Male sex, n (%) Body mass index (kg/m2) Body surface area (m2) Hypertension, n (%) Dyslipidemia, n (%) Diabetes mellitus, n (%) Impaired glucose tolerance, n (%) Chronic kidney disease, n (%) Current smoking, n (%) Hypertrophic cardiomyopathy, n (%) Concomitant medication ACE inhibitor or ARB, n (%) Beta-blocker, n (%) Calcium blocker, n (%) Nitrate, n (%) Statin, n (%) Echocardiographic data Left ventricular ejection fraction, % LVDd, mm LVDs, mm IVSTd, mm LVPWs, mm E/e′ Left ventricular mass index, g/m2 B-type natriuretic peptide, pg/mL Mean pulmonary wedge pressure, mm Hg Reactive hyperemic peripheral arterial tonometry
Table 1C Predictors of higher hyperemic microvascular resistance.
LVH group (n = 17)
Non-LVH group (n = 24)
62.9 ± 10.0 13 (77) 24.1 ± 3.6 1.69 ± 0.19 12 (71) 10 (59) 5 (29) 4 (24) 5 (29) 3 (18) 4 (24)
60.8 ± 13.4 10 (42) 22.4 ± 2.9 1.56 ± 0.21 11 (46) 14 (58) 3 (13) 5 (21) 3 (13) 4 (17) 0 (0)
0.8 0.03 0.11 0.03 0.12 1.0 0.2 1.0 0.2 1.0 0.02
6 (35) 2 (12) 7 (41) 1 (6) 9 (53)
6 (25) 2 (8) 12 (50) 7 (29) 8 (33)
0.5 1.0 0.6 0.11 0.2
63.7 ± 6.3 46.8 ± 6.5 28.6 ± 7.5 11.4 ± 2.3 10.9 ± 1.0 11.2 ± 3.7 135.5 ± 37.4 46.0 ± 79.8 9.9 ± 4.7 2.00 ± 0.52
64.0 ± 5.4 43.4 ± 5.7 27.6 ± 5.1 8.8 ± 0.8 8.5 ± 0.9 9.9 ± 2.4 88.2 ± 20.1 19.4 ± 16.5 8.2 ± 3.4 2.13 ± 0.75
P value
Variable
Univariate analysis Odds ratio (95% CI)
0.9 0.10 0.9 b0.0001 b0.0001 0.4 b0.0001 0.5 0.17 0.8
Data are presented as mean ± 1SD or number (%). LVH = left ventricular hypertrophy, ACE = angiotensin-converting enzyme, ARB = angiotensin receptor blocker, LVDd = left ventricular end-diastolic diameter, LVDs = left ventricular end-systolic diameter, IVSTd = interventricular septal thickness at diastole, LVPWs = left ventricular posterior wall thickness at systole.
Clinical factor Age Male BMI BSA Current smoking Hypertension Dyslipidemia Diabetes mellitus Chronic kidney disease Estimated GFR Medication ACEi or ARB Beta-blocker Calcium blocker Nitrate Statin Ultrasonic cardiographic parameters LVEF LVDd LVDs IVSTd LVPWs LV mass index E/e′ B-type natriuretic peptide Mean pulmonary wedge pressure
Multivariate analysis P value
Odds ratio (95% CI)
P value
1.10 (1.015–1.098)
0.02
0.15
1.44 (0.38–5.57) 1.08 (0.85–1.36) 0.30 (0.012–7.203) 0.77 (0.13–4.43) 2.39 (0.62–9.20) 0.73 (0.19–2.81) 1.00 (0.19–5.33) 6.43 (0.69–60.33) 0.94 (0.89–0.99)
0.6 0.5 0.9 0.8 0.2 0.7 1.0 0.10 0.01
1.07 (0.97–1.19) – – – – – – – – 0.95 (0.90–1.02)
1.62 (0.38–6.94) 1.67 (0.14–20.24) 1.00 (0.27–3.72) 0.75 (0.16–3.62) 1.80 (0.46–7.13)
0.5 0.7 N0.99 0.7 0.4
– – – – –
– – – – –
0.95 (0.84–1.07) 1.03 (0.92–1.14) 1.04 (0.92–1.16) 2.04 (1.09–3.81) 1.78 (1.03–3.08) 1.032 (1.003–1.062)
0.4 0.6 0.5 0.03 0.04 0.03
– – – – – 0.10
1.42 (1.05–1.91) 1.02 (0.99–1.06) 1.16 (0.96–1.40)
0.02 0.18 0.12
– – – – – 1.03 (1.00–1.06) – – –
– – – – – – – – 0.14
– – –
Data are presented as odds ratio (95% confidence interval). CI = confidence interval, BMI = body mass index, BSA = body surface area, GFR = glomerular filtration rate, ACEi =
and LV mass index were significantly greater in the LVH group than in the non-LVH group naturally, whereas other hemodynamic and endothelial parameters were comparable between the groups. Table 1B summarizes the Combowire-derived coronary hemodynamic parameters. Although there was no significance between-group difference in FFR within the clinically-nonsignificant levels, CFVR was significantly impaired, and hMR was pathologically increased in the LVH group than in the nonLVH group. Based on logistic regression analysis (Table 1C), older age, worse eGFR, and LVH were significantly associated with CMD (defined as ≥median value of hMR [1.6]) in univariate analysis, and LV mass index tended to predict CMD in multivariate analysis. Finally, scatter plots showed weak but positive association between hMR values and all echocardiographic LVH parameters (Fig. 1A). Also, there was significant negative correlation between hMR and eGFR, suggesting that the exacerbated “coronary” MV function might be associated with “systemic” concurrent development of MV dysfunction in patients with LVH (Fig. 1B).
Table 1B Coronary hemodynamic parameters in patients with and without LVH at hyperemia.
Fractional flow reserve (FFR) Coronary flow reserve (CFR): 3.0–4.0 (healthy), b2.0 (diseased) FFR/CFR Hyperemic stenosis resistance (hSR) Hyperemic microvascular resistance (hMR)
LVH group (n = 17)
Non-LVH group (n = 24)
P value
0.89 ± 0.10 1.96 ± 0.79
0.91 ± 0.04 2.55 ± 0.89
0.9 0.04
0.56 ± 0.23 0.19 ± 0.16 2.09 ± 0.79
0.41 ± 0.16 0.12 ± 0.09 1.60 ± 0.50
0.07 0.4 0.04
Data are presented as mean ± 1SD. LVH = left ventricular hypertrophy, FFR = fractional flow reserve, CFVR = coronary flow velocity reserve, hSR = hyperemic stenosis resistance, hMR = hyperemic microvascular resistance.
angiotensin-converting enzyme inhibitor, ARB = angiotensin receptor blocker, LVEF = left ventricular ejection fraction, LVDd = left ventricular end-diastolic diameter, LVDs = left ventricular end-systolic diameter, IVSTd = interventricular septal thickness at diastole, LVPWs = left ventricular posterior wall thickness at systole.
The coronary arterial system is composed of 3 compartments (conductive artery, prearteriole, and arteriole). Their main function is to dilate coronary artery to increase myocardial blood flow according to myocardium oxygen demand [5]. Epicardial coronary obstruction is usually the cause of myocardial ischemia, whereas CMD has also been ascertained as another cause of myocardial ischemia, and the importance of CMD has been recognized because patients who might have CMD have a worse outcome compared with those with normal MV function [6–8]. On the other hand, the exact pathogenic mechanisms underlying the adverse CV events in patients with LVH are still unclear. Pathologically, structural abnormalities have been presumed responsible for CMD in patients with LVH [2]. In such condition, morphologic changes are characterized by an adverse remodeling of intramural coronary arterioles consisting of vessel wall thickening, mainly due to hypertrophy of smooth muscle cells and increased collagen deposition in the tunica media, with variable degrees of intimal thickening [2,5]. In the absence of epicardial obstruction, therefore, the abnormal coronary circulation appeared to be mainly based on CMD in patients with pathologic LVH. Our results suggest that impaired MV function might be one of the underlying mechanisms of LV dysfunction in patients with LVH. In terms of indices of CMD, our current study demonstrated that direct estimation of MV resistance might be more reliable than relative approaches that are dependent on baseline measurements, as several studies have previously reported on the intrinsic reliability and reproducibility of nonrelative microcirculatory resistance obtained with a
K. Tsujita et al. / International Journal of Cardiology 187 (2015) 411–413
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Fig. 1. A. Correlation between hMR and severity of LVH. Scatter plots showed weak but positive association between hyperemic microvascular resistance (hMR) values and all echocardiographic left ventricular hypertrophy (LVH) parameters. B. Correlation between hMR and eGFR. There was significant negative correlation between hyperemic microvascular resistance (hMR) and estimated glomerular filtration ratio (eGFR), suggesting that the exacerbated coronary microvascular (MV) function might be associated with “systemic” concurrent development of MV dysfunction in patients with left ventricular hypertrophy.
combination of flow and pressure [9,10]. In conclusion, hMR was increased in patients with LVH, in association with the severity of LVH. Conflict of interest There are no conflicts of interest to disclose concerning this research project. Funding/support This work was supported by a Grant-in-Aid for Young Scientists B (24790769) and a Scientific Research C grant (26461075) from the Ministry of Education, Science, and Culture, Japan (to K. Tsujita) and the Smoking Research Foundation (SRF-46). Acknowledgments The authors thank Michiyo Saito, MT, Satomi Iwashita, MT, Daisuke Obara, BMET, Taiki Harada, BMET, Kosuke Mizuno, BMET, Takayuki Miyagawa, BMET, Yumie Harada, RT, Shuichi Tochihara, RT, and Koichi Ashimura, BMET for their dedicated assistance with measurement of hemodynamic parameters and data administration. References [1] L.M. Ruilope, R.E. Schmieder, Left ventricular hypertrophy and clinical outcomes in hypertensive patients, Am. J. Hypertens. 21 (2008) 500–508.
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