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Effects of Continuous Flow Left Ventricular Assist Device Support on Microvascular Endothelial Function Xiaoying Lou, Danielle L. Templeton, Ranjit John & Donald R. Dengel Journal of Cardiovascular Translational Research ISSN 1937-5387 Volume 5 Number 3 J. of Cardiovasc. Trans. Res. (2012) 5:345-350 DOI 10.1007/s12265-011-9321-z 1 23 Your article is protected by copyright and all rights are held exclusively by Springer Science+Business Media, LLC. This e-offprint is for personal use only and shall not be selfarchived in electronic repositories. If you wish to self-archive your work, please use the accepted author’s version for posting to your own website or your institution’s repository. You may further deposit the accepted author’s version on a funder’s repository at a funder’s request, provided it is not made publicly available until 12 months after publication. 1 23 Author's personal copy J. of Cardiovasc. Trans. Res. (2012) 5:345–350 DOI 10.1007/s12265-011-9321-z Effects of Continuous Flow Left Ventricular Assist Device Support on Microvascular Endothelial Function Xiaoying Lou & Danielle L. Templeton & Ranjit John & Donald R. Dengel Received: 9 June 2011 / Accepted: 9 September 2011 / Published online: 20 September 2011 # Springer Science+Business Media, LLC 2011 Abstract The effects of continuous flow left ventricular assist device (CF-LVAD) support on microvascular endothelial function in New York Heart Association (NYHA) class IV heart failure (HF) patients are currently unknown. Microvascular endothelial function was assessed by beat-to-beat plethysmographic measurement of finger arterial pulse wave signal changes for 5 min following reactive hyperemia. A group of seven NYHA class IV HF patients was evaluated before CF-LVAD placement (HF), and a second group of six NYHA class IV HF patients was evaluated 1–4 months following CF-LVAD placement (CF-LVAD). Additionally, a third group of seven age-matched healthy subjects served as controls (control). There was no significant (P>0.05) difference among the three groups in age, weight, or height. Systolic blood pressure (BP) was significantly higher in the control group (120±2 mmHg) as compared to that in the HF (97±8 mmHg, P=0.005) and CF-LVAD (106±4 mmHg, P= 0.003) groups. Diastolic BP was significantly lower in the HF group (57±5 mmHg) as compared to that in the control (71±2 mmHg, P=0.012) and CF-LVAD (80±7 mmHg, P= 0.008) groups. The reactive hyperemic index (RHI), a measure of endothelial function, was significantly higher in the control group (2.373±0.274) than in both the HF (1.543±0.173, P=0.013) and CF-LVAD (1.355±0.163, P= 0.004) groups; however, there was no significant (P=0.223) difference in RHI between the HF and CF-LVAD groups. The results of the present study demonstrate that while 1– 4 months of CF-LVAD support do not negatively affect microvascular endothelial function, 1–4 months of CFLVAD support do not significantly improve vascular function in resistance vessels. X. Lou College of Biological Sciences, University of Minnesota, Minneapolis, MN, USA Endothelial dysfunction is a systemic disorder and a wellestablished marker in the pathogenesis of atherosclerosis and its complications [1]. A number of studies have established a relationship between endothelial dysfunction and heart failure (HF) severity or prognosis [2–5]. Teerlink et al. [6] demonstrated impairment in endothelium-dependent vasodilation in chronic HF rats, which increased in severity as HF progressed. Recently, Shechter et al. [7] demonstrated that vascular endothelial dysfunction predicts risk for adverse cardiovascular events and mortality in New York Heart Association (NYHA) class IV ischemic HF patients; Katz et al. [8] reported similar findings in NYHA class II–III ischemic and nonischemic HF patients. However, these and other studies have relied on ultrasound imaging during flowmediated dilation of conduit vessels. It may well be that D. L. Templeton School of Kinesiology, University of Minnesota, Minneapolis, MN, USA R. John Veterans Affairs Medical Center, Division of Cardiothoracic Surgery, University of Minnesota Medical School, Minneapolis, MN, USA D. R. Dengel (*) Veterans Affairs Medical Center, School of Kinesiology, University of Minnesota, 1900 University Avenue S.E., 110 Cooke Hall, Minneapolis, MN 55455, USA e-mail: [email protected] Keywords Endothelial function . Reactive hyperemia index . Heart failure . Continuous flow left ventricular assist device . Resistance vessels . Microvascular . Endothelium . Vascular Author's personal copy 346 endothelial dysfunction also occurs in microvascular resistance vessels during HF. Left ventricular assist devices (LVADs) have been introduced as a bridge to heart transplantation, providing improved survival time [9] and functional independence [10] for those awaiting transplantation. Although the firstgeneration pulsatile flow LVADs (PF-LVAD) have been shown to improve arterial function [11, 12], the secondgeneration continuous flow LVADs (CF-LVAD) are currently being used with greater frequency due to their smaller size, lack of valves, and fewer moving parts, which improve mechanical reliability [13, 14]. The purpose of the present study sought to examine the effects of HF and CF-LVAD support on endothelial function in microvascular resistance vessels. Methods Patients Thirteen NYHA class IV HF patients were tested during two different treatment phases: seven patients were measured prior to LVAD surgery (HF), and another six HF patients were measured 1–4 months following CF-LVAD placement (CF-LVAD). All surgical patients received a HeartMate II (Thoratec Corporation, Pleasanton, CA) CFLVAD as a bridge to transplantation due to chronic endstage HF. All HF patients were recruited prospectively from the University of Minnesota Medical Center–Fairview (Minneapolis, MN). Study inclusion criteria were patients aged >18 years with NYHA class IV HF. In addition, seven healthy subjects were tested as age-matched controls (control). These subjects had no history of HF. The study protocol was reviewed and approved by the University of Minnesota Institutional Review Board. Written informed consent was given by all participants. Study Protocol All subjects were asked to fast for 8 h prior to testing, withhold morning medications until after the vascular studies, and refrain from strenuous physical activity for 12 h prior to testing. Height and weight were measured using a stadiometer (Ayrton Stadiometer, Model S100, Prior Lake, MN) and an electronic scale (ST Scale-Tronix, White Plains, NY), respectively. Body mass index (BMI) was calculated as weight (kilograms) divided by height2 (meters). Supine blood pressure (BP) on the right arm was obtained after 5 min of quiet rest using an automatic sphygmomanometer (Colin Press-Mate, Model BP-8800C, San Antonio, TX). Medication profile, medical history, and HF etiology were obtained from patient medical files. J. of Cardiovasc. Trans. Res. (2012) 5:345–350 Measurement of Endothelial Function All vascular testing was performed at the University of Minnesota Clinical and Translational Science Institute in a quiet room of constant temperature (22–23°C). Finger plethysmography (Endo-PAT2000, Itamar Medical, Caesarea, Israel) was used to non-invasively evaluate microvascular endothelial function following reactive hyperemia of the brachial artery. After 10 min of quiet rest in the supine position, finger probes were placed on the index fingers of both hands to measure baseline and reactive hyperemic pulse amplitude. The probes were inflated to apply a uniform pressure (10 mmHg less than diastolic BP) on the fingers and detect small pulse volume changes throughout the cardiac cycle. Following the collection of 5 min of baseline data, a BP cuff on the upper forearm (just below the elbow) was inflated to a suprasystolic level for 5 min. After cuff release, the change in pulse amplitude during reactive hyperemia was measured for 5 min. The ratio of the hyperemic and the baseline pulse amplitude (corrected for the same ratio on the control finger) was calculated using a computerized automated algorithm and expressed as the reactive hyperemic index (RHI). RHI is defined as the ratio of the average pulse wave amplitude during the 1-min period following the release of a BP cuff to the average pulse wave amplitude during a 210-s baseline period. Lower values of RHI indicate higher levels of endothelial dysfunction [15] and correlate with vascular abnormality [16]. The reliability of Endo-PAT2000 in assessing endothelial function has been previously validated [17, 18]. Statistical Analysis Data were analyzed by SPSS statistical package version 17.0 (2010 SPSS Inc., Chicago, IL), and graphical representations were performed using GraphPad Prism 5® (2007 GraphPad Software, Inc., La Jolla, CA). Analysis of variance was used to determine differences in descriptive characteristics and measures of endothelial function. An unpaired independent t test was used to compare ischemic and nonischemic HF etiologies between the HF and CFLVAD groups. A chi-square test for trend was used to compare medication profiles, disease conditions, and ethnicity between the groups. All data were expressed as mean ± standard error of the mean, and differences were considered significant when P<0.05. Results A summary of subject characteristics is presented in Table 1. There was no significant (P>0.05) difference among the three groups in age, weight, height, or BMI. Moreover, Author's personal copy J. of Cardiovasc. Trans. Res. (2012) 5:345–350 347 there was no significant difference in years with HF between the HF and CF-LVAD groups. Systolic BP was significantly higher in the control group as compared to that in the HF (P=0.005) and CF-LVAD (P=0.003) groups. There was no significant difference in diastolic BP between the control and CF-LVAD groups (P=0.108). However, the diastolic BP was significantly lower in the HF group as compared to that in both the control (P=0.012) and CFLVAD (P=0.008) groups. Pulse pressure was significantly higher in the control group as compared to that in both the HF (P=0.025) and CF-LVAD (P<0.001) groups; additionally, pulse pressure was significantly (P=0.029) higher in the HF as compared to that in the CF-LVAD group. The HF and CF-LVAD groups were on an array of medications; only two control subjects were on mild hypertension medication (Table 2). The breakdown for ischemic and nonischemic HF is evenly distributed among the HF and CF-LVAD groups, with a majority of subjects having ischemic etiologies. There was no significant difference between HF and CF-LVAD groups for peak oxygen uptake (P=0.222) or ejection fraction (P=0.631) (Table 1). The RHI was significantly greater in the control group (2.373 ±0.274) than in both the HF (1.543± 0.173, P=0.013) and CF-LVAD (1.355± 0.163, P= 0.004) groups; however, there was no significant (P= 0.223) difference in RHI between the HF and CF-LVAD groups (Fig. 1). Discussion To our knowledge, the present study is the first to demonstrate decreased microvascular endothelial function in a group of NYHA class IV HF patients as compared to age-matched healthy controls. Moreover, it is the first to report that microvascular endothelial function is not improved in HF patients who have undergone CF-LVAD implantation as compared to those who have not. Impaired endothelium-dependent vasodilation and relaxation have been well established in virtually all cardiovascular diseases [19, 20] including severe HF [21, 22]. However, whereas previous studies were performed in peripheral conduit vessels such as the brachial artery [23– 25], the present study is the first to use RHI to noninvasively assess microvascular endothelial function in severe HF patients. In a study by Houben et al. [26], the microvascular density, diameters, and morphology of vessels in the bulbar conjunctiva and skin nailfold of 14 NYHA class III–IV HF patients were examined using intravital microscopy. An increase in abnormal capillary morphologic features and a decrease in microvascular density and recruitment capacity were observed, suggesting the presence of structural and functional changes to the microcirculation. The results of the present study confirm the findings of Houben et al. [26], but whereas their study was performed on the static microvessels of the bulbar conjunctiva and skin nailfold, ours demonstrates the Table 1 Mean (±SE) descriptive characteristics of the age-matched control group (control), NYHA class IV heart failure group (HF), and continuous flow left ventricular assist device group (CF-LVAD) Control N Age (years) Gender (M/F) Ethnicity Caucasian African–American Asian Weight (kg) Height (cm) Body mass index (kg/m2) Years with HF Ejection fraction (%) Peak oxygen uptake (mL/kg/min) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Pulse pressure (mmHg) * CF-LVAD 7 50.7±3.3 6/1 7 49.8±3.3 6/1 6 43.2±3.6 6/0 6 0 1 89.9±7.6 179.1±3.8 28.0±1.6 – – – 120±5 71±4 52±4 6 1 0 94.5±7.6 176.9±3.8 30.2±1.6 7.1±1.6 14.7±2.4 11.7±1.1 96±5* 57±5*,** 38±4*,** 4 2 0 101.2±8.2 180.2±4.1 30.8±1.8 8.3±1.3 13.3±1.0 14.1±1.3 106±5* 80±5 24±5* P<0.05 (significantly different than the control value); P<0.05 (significantly different than the CF-LVAD value) ** HF Author's personal copy 348 J. of Cardiovasc. Trans. Res. (2012) 5:345–350 Control Number HF CF-LVAD 7 7 6 28 0 86 86* 67 67* Angio II antagonists 0 29 17 Digitalis Anti-arrhythmias Ca+ channel blockers 0 0 0 29 29 0 17 17 0 Vasodilators Diuretics 0 0 29 86* 17 83* Other medications Laxatives 0 29* 67* Cholesterol Anti-coagulates 0 0 0 29* 33 50* Anti-bacterials Pain medications Ulcer/GERD medications 0 0 0 0 43* 43* 33 50* 50* 0 0 43* 71 83* 17 0 0 0 43* 57* 100* 50* 83* 66* 0 0 57* 43 67* 33 CV medications Beta-blockers ACE inhibitors Disease conditions Diabetes Smoking Kidney disease Asthma Anxiety/depression HF etiology Ischemic Nonischemic *P<0.05 (significantly different than the control group) impairment of microvascular endothelial vasoreactivity in dynamic microvessels of a different vessel bed, thus contributing to the growing body of evidence indicating that endothelial function of microvascular resistant vessels is compromised in HF patients. To date, few studies have examined the effects of LVAD support on endothelial function. Khan et al. [12] reported that PF-LVAD implantation did not improve vascular conductance in severe HF patients until late (8 to 12 weeks) postoperative recovery phase; moreover, no improvement in vascular conductance was observed in the early (<4 weeks) postoperative recovery phase after PF-LVAD implantation. Amir et al. [27] compared the effects of LVAD type (CF-LVAD versus PF-LVAD) on endothelial function in conduit arteries. HF patients supported with CFLVADs had significantly lower endothelial function than HF patients supported with PF-LVADs, indicating that the pulsatile blood flow characteristics of PF-LVADs offer significant vascular benefits over the continuous blood flow characteristics of CF-LVADs. Bittner et al. [28] compared microvascular forearm responses to reactive hyperemia in healthy controls versus end-stage HF patients treated with the Berlin heart biventricular assist device system (BVAD). The time taken to reach peak post-occlusive reactive hyperemia values was lower in BVAD patients than in healthy controls, indicating the presence of microvascular dysfunction in these patients. Drakos et al. [28] examined myocardial tissue obtained from the LV apical core in HF patients prior to LVAD implantation and cardiac transplantation. LVAD implantation resulted in increased microvascular density and decreased microvascular luminal area, suggesting an improvement in microvascular function. It should be noted that Drakos et al. [28] examined HF patients implanted with a PF-LVAD and not a CF-LVAD as used in the present study. The results of the present study support previous research that endothelial function in HF patients is not improved after implantation with a CFLVAD. Moreover, our data suggest that the lack of improvement in endothelial function is extended to resistance blood vessels and is not exclusive to conduit blood vessels. Current clinical evidence indicates that CF-LVADs have been successful in managing end-organ perfusion and function for extended durations but may not markedly improve vascular flow and pulsatility [29–33]. Although vascular pulsatility appears to decrease immediately postoperatively, it chronically increases after prolonged CF-LVAD support, likely due to vascular stiffening [30]. It is thought that the attenuated cushioning effect of stiff arteries amplifies pressure pulsatility and increases transmission of potentially harmful pulsatile energy to the peripheral vessels. Because of the relatively small diameters of these vessels (∼300 μm), pressure pulsatility damage is further compounded in the microcirculation and by microvascular remodeling, resulting Control Heart Failure Reactive Hyperemic Index (RHI) Table 2 Medication profiles, disease conditions, and heart failure etiologies of the age-matched control group (control), NYHA class IV heart failure group (HF), and continuous flow left ventricular assist device group (CF-LVAD), expressed as a percentage of total number of subjects in each group 3 2 CF-LVAD * * 1 0 Fig. 1 RHI in the control (closed bar), NYHA class IV heart failure (open bar), and continuous flow left ventricular assist device (striped bar) patients. *P<0.05, significantly different than the control subjects Author's personal copy J. of Cardiovasc. Trans. Res. (2012) 5:345–350 349 in target organ damage to high blood flow low-impedance organs like the brain and the kidneys [31]. Moreover, decreased peripheral microvascular distensibility and compliance result in increased end-systolic pressure in the left ventricle, leading to increased ventricular pressure, cardiac hypertrophy, and ventricular workload. The long-term implications of decreased RHI in this study's patient population even 1–4 months after LVAD surgery indicate the need for increased surveillance and further intervention post-LVAD placement. The observed changes in RHI may be involved in increasing the hemodynamic load on LVAD function and may be relevant to the medical management of LVAD patients and the longevity of the device itself. There is evidence for the preoperative use of medications such as statins and highly selective β-1 receptor antagonists in improving microvascular endothelial function [32]. Consideration of these factors will be especially important as CF-LVADs become increasingly utilized as destination therapy for severe HF patients. vessels is impaired in NYHA class IV HF and is not improved 1–4 months following CF-LVAD surgery. To our knowledge, this is the first study to investigate the effects of severe HF and CF-LVAD support on endothelial function in the microvasculature. These studies confirm previous research that CF-LVAD does not improve endothelial function, and this work has now been extended to resistance vessels. Future studies are needed to examine the longitudinal changes in endothelial function following LVAD placement in HF patients. Limitations 1. Bonetti, P. O., Lerman, L. O., & Lerman, A. (2003). Endothelial dysfunction a marker of atherosclerotic risk. Arteriosclerosis, Thrombosis, and Vascular Biology, 23, 168–175. 2. Bank, A. J., Lee, P. C., & Kubo, S. H. (2000). Endothelial dysfunction in patients with heart failure: relationship to disease severity. Journal of Cardiac Failure, 6, 29–36. 3. Kubo, S. H., Rector, T. S., Bank, A. J., et al. (1991). Endotheliumdependent vasodilation is attenuated in patients with heart failure. Circulation, 84, 1589–1596. 4. Katz, S. D., Biasucci, L., Sabba, C., et al. (1992). Impaired endothelium-mediated vasodilation in the peripheral vasculature of patients with congestive heart failure. Journal of the American College of Cardiology, 19, 918–925. 5. Drexler, H., Hayoz, D., Münzer, T., et al. (1992). Endothelial function in chronic congestive heart failure. The American Journal of Cardiology, 69, 1596–1601. 6. Teerlink, J. R., Clozel, M., Fischli, W., et al. (1993). Temporal evolution of endothelial dysfunction in a rat model of chronic heart failure. Journal of the American College of Cardiology, 22, 615–620. 7. Shechter, M., Matetzky, S., Arad, M., et al. (2009). Vascular endothelial function predicts mortality risk in patients with advanced ischaemic chronic heart failure. European Journal of Heart Failure, 11, 588–593. 8. Katz, S. D., Hryniewicz, K., Hriljac, I., et al. (2005). Vascular endothelial dysfunction and mortality risk in patients with chronic heart failure. Circulation, 111, 310–314. 9. Radovancevic, B., Vrtovec, B., de Kort, E., et al. (2007). Endorgan function in patients on long-term circulatory support with continuous- or pulsatile-flow assist devices. The Journal of Heart and Lung Transplantation, 26, 815–818. 10. Nguyen, T., Pham, L., Vinh, P., et al. (2007). Heart failure. In T. Nguyen, D. Hu, M. Kim, & C. Grines (Eds.), Management of complex cardiovascular problems: the evidence-based medicine approach (3rd ed., p. 198). Malden: Blackwell Futura. 11. Papaioannou, T. G., Mathioulakis, D. S., & Tsangaris, S. G. (2003). Simulation of systolic and diastolic left ventricular dysfunction in a mock circulation: the effect of arterial compliance. Journal of Medical Engineering & Technology, 27, 85–89. 12. Khan, T., Levin, H. R., Oz, M. C., et al. (1997). Delayed reversal of impaired metabolic vasodilation in patients with end-stage heart There are several important limitations of the present study. First, due to its cross-sectional design, there is an inherent possibility that genetic and/or other lifestyle behaviors, independent of cardiovascular disease, influenced our results. It also remains a possibility that the decreased reactive hyperemic indices of these patients were related to co-morbid conditions associated with endothelial dysfunction. Second, there was a range of HF etiologies and physiological variation among subjects and between groups. Moreover, a large percentage of study participants were on an intensive regimen of cardiovascular drugs such as beta-blockers, ACE inhibitors, and diuretics, which were withheld for only 12 h prior to study measurements. Due to post-surgical complications and illness, post-implantation measures were done between 1 and 4 months. A number of alterations are occurring during this time period that may affect the results. Finally, the relatively small sample size and the short 1–4-month duration of the study postimplantation prevent widespread and longitudinal extrapolation of our results. It is possible that longer (>1 year) durations of CF-LVAD use could alter our findings; longitudinal testing of a larger number of advanced NYHA class IV HF patients is indicated in future studies. Conclusion The purpose of the present study was to determine the effects of chronic HF and CF-LVAD support on the endothelial function of microvascular resistance vessels. 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