Tremendous advancement has occurred during the past 2 decades in the development and implementation of continuous flow left ventricular assist devices (CF LVADs) for end-stage heart failure.1 Adaptation and evolution of rotary pump designs with greater hemocompatability have allowed for device miniaturization, enhanced durability, and reduction in adverse events such as device thrombosis.2 Beyond improvements in device design, blood pressure (BP) control during device management has emerged as an important modifiable target for reducing neurologic events such as ischemic and hemorrhagic stroke.
Hypertension is a well-established risk factor for stroke in the general population, and BP control is the cornerstone of preventing such adverse events.3 Several large global clinical trials have shown a marked reduction in stroke with improved BP control.4 Hypertension may lead to stroke through a variety of mechanisms including direct vascular damage from increased intraluminal pressure, inducing loss of wall integrity to promote aneurysm formation, and through lipohylanosis of small blood vessels supplying the white matter contributing to lacunar infarcts and brain hemorrhage.5 At a cellular level, hypertension promotes endothelial dysfunction by augmenting oxidative stress and inflammation, which contribute toward atherosclerotic plaque formation in cerebral arteries and arterioles leading to occlusive ischemic injury and cerebral infarction.5
Although it remains uncertain to what degree the aforementioned hypertension-related mechanisms impact the occurrence of stroke during CF LVAD support, multiple investigations implicate that a low pulsatile circulation already creates a vulnerable vascular substrate that could be ripe for further injury. A comparison of aortic tissue before and after CF LVAD support has shown increased vascular inflammation with higher expression of vascular adhesion markers and greater adventitial fibrosis.6 Flow-mediated vasodilation, a marker of endothelial dysfunction, is also noted to be reduced in CF LVAD patients.7 Such studies are complemented by animal models that show reduced nitric oxide production and increased reactive oxygen species by loss of vascular stretch under nonpulsatile conditions, thereby leading to inflammatory damage and endothelial dysfunction.8
Concerns that pathologic vascular changes during CF LVAD support may be a nidus for stroke when coupled with hypertension have materialized in numerous clinical studies. Investigation of various CF LVADs has shown a strong association of elevated BP with subsequent stroke, particularly a hemorrhage subtype. In a posthoc analysis of the ADVANCE (Evaluation of the HeartWare Left Ventricular Assist Device for the Treatment of Advanced Heart Failure) trial, it was noted that an elevated mean arterial pressure (MAP) > 90 mm Hg during HeartWare ventricular assist device (HVAD) support was highly associated with an eventual hemorrhagic stroke (odds ratio: 9.9, p < 0.0001).9 Furthermore, it was reported that sites with a strict BP control protocol had reduced stroke burden (10.8 vs. 1.8%, p = 0.0078).9 The ENDURANCE supplemental trial applied a prospective protocol for BP control in HVAD patients, and there was a substantial reduction in hemorrhagic strokes in comparison to the historical Endurance HVAD cohort (10.5 vs. 5.2%, p = 0.02).10
In mainly HeartMate (HM) II populations, retrospective studies have also shown an increased likelihood of stroke, with a Doppler BP > 90 mm Hg,11 MAP > 90 mm Hg, and a systolic blood pressure (SBP) >101 mm Hg.12,13 These outcomes data combined with guidelines from the International Society of Heart and Lung Transplantation, which recommends maintenance of a MAP ≤ 80 mm Hg14 during CF LVAD support, have led most implanting centers to focus more aggressively on BP control. Such clinical practice is evident in a temporal comparison of HM II control subjects in Endurance, Endurance supplemental, and the Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy with HeartMate 3 (MOMENTUM 3) trials. Across these three trials, the average MAP in HM II patients was reduced from more than 85 mm Hg to near 80 mm Hg.10,15
Although BP control has become a mainstay of device management, the unique low pulsatile circulation created by CF LVADs presents a challenge for accurate and reliable BP measurement. Depending on the residual contribution by the native left ventricle, patients with a CF LVAD have reduced and at times loss of an arterial pulse pressure (PP). Because of this reduction in PP, the standard method of noninvasive BP measurement by deflating a sphygmomanometer reliant on transduction of acoustics or vibratory oscillations can only give measurements in at best 60% of the patients,16 notwithstanding accuracy. To overcome these limitations, several noninvasive methods of BP measurement have been proposed (Figure 1)17–20 At this time, Doppler ultrasound is the most commonly used method for BP measurement during CF LVAD support. However, this Doppler technique, which yields the highest pressure that arterial flow is restored during cuff deflation, has limited ability to distinguish between SBP and MAP. For Doppler measurements, studies have only noted a good correlation with invasive SBP (r = 0.73) but not MAP (r = 0.53).17 Although Doppler BP can be interpreted more accurately as SBP by noting a palpable pulse,21 there remain inherent complexities of measurement requiring trained staff and potential for misinterpretation as MAP, which may lead to over treatment and risk of adverse hypotension-related events. Similar to the Doppler technique, BP recordings taken when finger pulse oximetry readings are restored during arm cuff deflation also have limited discrimination between SBP and MAP and are not obtainable in all patients.18 BP measurement by slow cuff deflation systems such as the Terumo Elemano can further distinguish between MAP and SBP, but only yield consistent repeat measurements in 70–80% of patients.17 Finger cuff methods such as the Nexfin device have provided accurate BP measurements at higher CF LVAD speeds corresponding to low PP, but these devices have not been validated in a large number of patients, require specialized equipment, and may not yield measurements during vasoconstriction apparent by cold extremities.19
To surmount limitations of noninvasive BP measurement in CF LVAD patients, Sajgalik et al.20 assessed the validity, repeatability, and measurement success rate of a novel brachial cuff pressure experimental BP (ExpBP) monitor. This ExpBP device used standard oscillometric mechanics, with customized hardware and software for low pulsatility and an ability to measure pulsations during cuff deflation at 2 mm Hg/second. MAP was derived at maximum peak to peak amplitude of oscillations by a programmed algorithm, and SBP and diastolic blood pressure (DBP) were obtained using previously validated height-based criteria. Measured in both HM II (n = 20) and HVAD (n = 11) patients during the postoperative period at 2.6 ± 3.4 days after LVAD implantation by a single operator, the ExpBP monitor yielded a mean absolute difference (MAD) in MAP of 3.9 ± 1.1 mm Hg versus intraarterial (IA) measurements. In comparison, Doppler yielded a MAD of 7.5 ± 1.0 mm Hg in MAP in comparison to IA recordings. The ExpBP monitor also had good correlation with IA measurements for SBP (r = 0.84), DBP (r = 0.80), and PP (r = 0.73). The measurement rate for three successful attempts was higher for Doppler at 97 vs. 86% for the ExpBP monitor. As noted in earlier studies, Doppler BP was noted to be less representative of MAP with higher PP.21
The authors are to be praised for thoroughly assessing a novel noninvasive BP monitoring system to potentially improve clinical outcomes. Overall, the ExpBP monitor demonstrated better agreement with IA recordings for MAP in comparison to Doppler and provided additional BP measures including SBP, DBP, and PP in most patients. However, it is noteworthy that SBP and DBP were within 5 mm Hg of IA measurements in only 65% and 57% of the patients, respectively. Although this ExpBP monitoring device shows promise in this prototype phase, several considerations need to be further evaluated before clinical approval and widespread adaptation, including: 1) validation in CF LVADs with a slowdown phase to generate intermittent changes in PP, 2) focused analyses in those with a reduced PP below a palpable pulse and in whom readings could not be obtained, 3) assessment in a larger population of outpatients with longer follow-up, 4) ease and accuracy of interpretation by nontrained staff and even patients, and 5) cost comparisons with the Doppler technique.
With exceptional survival on contemporary CF LVADs, the focus has shifted to prevention of adverse events, and BP control is a key component for reducing stroke. Given physiologic challenges of accurate BP measurement during low pulsatile CF LVAD conditions, the pressure is on to develop an accurate, reliable, user-friendly, and cost-effective device.
1. Jorde UP, Kushwaha SS, Tatooles AJ, et al; HeartMate II Clinical Investigators: Results of the destination therapy post-food and drug administration approval study with a continuous flow left ventricular assist device: a prospective study using the INTERMACS registry (Interagency Registry for Mechanically Assisted Circulatory Support). J Am Coll Cardiol 2014.63: 1751–1757.
2. Mehra MR, Goldstein DJ, Uriel N, et al; MOMENTUM 3 Investigators: Two-year outcomes with a magnetically levitated cardiac pump in heart failure. N Engl J Med 2018.378: 1386–1395.
3. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines. J Am Coll Cardiol 2018.71: e127–e248.
4. Gaciong Z, Siński M, Lewandowski J. Blood pressure control and primary prevention of stroke: summary of the recent clinical trial data and meta-analyses. Curr Hypertens Rep 2013.15: 559–574.
5. Yu JG, Zhou RR, Cai GJ. From hypertension to stroke: mechanisms and potential prevention strategies. CNS Neurosci Ther 2011.17: 577–584.
6. Ambardekar AV, Hunter KS, Babu AN, Tuder RM, Dodson RB, Lindenfeld J. Changes in aortic wall structure, composition, and stiffness with continuous-flow left ventricular assist devices: a pilot study. Circ Heart Fail 2015:CIRCHEARTFAILURE. 114.001955.
7. Witman MA, Garten RS, Gifford JR, et al. Further peripheral vascular dysfunction in heart failure patients with a continuous-flow left ventricular assist device: the role of pulsatility. JACC Heart Fail 2015.3: 703–711.
8. Thacher T, Gambillara V, da Silva RF, Silacci P, Stergiopulos N. Reduced cyclic stretch, endothelial dysfunction, and oxidative stress: an ex vivo model. Cardiovasc Pathol 2010.19: e91–e98.
9. Teuteberg JJ, Slaughter MS, Rogers JG, et al; ADVANCE Trial Investigators: The HVAD left ventricular assist device: risk factors for neurological events and risk mitigation strategies. JACC Heart Fail 2015.3: 818–828.
10. Milano CA, Rogers JG, Tatooles AJ, et al; ENDURANCE Investigators: HVAD: the ENDURANCE supplemental trial. JACC Heart Fail 2018.6: 792–802.
11. Saeed O, Jermyn R, Kargoli F, et al. Blood pressure and adverse events during continuous flow left ventricular assist device support. Circ Heart Fail 2015.8: 551–556.
12. Nassif ME, Tibrewala A, Raymer DS, et al. Systolic blood pressure on discharge after left ventricular assist device insertion is associated with subsequent stroke. J Heart Lung Transplant 2015.34: 503–508.
13. Pinsino A, Castagna F, Zuver AM, et al. Prognostic implications of serial outpatient blood pressure measurements in patients with an axial continuous-flow left ventricular assist device. J Heart Lung Transplant 2018.
14. Feldman D, Pamboukian SV, Teuteberg JJ, et al; International Society for Heart and Lung Transplantation: The 2013 International Society for Heart and Lung Transplantation guidelines for mechanical circulatory support: executive summary. J Heart Lung Transplant 2013.32: 157–187.
15. Colombo PC, Mehra MR, Goldstein DJ, et al. Comprehensive analysis of stroke in the long-term cohort of the MOMENTUM 3 study: a randomized controlled trial of the HeartMate 3 versus the HeartMate II cardiac pump. Circulation 2018.
16. Bennett MK, Roberts CA, Dordunoo D, Shah A, Russell SD. Ideal methodology to assess systemic blood pressure in patients with continuous-flow left ventricular assist devices. J Heart Lung Transplant 2010.29: 593–594.
17. Lanier GM, Orlanes K, Hayashi Y, et al. Validity and reliability of a novel slow cuff-deflation system for non-invasive blood pressure monitoring in patients with continuous-flow left ventricular assist device. Circ Heart Fail 2013:CIRCHEARTFAILURE. 112.000186.
18. Hellman Y, Malik AS, Lane KA, et al. Pulse oximeter derived blood pressure measurement in patients with a continuous flow left ventricular assist device. Artif Organs 2017.41: 424–430.
19. Martina JR, Westerhof BE, de Jonge N, et al. Noninvasive arterial blood pressure waveforms in patients with continuous-flow left ventricular assist devices. ASAIO J 2014.60: 154–161.
20. Sajgalik P, Kremen V, Fabian V, et al. Noninvasive blood pressure monitor designed for patients with heart failure supported with continuous-flow left ventricular assist devices. ASAIO J 2019;65:127–133.
21. Rangasamy S, Madan S, Saeed O, et al. Noninvasive measures of pulsatility and blood pressure during continuous-flow left ventricular assist device. ASAIO J 2018.