Bionic women and men ‐ Part 1: Cardiovascular lessons from heart failure patients implanted with left ventricular assist devices

What is the topic of this review? Patients with advanced heart failure who are implanted with left ventricular assist devices (LVADs) present an opportunity to understand the human circulation under extreme conditions. What advances does it highlight? LVAD patients have a unique circulation that is characterized by a reduced or even absent arterial pulse. The remarkable survival of these patients is accompanied by circulatory complications, including stroke, gastrointestinal bleeding and right‐heart failure. Understanding the mechanisms related to the complications in LVAD patients will help the patients and also advance our fundamental understanding of the human circulation in general.


INTRODUCTION
Whilst knowledge of the human circulation has increased substantially over the past centuries, our understanding of the interdependence of the heart and arteries in health and disease warrants ongoing study. wileyonlinelibrary.com/journal/eph presence of a non-physiological pulse, and postulate new hypotheses in cardiovascular science that arise from the special insight these bionic women and men gift us.

WHO ARE THE 'BIONIC WOMEN AND MEN'?
In some heart failure patients, the disease progresses unfavourably with conventional medical therapy. Although the preferred next step would be a heart transplant, in most countries there are not enough donor hearts available. For these patients, the surgical implantation of an LVAD is the best option, and the positive results in recent clinical trials are testimony to the success of this medical feat (see Figure 1; Colombo et al., 2019;Mehra et al., 2018;Mehra et al., 2019). These patients not only are 'bionic' because they walk around with a metal pump in their hearts, the continuous flow produced by the mechanical pumps also changes the flow characteristics typically produced by the native heart -LVAD patients live 'without a pulse' (Purohit, Cornwell, Pal, Lindenfeld, & Ambardekar, 2018). This unique physiological state can be detected in large and medium-sized arteries and varies between patients as shown in more detail in Figure 2 (Castagna et al., 2017). Accordingly, there has been much debate around the role of the arterial pulse (Cornwell, Tarumi, Lawley, & Ambardekar, 2019;Cornwell, Urey, Drazner, & Levine, 2015;Floras, Rao, & Billia, 2015;Stöhr, McDonnell, Colombo, & Willey, 2019). The fact that the overall health of LVAD patients continues to improve suggests that humans may not need a pulse to live. Conversely, other data indicate that the complications LVAD patients experience may be linked to the low pulse, and that the reduced pulsatility may be as detrimental as the increased pulsatility in hypertensive patients (Ambardekar et al., 2015;Cornwell et al., 2015). The following section discusses the clinical complications that LVAD patients experience that may be attributable to the absent pulse.

CLINICAL PRESENTATION OF LVAD PATIENTS
Historically, patients with advanced heart failure who did not receive a heart transplant were surgically implanted with pulsatile heart pumps.
The prognosis of these patients was relatively poor and was only improved when continuous-flow LVADs emerged (Slaughter et al., 2009). The recent MOMENTUM 3 trial shows a further improved survival and a much-reduced rate of stroke in LVAD patients Mehra et al., 2017Mehra et al., , 2018Mehra et al., , 2019Uriel et al., 2017). Interestingly, the lower rate of strokes was not attributed to blood pressure , suggesting that the contribution of blood pressure to stroke may be different in patients with a continuous-flow circulation (see 'Bionic Women and Men. Part 4' by Buchanan et al. 2020). This has implications for the risk factors for stroke in the general population as it is currently believed that increased blood pressure is a major risk factor for stroke (Seshadri et al., 2001).

New Findings
• What is the topic of this review?
Patients with advanced heart failure who are implanted with left ventricular assist devices (LVADs) present an opportunity to understand the human circulation under extreme conditions.
• What advances does it highlight?
LVAD patients have a unique circulation that is characterized by a reduced or even absent arterial pulse.
The remarkable survival of these patients is accompanied by circulatory complications, including stroke, gastrointestinal bleeding and right-heart failure. Understanding the mechanisms related to the complications in LVAD patients will help the patients and also advance our fundamental understanding of the human circulation in general.
A second complications in LVAD patients is the high prevalence of gastrointestinal bleeding, which suggests that the continuous-flow circulation impacts clotting factors and/or disruption of the integrity of the arterial wall. The necessary anti-coagulation regimen may contribute to gastrointestinal (GI) bleeding as well as the development of angiodysplasia, although the latter may originate already in heart failure and only manifest itself in GI bleeding during LVAD support (Patel et al., 2018). Additionally, degradation of the von Willebrand factor, which typically 'mediates platelet adhesion to both the subendothelial matrix and endothelial surfaces and acts as a carrier for coagulation factor VIII in the circulation' (Starke et al., 2011) has been widely reported in LVAD patients (Bartoli et al., 2014(Bartoli et al., , 2018Nascimbene, Neelamegham, Frazier, Moake, & Dong, 2016). This has been largely attributed to the altered conformation of the high molecular mass multimers caused during the passage of blood through the bearings of the mechanical pumps and may be an important contributor to the increased prevalence of GI bleeding as well as microcirculatory bleeds in the brain of continuous-flow, second generation LVAD patients (Yoshioka et al., 2017). One study has proposed the intriguing idea that an increased arterial pulsatility can counter the von Willebrand factor degradation caused by the passage of blood through the mechanical bearings of the LVAD (Vincent et al., 2018). Since the HeartMate 3 (HM3) LVAD is generally thought to reduce mechanical shear, the idea by Vincent and colleagues fits the report of a greater preservation of the von Willebrand factor in HM3 patients compared with HeartMate II (HMII) (Netuka et al., 2016). However, the incidence of GI bleeding remains similar between HMII and HM3 patients and the true peripheral pulsatility, including that in the microcirculation, of both HMII and HM3 patients remains to be unveiled. To identify the mechanisms for altered bleeding is thus of great importance and we speculate that the same mechanisms that lead to GI bleeding may also be responsible for non-thrombotic, haemorrhagic strokes in LVAD patients (Lai et al., 2019). Solving this riddle, perhaps via a combination show. Consequently, it is possible that the occurrence of right heart failure may be reduced by a more gradual increase in LVAD speed to slowly accustom the right ventricle to the increased volumetric load. In general, the insight from the sudden improvement in left sided output because of the LVAD with the simultaneous impact on the right ventricle provides new knowledge into the regulation of right heart function and pulmonary artery pressures beyond the specific LVAD condition.

THE ROLE OF PULSATILITY
Many of the factors discussed above can be related to the reduction or even total absence of pulsatility. Whilst an increased pulse pressure has been associated with an increased risk of morbidity and mortality, it is also known that low arterial flow pulsatility disrupts normal arterial processes. As reported previously, 'Pulsatility of flow causes cyclical stretch of the arterial wall that is a critical contributor to endothelial production of nitric oxide and cardiovascular health (Hahn & Schwartz, 2009). The high occurrence of bleeding events, such as GI bleeding and haemorrhagic strokes, indicates a primary problem with endothelial integrity' (Stöhr et al., 2019). In other words, pulsatility may not just be important because it is the natural state of the human cardiovascular system -a fait accompli argument that is often read in articles or heard at conferences. Rather, studies on the physiology show that there are clear biological processes that depend on a minimum amount of pulsatility to optimize arterial function and health. For example, pulsatility releases the vasoactive nitric oxide, thus contributing to the ability of the artery to respond adequately to circulatory changes (Nakano, Tominaga, Nagano, Okabe, & Yasui, 2000). Equally, too much pulsatility has been associated with a greater risk of cardiovascular disease (Chuang et al., 2016). Although the impact of the 'artificial pulse' in HM3 patients it not known, it is possible that some of the clinical and functional improvements in these patients may be attributed to an overall improved biology because of a moderately increased pulsatility. That said, it is unknown at this time whether the automated modulations in the HM3 pump speed translate into any meaningful pulse throughout the circulation. Of course, in the context of a continuous-flow circulation that constantly pushes blood forward through the system, a normal pulsatility may also not be beneficial, since too much pulsatility may be transported into the microcirculation of end-organs Webb et al., 2012). This effect may be even worse in LVAD patients with increased arterial stiffness (see 'Bionic Women andMen. Part 4' by McDonnell et al. 2020, Patel et al., 2017;Rosenblum et al., 2018), likely impacting on the brain and GI tract as well as the right heart. It can be expected that the study of the complex interactions between the heart, arterial blood pressure, pulsatility and stiffness in LVAD patients will reveal new insight into the mechanisms that impact cardiovascular health in all humans.