systemic consequences of ventricular assist devices: alterations of coagulation, immune function,...

Systemic Consequences of Ventricular Assist Devices:Alterations of Coagulation, Immune Function,Inflammation, and the Neuroendocrine System

Craig R. Hampton and Edward D. Verrier

The Division of Cardiothoracic Surgery, Department of Surgery, The University of Washington, Seattle, Washington, U.S.A.

Abstract: Implantable ventricular assist devices haveproven efficacious as a bridge to transplantation and as abridge to recovery. Although current indications for use ofassist devices are somewhat limited, they are likely to ex-pand in the upcoming years, including their use as desti-nation therapy for end-stage heart failure. Recipients ofassist devices, however, are prone to certain device-specific complications, including excessive postoperative

bleeding, late propensity for thromboembolism, infections,and systemic inflammation, which may contribute to end-organ dysfunction. This article reviews the systemic bio-chemical alterations underlying these clinical phenomena.As assist devices are increasingly used, better understand-ing of these systemic perturbations is imperative. KeyWords: Assist device—Coagulation—Inflammation—Infection—Ventricular assist device.

INTRODUCTION

Congestive heart failure (CHF) is a significanthealth problem in the United States. Currently, 4.7million Americans have been diagnosed with CHF,which led to 978,000 hospital discharges in 1998 at acost to society of $3.7 billion (1). Although bettermedical management has improved outcomes forheart failure, definitive therapy has proven elusive,with a 5 year mortality rate of 50% (1). Accordingly,nearly 60,000 patients in the United States couldbenefit from therapies alternative to medical man-agement, including heart transplantation or long-term mechanical circulatory support (2). Unfortu-nately, despite efforts to increase donor organsupply, there remains a significant disparity betweenthe number of patients awaiting heart transplanta-tion and the number of donor hearts available whichcurrently total about 2250 per annum (3). For many

of these patients with CHF, mechanical circulatorysupport provides a reasonable alternative to cardiactransplantation and possibly an alternative to opti-mal medical therapy for end-stage heart failure. Infact, the Randomized Evaluation of Mechanical As-sistance for the Treatment of Congestive Heart Fail-ure (REMATCH) trial revealed a survival benefit at1 and 2 years and improved quality of life for thosereceiving ventricular assist device (VAD) supportover medical management (4). Certainly, as long asthe outcomes of medically managed end-stage heartfailure do not dramatically improve and the organdonor supply remains insufficient, the use of me-chanical devices to support or supplant the failingheart will increase. For this reason, it is imperativethat the interactions between the host and the me-chanical device be better understood. This articlewill review the systemic biochemical perturbationsthat are consequent to assist device placement.

EFFECTS ON THE CASCADES OFCOAGULATION AND FIBRINOLYSIS

Early postoperative bleeding and late thrombo-embolic events are 2 of the main complications ofassist devices. Reoperation for postoperative hemor-rhage occurs in 20–40% of patients after assist device

Received June 2002.Presented in part at the 9th Congress of the International So-

ciety for Rotary Blood Pumps, held August 17–20, 2001, in Se-attle, Washington.

Address correspondence and reprint requests to Dr. Edward D.Verrier, Vice Chairman, Department of Surgery, William K. Ed-mark Professor of Cardiovascular Surgery, Chief, Division of Car-diothoracic Surgery, The University of Washington, Box 356310,1959 NE Pacific Street, Seattle, WA 98195-6310, U. S. A. E-mail:[email protected]

Artificial Organs26(11):902–908, Blackwell Publishing, Inc.© 2002 International Society for Artificial Organs

902

placement, and late symptomatic thromboembolicevents may occur with equal frequency (7–9). Withthe recognition that contact of blood with the foreignsurfaces of the assist devices is thrombogenic, recentassist devices have been developed with a texturedsurface to facilitate the formation of a pseudoneo-intima, which likely decreases, but does not elimi-nate, the incidence of thromboembolism (9). Despitethese technological improvements, bleeding andthromboembolism remain complications of assist de-vice placement resulting from systemic alterations ofthe coagulation and fibrinolytic cascade. Moreover,the tendency toward early hemorrhage is potenti-ated by changes attendant to cardiopulmonary by-pass (CPB) namely platelet consumption, plateletdysfunction, and hemodilution of coagulation factorsand platelets.

To assess the effects of assist device placement onthe coagulation and fibrinolytic cascades, Himmel-reich et al. determined hemostatic laboratory valuesin 12 bridging patients after placement of assist de-vices until transplantation or until 51 days (10). Theyobserved decreased levels of contact factors XI, XII,and prekallikrein within 15 days of assist deviceplacement, indicating activation and consumption ofthe intrinsic coagulation pathway factors. Coinciden-tally, levels of plasmin-�2-antiplasmin (PAP) com-plexes were elevated, indicating generation of plas-min through the intrinsic fibrinolytic pathwaytriggered by contact activation. Starting in the thirdpostoperative week, factors XI, XII, and prekal-likrein started increasing, whereas PAP remained el-evated. Throughout the postoperative period, levelsof thrombin-antithrombin (TAT), platelet factor 4,and �-thromboglobulin remained elevated, indicat-ing thrombin generation and platelet activation, re-spectively. Wang et al. also examined the laboratoryhemostatic profiles in patients requiring VADs andobserved a 16% incidence of early hemorrhage re-quiring reoperation (11). In these patients, hepaticsynthetic dysfunction resulted in low levels of thecoagulant proteins. Furthermore, preoperatively,there were elevated D-dimer levels indicating fibri-nolysis. To tease out the relative contributions of theCPB circuit and the assist device itself, Livingston etal. examined similar laboratory values in patients re-ceiving VADs versus those undergoing coronary ar-tery bypass grafting (CABG) with CPB (12). Al-though the study had small numbers and somemethodological flaws, they reported some interest-ing findings. Compared with controls, left ventricularassist device (LVAD) patients had a significant in-crease in TAT and prothrombin fragment 1 + 2 (PF1 + 2) 2 h after surgery. Furthermore, significantly

greater levels of PAP and D-dimers were observedin those receiving LVADs, whereas platelet activa-tion was similar between groups. Taken together,these data indicate that the causes of early postop-erative bleeding are multiple and include preexistinghepatic dysfunction, platelet dysfunction, preexistinganticoagulation therapy, anemia, and a shift in thecoagulation/fibrinolysis balance toward excessive fi-brinolysis.

Spanier et al. assessed late activation of coagula-tion and fibrinolytic pathways at random times inpatients with HeartMate (HeartMate LVAD, Tho-ratec Corporation, Inc., Woburn, MA, U.S.A.)LVADs, comparing them with patients with NewYork Heart Association (NYHA) class IV CHF, andnormal volunteers (13). In the patients with LVADs,the duration of treatment was 5 to 335 days at thetime of sampling. There were no differences betweengroups with respect to platelet count, prothrombinand partial thromboplastin times, and levels ofplasma fibrinogen. However, compared with boththe control and CHF group, the LVAD group hadsignificant increases in TAT complexes and PF 1 + 2,indicating procoagulant activity. Furthermore, com-pared with the control group and the CHF group,patients with LVADs had significantly higher D-dimers (p < 0.0001) and fibrin degradation products(FDPs) (p < 0.0001), indicating fibrinolytic activity.These differences were irrespective of the type ofLVAD or treatment with aspirin. These data indi-cate that despite normal-appearing laboratory valuesof hemostasis, patients with LVADs have ongoingbalanced procoagulant and fibrinolytic activity. Be-cause these opposing biochemical cascades are usu-ally finely balanced to maintain the fluidity of bloodelements, additional perturbations could tip the bal-ance toward hemorrhage or thrombosis.

In a subsequent study, Spainier et al. sought todetermine whether these hemostatic abnormalitiesresulted from cells adsorbed onto the surface of theLVAD or from circulating cells (14). Two interestingfindings were reported. First, they observed that cir-culating monocytes from patients with LVADs hadhigher baseline tissue factor (TF) expression thanboth unstimulated and lipopolysaccharide (LPS)-stimulated control monocytes. Furthermore, LPSstimulation of circulating monocytes from VAD re-cipients dramatically potentiated TF expression be-yond the elevated baseline expression. Second, theyfound that cells adsorbed onto the surface of theLVAD have 40% more baseline TF expression thancontrol cells. In effect, they are in a continuous pro-coagulant state. These data have important implica-tions. They indicate that circulating monocytes in

SYSTEMIC CONSEQUENCES OF ASSIST DEVICES 903

Artif Organs, Vol. 26, No. 11, 2002

LVAD patients are in a perpetual procoagulant statewhich is potentiated by proinflammatory stimuli(e.g., LPS). Moreover, cells adsorbed onto the sur-face of the LVAD, primari ly monocytes /macrophages and pluripotent hematopoietic cells,perpetuate the systemic procoagulant and proin-flammatory activity observed in VAD recipients andmay underlie the propensity for late thromboem-bolic events in VAD recipients.

These data characterize the systemic abnormali-ties of coagulation and fibrinolysis that occur afterplacement of assist devices. Clearly, there is a bio-chemical basis for the tendency for early postopera-tive bleeding followed by late thromboembolism.Moreover, the data imply that even with the newer,textured surface assist devices, there are consider-able interactions between the host and assist devicethroughout the duration of implantation. Increasedunderstanding of the causes and effects of these he-mostatic abnormalities is imperative to help guideclinical management of these patients, particularlywith respect to pharmacological strategies to mini-mize hemorrhage and thromboembolism.

IMMUNOMODULATORY EFFECTS OFASSIST DEVICES

In addition to bleeding and thromboembolism, re-cipients of VADs are prone to both nosocomial anddevice-related infections (15). In a review of 2000VAD patients, clinically important infections oc-curred in 28% of VAD recipients (16). Althoughdevice-related bacterial infections are the most com-mon type of infection resulting, at least in part, to thedrive-line exit site, nosocomial infections are alsoprevalent, resulting from myriad factors (2). In thisregard, although the most common pathogens arebacterial, up to 28% of patients have a significantfungal infection after VAD implantation (15,17). Asa result of this high incidence of infections withpathogens that typically do not threaten immuno-competent hosts, the immunological effects of VADshave been examined and reviewed in detail (18).

In an elegant study, Ankersmit et al. examined therate of candidal infection in 78 patients with NYHAclass IV CHF who received an LVAD (n � 40) orthose managed medically (17). By 3 months afterVAD implantation, the risk of disseminated candidalinfection was 28% in those with VADs and only 3%in controls. To assess in vivo T cell function, dermalinjection of common antigens was performed. Al-though 100% of controls responded appropriately todermal mumps antigen, 86% (6 of 7) of VAD recipi-ents were anergic, indicating abnormal in vivo T-cell

function. T-cells from VAD patients showed defec-tive proliferation after activation through the T-cellreceptor (TCR) but proliferated comparably to con-trols when stimulated by non-TCR pathways. Fur-thermore, T-cells from VAD patients had highercell-surface CD95 (Fas) expression (p < 0.001) and ahigher rate of spontaneous apoptosis (p < 0.001)than controls. Moreover, T-cells from VAD patientswere significantly more susceptible to activation-induced cell death. Separately, Itescu et al. haveshown that this increased susceptibility to activation-induced cell death may lead to selective loss of T-cells producing Th-1 cytokines (e.g., IL-2 and inter-feron-gamma) and unopposed T-cell production ofTh-2 cytokines (e.g., IL-10 and transforming growthfactor-beta), further worsening the defect in immunefunction (18). These data establish that multiple,progressive defects in cell-mediated immunity occurafter VAD placement which likely underlie the ob-served increased susceptibility to systemic infections(17).

Recent studies have expanded our understandingof the immunomodulatory effects of VADs (19,20).To assess the effects of VAD placement on B- andT-cell–associated immune response, Rothenburgeret al. studied laboratory end points in 55 patientswith heart failure who underwent LVAD placementand compared them with preoperative values (19).They observed a significant decrease of lymphocytes,CD3, CD4, CD8, natural killer cells, and CD4/CD45RO by the first postoperative day which wassustained during the first postoperative month. Co-incidentally, there was an increased production ofIL-6 and marked activation of B-cells during the first30 postoperative days. After this time, most immu-nological parameters returned to baseline whereasT-cells and their subsets remained decreased duringthe entire observation period. Furthermore, the ratioof CD4/CD8 T-cells significantly decreased after 30days of VAD implantation (19). The same investi-gative group focused their attention on B-cells andIL-6 in a similar study (20). Compared with patientsundergoing CPB alone (without VAD placement),patients receiving VADs had a steady increase inB-cells up to postoperative day 32 after which theydeclined to preimplant level. This was paralleled bychanges in IL-6, the so-called B-cell stimulatory fac-tor. IgG significantly increased after VAD place-ment and remained elevated throughout the obser-vation period, whereas IgA transiently increased,and IgM did not change postoperatively (20). Thesechanges were irrespective of the type of VAD in-serted.

The immunomodulatory effects of VAD place-

C.R. HAMPTON AND E.D. VERRIER904


ment have been recently reviewed and are beyondthe scope of this report (18). However, the previ-ously mentioned data establish that VAD recipientslikely are in a chronically immunocompromisedstate, evidenced by the high incidence of systemicinfections with atypical pathogens. In contrast to co-agulation abnormalities, which may be diminishedby newer textured-surface assist devices, the changesin immune system function seem to be irrespectiveof the type of VAD placed. This immunocompro-mised state can be characterized as a state of B-cellhyperreactivity with increased production of immu-noglobulins, coincidental T-cell dysfunction, a de-crease in the ratio of Th-1/Th-2–type cytokines, anda decrease in the ratio of CD4/CD8 T-cells. Theseimmune system defects predispose VAD recipientsto infectious complications and warrant further in-vestigation to determine therapeutic strategies toreduce infectious complications after VAD place-ment. Furthermore, the impact of B-cell hyperre-activity and increased production of immunoglobu-lins on subsequent allograft survival (i.e., graftrejection caused by alloreactivity) after transplanta-tion warrants further investigation and therapeuticattention.

VADs AND SYSTEMIC INFLAMMATION

The systemic inflammatory response associatedwith CHF and CPB has been well described (21,22).In VAD patients, systemic levels of the proinflam-matory cytokines IL-6 and IL-8 have predicted out-come before allograft transplantation, underscoringthe paradigm that inflammatory cytokines may af-fect the disease course (23). As a result, there hasbeen interest in explaining the effects of VAD place-ment on systemic inflammation.

Goldstein et al. assessed systemic levels of the pro-inflammatory cytokines tumor necrosis factor-alpha(TNF-�), IL-6, and IL-8 in 14 patients undergoingLVAD placement and compared them with normalcontrols (24). In contrast to normal controls who hadimmeasurable levels of these proinflammatory cyto-kines, in those receiving VADs IL-6 was elevated in79% of patients, IL-8 was increased in 71% of pa-tients, and TNF-� in 14% of patients. After VADplacement and hemodynamic recovery, IL-6 de-creased from 33.6 ± 9 pg/mL to 11.3 ± 4 pg/mL (p �0.05), IL-8 decreased from 122 ± 34 pg/mL to 19.7 ±8 pg/mL (p � 0.005), whereas TNF-� did notchange. The reductions in proinflammatory cyto-kines were temporally associated with improvedend-organ function although a causative link was notestablished. These data indicate that inflammatory

cytokines both contribute to and result from the end-organ damage associated with states of decreasedsystemic perfusion.

Recent findings by Torre-Amione et al. corrobo-rate the idea that proinflammatory cytokines con-tribute to myocardial dysfunction and that this effectis diminished with VAD placement (25). The au-thors evaluated myocardial tissue TNF-� content in8 patients receiving LVAD support for end-stagecardiac failure. Myocardial tissue samples were ob-tained at the time of VAD placement, reflectingTNF-� levels in failing myocardium, and at thetime of VAD removal (4 of 8, 50%) or allografttransplantation (4 of 8, 50%). Three salient obser-vations were made. First, TNF-� content was sig-nificantly increased in failing myocardium com-pared with controls. Second, in a semiquantitativeanalysis, VAD support significantly decreased myo-cardial TNF-� content by 10–95%. Third, in thosewho recovered myocardial function and wereweaned from VAD support, there was a significantlygreater reduction in TNF-� content comparedwith those who ultimately required allograft trans-plantation. In a similar study, Birks et al. demon-strated elevated serum and myocardial levels ofIL-6 and TNF-� in those patients receiving VADscompared with those undergoing cardiac trans-plantation (26). They observed a 9.78-fold increaseof myocardial IL-1� mRNA expression in the VADgroup, whereas the serum levels were not dif-ferent between groups. These novel findings indi-cate that myocardial TNF-� content negatively cor-relates with myocardial recovery and supports theparadigm that proinflammatory cytokines, particu-larly TNF-�, may induce cardiac injury and dysfunc-tion (25).

In addition to proinflammatory cytokines, cardiacsurgery causes profound activation of the comple-ment cascade, including generation of the anaphylo-toxins C5a and C3a. Corry et al. recently assessedthe effect of VAD placement on systemic levels ofC3a (27). In 8 patients receiving VADs as a bridge totransplantation, systemic levels of C3a were deter-mined at various time points up to 6 weeks postop-eratively. These data were compared with age-matched controls and literature-derived values forthose undergoing routine cardiac surgery with CPB.C3a levels were significantly elevated before LVADplacement compared with age-matched controls.Postoperatively, there was a transient rise in C3alevels similar to those undergoing routine cardiacsurgery and a rapid return to baseline values within24 h. C3a levels continued to decline over the obser-vation period, significantly falling to below pre-



LVAD levels and approximating age-matched con-trols.

Taken together, these data indicate that proin-flammatory cytokines and complement are elevatedpreoperatively in those patients requiring VAD sup-port, either as a bridge to recovery or transplanta-tion. Circulatory support with VADs is associatedwith favorable changes in systemic levels of thesemediators which correlate with improved end-organfunction. Furthermore, mechanical unloading of theheart with VADs reduces myocardial TNF-� contentwhich may be positively prognostic for myocardialrecovery and weaning of VAD support. Additionalresearch is needed to exactly define the causal rolethat inflammatory cytokines and activated comple-ment may play in the end-organ dysfunction associ-ated with cardiac failure and myocardial recoveryafter VAD placement. Increased understanding ofthe link between the hemodynamic and end-organconsequences of cardiac failure and the underlyingmolecular biology may lead to focused, novel thera-peutic strategies (e.g., anti TNF-� pharmacologicalstrategies) to blunt or interrupt the elaboration ofdetrimental cytokine cascades.

VADs ANDNEUROENDOCRINE ACTIVATION

Cardiogenic shock is defined by hypoperfusion ofsystemic capillary beds. In this setting, the body’scompensatory mechanisms activate the neuroendo-crine axis, including elaboration of catecholamines,activation of the renin-angiotensin system, and in-creased levels of arginine vasopressin (AVP) andatrial natriuretic peptide (ANP). Because VADsnormalize systemic hemodynamics leading to myo-cardial recovery in some recipients, the effect ofVADs on the neuroendocrine axis have been stud-ied.

James et al. assessed neuroendocrine activation in13 patients receiving VADs as a bridge to transplan-tation (28). Plasma ANP, epinephrine (Epi), norepi-nephrine (NE), plasma renin activity (PRA), angio-tensin II (Ang II), and AVP were determined atbaseline (pre-LVAD) and just before VAD removalor transplantation. There was a significant reductionin all measured neurohormone levels, includingPRA, Ang II, Epi, NE, and AVP. These reductionswere associated with significantly improved hemo-dynamics over the observation period. In a subse-quent, similar study, James et al. demonstrated thatthese neurohormonal changes preceded a reductionin plasma volume after VAD placement, consistentwith the known effects of these mediators (29).

These data strongly indicate that VAD placementinduces favorable changes of the neuroendocrineaxis toward normalization which is associated withimproved systemic hemodynamics.

Delgado et al. studied the effect of VAD place-ment on plasma norepinephrine (PNE) levels in theearly postoperative period in 5 consecutive patientsreceiving VAD support (30). Pre-VAD placementPNE levels were elevated above normal controls. By3 weeks postoperatively, PNE levels were signifi-cantly decreased and approached normal by 5 weeks.Although these data are confounded by the high in-cidence of inotropic support perioperatively, theysuggest that PNE is significantly reduced after VADplacement.

These data have recently been extended byNoirhomme et al., who examined activation of theneuroendocrine axis in those receiving VAD supportfor end-stage heart failure (31). In addition to thepreviously mentioned hormones, after VAD place-ment T3, cortisol, and testosterone returned towardnormal by 90 days postoperatively.

In summary, cardiac failure is associated withmyriad abnormalities in the neuroendocrine axis.Although teleologically advantageous toward pre-serving perfusion to the body’s capillary beds, theseadaptive responses can also be detrimental in thesetting of cardiac failure. VAD placement, whichmechanically unloads the myocardium and restoreshemodynamics, reverses the neuroendocrine ab-normalities toward normal. In this regard, VADslikely assist with improved end-organ function, in-cluding the myocardium, by halting the progressionof this detrimental cycle. Indeed, in end-stage heartfailure patients who require VAD support, normal-ization of the neuroendocrine axis subsequent toVAD placement may contribute to comparable post-transplant outcomes compared with those patientsnot requiring VAD support before transplantation(32).

CONCLUSIONS

The indications for use of mechanical support ofthe failing heart are expanding, and long-term me-chanical support as destination therapy will be in-creasingly realized in the near future. As technologi-cal advances continue to expand the indications, theimportance of understanding the interactions be-tween the patient and device increases. Clearly, me-chanical assist devices induce biochemical alter-ations of the coagulation cascade, immunologicalsystem, systemic inflammation, and the neuroendo-crine axis. Although some of these changes may be



beneficial for patients, others are detrimental. Ac-cordingly, additional work is needed to fully explainthe biochemical perturbations underlying these clini-cal phenomena, most importantly, the causes andeffects of these perturbations. Although device-related improvements (e.g., textured surface VADs)have likely decreased the incidence of postoperativethromboembolic complications, the incidence ofearly postoperative hemorrhage and infectious com-plications has remained unchanged, and they con-tinue to be clinically significant problems. Noveltherapeutic strategies will emerge as meaningful bio-chemical targets are identified through enhanced un-derstanding of the changes in these systemic cas-cades consequent to placement of mechanical assistdevices.

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