The Management of Stage D Heart Failure

MOUNT SINAI JOURNAL OF MEDICINE 76:404–414, 2009 404

SPECIAL FEATURE

Management of Stage D Heart FailureMark Harrison, MD, Anelechi Anyanwu, MD, and Sean P. Pinney, MD

Mount Sinai School of Medicine, New York, NY

Chronic heart failure is a major public health issue.1 Itaffects more than 5.2 million Americans and accountsfor more than 1 million hospitalizations annually.Heart failure is a deadly condition. After being diag-nosed with heart failure, 1 in 5 patients will die within1 year. Eighty percent of men and 70% of women lessthan 65 years of age who have heart failure will diewithin 8 years. Caring for patients with heart failure isexpensive. In 2008, the annual estimated cost of car-ing for patients with heart failure was over 34 billiondollars.

In 2001, the American College of Cardiologyand the American Heart Association reclassified thestages of heart failure, emphasizing that heart failureis a spectrum that encompasses patients with riskfactors for the development of heart failure (stage A),those with structural heart disease who have neverhad symptoms of heart failure (stage B), those withsymptomatic heart failure (stage C), and those withend-stage heart failure (stage D). The stages of heartfailure progress linearly (Figure 1). For example, asurvivor of a myocardial infarction who is initiallyfree of heart failure symptoms is best classified asbeing in stage B. That individual will remain in thatstage until heart failure symptoms develop, therebyadvancing to stage C. Even if symptoms fully resolve,that individual will be identified as being stage C untilheart failure progresses to its advanced and terminalstage, stage D.

The focus of this review is to highlight themanagement of patients with stage D heart failure.

Address Correspondence to:

Sean P. PinneyAdvanced Heart Failure andCardiac Transplant ProgramMount Sinai Medical Center

New York, NYEmail: [email protected]

Although the number of patients with asymptomaticheart failure (stages A and B) is about 4 times greaterthan the number of patients with symptomatic heartfailure (stages C and D), the mortality rate for stage Dheart failure patients is significantly higher, exceedingthat of most cancers.2 By the best estimates, there arecurrently about 250,000 patients with stage D heartfailure, and their numbers are growing. Nonetheless,there is reason to be optimistic as the potential toimprove the quality and extend the life expectancyof these individuals is greater now than at any othertime in the past.

PROGNOSIS

Stage D heart failure is end-stage heart failure. Ingeneral, patients with a life expectancy of less than6 to 12 months are best classified as belonging tostage D. Although one would desire to know whena heart failure patient transitions from stage C toD, the current level of diagnostic accuracy is lack-ing. Instead, heart failure cardiologists must rely ona combination of risk prediction models and clini-cal acumen. Two of the best prediction models arethe Heart Failure Survival Score3 and the SeattleHeart Failure Model.4 The latter has the advan-tage of being offered as a web-based application(www.seattleheartfailure.com) and is derived solelyfrom noninvasive clinical data. The Heart Failure Sur-vival Score incorporates cardiopulmonary exercisetesting and is the only model that has proven repro-ducibility over time.5 Some of the strongest predictorsof poor survival include low serum sodium, an ele-vated resting heart rate, systemic hypotension, aninability to increase or a need to decrease the dose ofan angiotensin-converting enzyme (ACE) inhibitor orbeta-blocker, and a peak oxygen consumption of lessthan 12 mL/kg/minute.3,4 Recurrent hospital admis-sion for the treatment of decompensated heart failureis not incorporated in these models but identifies

Published online in Wiley InterScience (www.interscience.wiley.com).DOI:10.1002/msj.20124

2009 Mount Sinai School of Medicine

MOUNT SINAI JOURNAL OF MEDICINE 405

Fig 1. Stages of heart failure. Abbreviations: ACE, angiotensin-converting enzyme; FHx CM, family history ofcardiomyopathy; HF, heart failure; IV, intravenous; LV, left ventricular; MI, myocardial infarction. Reprinted withpermission from Evaluation and Management of Chronic Heart Failure in the Adult ACC/AHA Pocket Guideline.26

Copyright 2002, American College of Cardiology/American Heart Association. [Color figure can be viewed in the onlineissue, which is available at www.interscience.wiley.com.].

a group of heart failure patients at greatest risk forrecurrent admission and death.6

TREATMENT

The treatment options for stage D heart failurepatients are limited (Figure 2). They include acontinuous infusion of a positive inotrope, cardiactransplantation, implantation of a ventricular assistdevice (VAD) for destination therapy (DT), andpalliative care. Cardiac transplantation and DTare able to extend and improve quality of lifebut are limited by a lack of access, and theyconsume a great deal of healthcare resources.7

By comparison, continuous outpatient support withinotropes (COSI) and hospice care offer comfort andrelief from dyspnea but do not extend survival and, insome cases, may shorten life expectancy.8 Decidingbetween these 4 options requires an open dialoguebetween the heart failure cardiologist and patient so

that the patient understands what can be achieved,recognizing that for many, particularly those withadvanced age or significant comorbidities the bestroute may be to choose improving quality of life.

Continuous Inotropic SupportPositive inotropic drugs, such as dobutamine and mil-rinone, have long been used to treat acute decompen-sated heart failure. The routine outpatient infusion ofthese medications is frowned upon because of theassociation with truncated survival. In stage D heartfailure, these drugs are frequently employed to aug-ment cardiac output, and occasionally patients aredischarged home on a continuous infusion, usuallywhile awaiting transplantation. Continuous outpatientsupport can offer palliation for those patients not eli-gible for cardiac transplantation or DT. This approachalleviates the symptoms of fatigue and dyspnea thataccompany end-stage heart failure, but COSI doesnot prolong survival.8 More than half of patients on

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406 M. HARRISON ET AL.: SPECIAL FEATURE–MANAGEMENT OF STAGE D HEART FAILURE

Fig 2. Therapies for the advancing stages of heart failure. Abbreviations: ACE, angiotensin-converting enzyme;ARB, angiotensin II receptor blocker; VAD, ventricular assist device. Adapted from the New England Journal ofMedicine.27 [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

Fig 3. Probability of survival for advanced heart failurepatients dependent on a continuous infusion of a positiveinotrope. Adapted from the Journal of Cardiac Failure.8

COSI will die within the first 3 months, and only 5%to 10% will survive for 1 year (Figure 3). Althoughthere remains a frequent need for hospitalization,many patients will be able to live at home until theend, maintaining some sense of independence.

Cardiac TransplantationCardiac transplantation remains the best choicefor long-term survival for patients with stage D

heart failure. The first cardiac transplant was axenotransplant performed by James Hardy in 1964when he implanted a chimpanzee heart into a younggirl (Figure 4). The honor of performing the firsthuman allograft transplant belongs to Dr. ChristiaanBarnard. In December 1967, he operated on a 53-year-old man in Cape Town, South Africa. The firsttransplant on American soil as well as the firstpediatric transplant was performed days later byDr. Adrian Kantrowitz in Brooklyn, NY. Dr. NormanShumway, one of the most revered cardiac transplantsurgeons because of his monumental contributionsto the field, performed the fourth transplant inJanuary 1968. His tireless research throughout muchof the 1970s allowed the field to persevere whenmany were calling for a moratorium on cardiactransplantation. Many viewed the procedure asmacabre, organs being harvested from brain-deaddonors and implanted in recipients who often livedfor merely weeks and frequently never left thehospital. Heart transplantation remained a medicalcuriosity until the introduction of cyclosporine inthe 1980s. With this advance in immunosuppression,survival rates dramatically improved, and the numberof heart transplants grew exponentially (Figure 5).Heart transplantation soon became the standardof care for advanced heart failure, offering 1-yearsurvival rates in excess of 80%.

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Fig 4. History of cardiac transplantation. Abbreviation: txp, transplant.

Fig 5. Number of heart transplants reported by year and location. Adaptedfrom the International Society for Heart and Lung Transplantation.28

The outcomes for heart transplant recipientscontinue to improve. One-year survival in the currentera is between 85% and 90%, and median survivalis nearly 10 years.9 Long-term survivors are now theexpectation rather than the exception. Those patientswho survive the first year, with its attendant risk fromsurgery, maximal immune suppression, and greatestrisk of rejection, can expect a median survival of13 years. Heart transplantation also improves qualityof life. Ninety percent of recipients will have nolimitation in their daily activities, and only 5% will

need some form of assistance. Total disability is rare(Figure 6).

Once again, there is a call from some in theheart failure community to perform a randomizedclinical trial of heart transplantation.10 The basis forthis call comes from the fact that survival is improv-ing for chronic heart failure patients. The adventof neurohormonal antagonists, implantable cardiacdefibrillators, and resynchronization devices (cardiacresynchronization therapy) has improved the sur-vival of patients, including those currently waiting for

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Fig 6. Functional status of surviving heart transplant recipients. Adaptedfrom the International Society for Heart and Lung Transplantation.28

transplantation.11 Ambulatory patients listed for trans-plant but not requiring a positive inotrope infusion(status 2) now have a 1-year survival of nearly 90%.This appears to match or, in some cases, exceedexpected posttransplantation survival. Although thiscomes from censored data, it appears that patientswhose heart failure is not advanced to the point ofrequiring positive inotrope infusions may have littleto gain by early transplantation. Because donationrates have not increased over the past 15 years, itis reasonable to delay listing for transplantation untilsuch time as positive inotropes are required. In fact,a review of the listing status over the past 20 yearshighlights a trend away from listing status 2 patientsand reserving listing for those with more advancedsymptoms and shorter life expectancy.11

Referral to a transplant center should be con-sidered before patients are dependent on positiveinotropes. This allows time for an adequate eval-uation to determine if transplantation is necessaryand provides patients with enough opportunity tomake an informed decision. Although no strict refer-ral criteria exist, there are several indicators thatshould prompt evaluation (Table 1). Most of thesehave been mentioned previously as predictors ofpoor heart failure survival. In addition to low serumsodium, intolerance of neurohormonal antagonists,and frequent heart failure hospitalization, one shouldconsider evaluation for patients with New York HeartAssociation (NYHA) functional class III symptoms, ablood urea nitrogen level greater than 40 mg/dL,a diuretic requirement greater than 1.5 mg/kg/dayfurosemide or its equivalent, or a B-type natriureticpeptide or N-terminal pro–B-type natriuretic pep-tide level greater than 5 times the upper limit ofnormal. Once referred, heart failure patients consult

Table 1. Referral for Cardiac Transplantation.

NYHA III (unable to walk 2 blocks)One or more heart failure hospitalizations in 6 monthsIntolerant of ACE-I/ARB/beta blockersSerum sodium <136 mmol/LBUN >40 (excluding dehydration)BNP or NT-proBNP >5 times normalDiuretic requirement ≥ 1.5 mg/kg/day furosemide or

equivalent

Abbreviations: ACE-I, angiotensin-converting enzymeinhibitor; ARB, angiotensin II receptor blocker; BNP, B-typenatriuretic peptide; BUN, blood urea nitrogen; NT-proBNP,N-terminal pro–B-type natriuretic peptide; NYHA, NewYork Heart Association.

with a cardiologist to ensure that reversible factorshave been corrected, medical therapy has been max-imized, and no significant comorbidities have beenidentified. A list of the exclusion criteria for our centeris listed in Table 2.

The amount of time that one spends waiting foran acceptable donor is determined by listing status,body size, and blood type. In the United States, anew organ allocation protocol has been designedto distribute organs preferentially to patients witha higher listing status. Patients listed as status 1Ahave an expected life expectancy of 1 week. This isdefined as the need for intensive care unit admissionwith the use of a pulmonary artery (Swan-Ganz)catheter to guide therapy. Status 1A patients must bereceiving an infusion of a single, high-dose positiveinotrope or a combination of 2 inotropes. Othercriteria include the need for an intra-aortic bloodpump, a VAD for less than 30 days, or mechanicalventilation. Status 1B patients are defined by theneed for a continuous infusion of positive inotropes

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Table 2. Exclusion Criteria for Cardiac Transplantation.

Age >70Pulmonary hypertension: PVR >6 wood unitsChronic renal disease with CLcr <40 or serum

creatinine >2.5 mg/dLActive smoking, drug, or alcohol dependencyDiabetes with end-organ disease (retinopathy,

nephropathy, and vasculopathy)Severe obstructive/restrictive lung diseaseChronic liver diseasePulmonary infarction within past 6 weeksMajor chronic disabling diseaseSevere peripheral arterial or cerebrovascular diseaseObesity with BMI >35Active or recent malignancy (within 5 years)Psychological or social barriers that would preclude

one’s ability to reliably comply with medical therapyand follow-up examinations

Abbreviations: BMI, body mass index; CLcr, creatinineclearance; PVR, pulmonary vascular resistance.

or the presence of a VAD for more than 30 days.Status 2 patients are those listed for transplant butnot requiring any of the above. The institution of thisnew allocation protocol has succeeded in distributingmore organs to status 1A and 1B patients by sendingdonor hearts out of a given organ allocation region.The net result has been an appropriate redistributionto the neediest patients and a reduction in waiting listmortality. It has also created a situation in which onemust be sicker in order to undergo transplantation.This is particularly true for patients with blood typesassociated with longer wait times, such as O andA, and those with a larger body habitus. As timespent on the waiting list increases, more patients arereceiving a VAD to bridge the time from listing toidentification of a suitable donor.

VENTRICULAR ASSIST DEVICES:BRIDGE TO TRANSPLANTATION

There are now 3 generations of VADs (Figures 7–9).First-generation VADs are pulsatile, positive-displacement pumps. They are by definition bulkyas they must contain 60 to 80 mL of stroke volumeto be displaced per ejection. All but one of the cur-rent Food and Drug Administration (FDA)–approveddevices fall into this category. Examples of these first-generation pumps are the Heartmate XVE, the Tho-ratec paracorporeal VAD, the Thoratec implantableVAD, and the Novocar left ventricular assist sys-tem. Second-generation or axial-flow pumps generatea continuous flow through the use of a rotaryimpeller suspended in the blood stream by con-tact bearings. By comparison, these pumps are

Fig 7. The Heartmate XVE left ventricular assist device isa first-generation, pulsatile ventricular assist device with atextured titanium surface, which allows for the formationof a pseudointima that is resistant to thrombus formation.[Color figure can be viewed in the online issue, which isavailable at www.interscience.wiley.com.].

Fig 8. The Heartmate II is a second-generation, axial-flowdevice. It is smaller in size and quieter than first-generationpumps and is the only continuous-flow ventricular assistdevice currently approved for bridge to transplantation.[Color figure can be viewed in the online issue, which isavailable at www.interscience.wiley.com.].

miniature, being about one-fifth of the size of thefirst-generation pumps. Only one, the Heartmate II,is FDA-approved for bridging to transplant. Otherinvestigational second-generation devices include theJarvik 2000 and Micromed Debakey pumps. Third-generation VADs also create continuous flow but

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Fig 9. The Ventrassist is a third-generation ventricular assist device under clinicalinvestigation for bridge to transplantation and destination therapy. It has a singleimpeller, which is hydrodynamically elevated and spins inside an electromagnetic field.

do so by the use of a single rotary impeller that iseither magnetically or hydrodynamically suspended.By eliminating the need for contact bearings, thesedevices could, in theory, last forever and may beless prone to thrombus formation. Examples of theseinvestigational devices include the Ventrassist, Heart-ware, and Duraheart pumps.

Many centers are turning away from the use offirst-generation VADs, preferring instead to implantcontinuous-flow pumps. Despite their proven successin bridging patients to transplant,12 the durabilityof these pulsatile VADs is limited by bearing wearand valvular insufficiency. Half of all Heartmate XVEpumps will experience a major device malfunctionwithin 18 months of implantation.13 Pulsatile VADsare further disadvantaged by their bulky size andneed for greater surgical dissection, which cancomplicate postoperative recovery. The need toventilate the air that is displaced with each strokerequires a larger driveline that can be difficult tosecure and is prone to infection. Moreover, patientsfrequently complain that these pumps are loud. Onthe other hand, the Heartmate XVE is the only VADthat does not require systemic anticoagulation. Itstextured titanium surface allows for the formationof a pseudointima that is resistant to thrombosis.Unfortunately, this surface is also biologically activeand can stimulate the production of alloantibodies,which in turn increase the risk of rejection followingtransplantation. Their presence effectively reducesthe eligible donor pool and prolongs waiting times.

Continuous-flow VADs are quickly becoming thepumps of choice for bridge to transplantation. Theyare small, quiet, and durable. They have drivelinesabout the size of a telephone cord that are easy to

secure and rarely become infected. The Heartmate IIis the first FDA-approved continuous-flow VAD. Inthe pivotal bridge-to-transplant trial, 80% of recipientseither were alive on support or had received atransplant at 6 months of follow-up.14 Similar resultswere recently reported for the VentraCor Ventrassist,a third-generation device (Figure 10). Despite theiradvantages over pulsatile pumps, these devices dopose some challenges. All continuous-flow VADsrequire systemic anticoagulation to prevent thrombusformation. Hemolysis is occasionally produced by thehelical blades, which typically spin at 10,000 rpm forthe Heartmate II and 2100 rpm for the Ventrassist.Higher spin rates produce greater rates of hemolysis,which in turn increase the chance of thrombusformation, particularly at the site of contact bearingswhere radial velocity is minimal. These VADsprovide continuous, nonpulsatile flow. Althoughorgan function does not seem to be negativelyaffected by the lack of pulsatility, continuous flowdoes make it difficult for clinicians to monitor patientsbecause they may not be able to palpate a pulse orauscultate a blood pressure.

The small size and durability of these pumpsare already producing remarkable results. Surgeonsat Mount Sinai Medical Center reported the firstimplantation of a Jarvik 2000 through a median ster-notomy without the use of cardiopulmonary bypass15

(Figure 11). The recipient of this device was removedfrom mechanical ventilation in less than 24 hoursand sat up out of bed by the first postopera-tive day. Early reports such as these have beenreinforced by observed shorter recovery times, areduction in hospital length of stay, and improvedsurvival. Patients occasionally feel so well with

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Fig 10. The competing outcomes of the pilot bridge-to-transplant trial of theVentrassist device demonstrate excellent survival, with 86% of recipientshaving received a transplant or being alive on support 6 months afterimplantation.

Fig 11. First reported implantation of a Jarvik 2000 left ventricular assist device througha median sternotomy without the use of cardiopulmonary bypass (see Anyanwu et al.15

for details).

these second-generation and third-generation devicesthat they forego transplantation entirely. One well-documented patient, supported by a Jarvik 2000,survived more than 7 years, ultimately dying fromnoncardiac causes.16 A postmortem inspection of hisdevice showed minimal to no bearing wear, suggest-ing that, in the absence of damage to the drivelineor battery failure, this pump could reliably run fordecades.

The timing of device implantation greatlyinfluences clinical outcomes. Implantation of a VADin the setting of chronic heart failure should ideallybe a planned, semi-elective procedure. Emergencyor bailout VAD implantation should be infrequentand reserved for acute onset cardiogenic shock.Early referral to specialized VAD centers is criticalto obtaining successful outcomes.

The timing of VAD implantation is now guidedby a stage D heart failure patient’s INTERMACS (Inter-agency Registry for Mechanically Assisted Circulatory

Support) level (Table 3). The first registry report fromINTERMACS, a multi-institutional database of out-comes for patients receiving FDA-approved VADs,has shown that postimplantation survival is adverselyimpacted by operations on patients with moreadvanced hemodynamic instability.17 For instance,if one were to wait for patients to develop critical

Table 3. INTERMACS Level.

1. Critical cardiogenic shock: ‘‘crash and burn’’2. Progressive decline: ‘‘sliding fast’’3. Stable but inotrope-dependent: ‘‘inotrope-dependent’’4. Recurrent advanced heart failure: ‘‘frequent flyer’’5. Exertion-intolerant: ‘‘housebound’’6. Exertion-limited: ‘‘walking wounded’’7. Advanced NYHA III

Abbreviations: INTERMACS, Interagency Registry forMechanically Assisted Circulatory Support; NYHA, NewYork Heart Association.

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cardiogenic shock before implanting a VAD, nearly 1of 3 recipients would die by the third postoperativemonth. The same is true for nearly 1 of 5 patientswho are ‘‘sliding fast’’ at the time of implantation. Onthe other hand, patients who are less acutely sick aremore likely to survive by undergoing surgery beforethe advent of multiorgan failure accompanying car-diogenic shock. This is not to say that these patientsare not sick. We know from clinical trials that the1-year mortality rate for patients with NYHA IV heartfailure is at least 75%.18,19 Although the actual timingof surgery remains a fluid decision, in general it issafe to conclude that earlier is better than later.

VENTRICULAR ASSIST DEVICES:DESTINATION THERAPY

Despite transplantation’s clinical success, not allpatients with stage D heart failure are eligible forthis therapy. Even if they were, the rates of organdonation have not increased over the past 15 years.As a result, transplantation is clinically meaningfulfor the lucky few who receive a new heart butis epidemiologically trivial. Best estimates are that250,000 patients have advanced heart failure, butonly 1% will receive a transplant. VADs can helpbridge this gap between supply and demand.

DT with a VAD can extend and improve qualityof life for stage D heart failure patients. The landmarkREMATCH (Randomized Evaluation of MechanicalAssistance for the Treatment of Congestive HeartFailure) trial randomized transplant-ineligible patientseither to receive the Heartmate XVE or to continuewith optimal medical therapy.18 One-year survivalwith a VAD was nearly double that with optimalmedical therapy. In addition, surveys of NYHAfunctional class and overall sense of well beingimproved with device therapy in comparison withpatients in the medical therapy group. AlthoughREMATCH is best viewed as proof of principle for DT,critics have pointed out that 1-year survival was only50% for VAD recipients and that 3 of 4 patients haddied by 2 years. Since REMATCH was published, apromising sign has emerged that familiarity with thedevice and improved management protocols haveimproved clinical outcomes.20 Two-year survival nowapproaches 50% and has been accompanied byreductions in clinical adverse events and hospitallength of stay. These improvements should lead toimproved outcomes for VAD recipients and reducedcosts for healthcare payers.7

Before becoming the treatment of choice forthe majority of patients with advanced heart failure,

VAD therapy must further improve. Providers mustknow that they are choosing the right pump for theright patient at the right time. With their reducedsize and improved durability, continuous-flow VADsare likely to become the pumps of choice for DT.Conclusive clinical trial results are as yet unknown,but the early termination of the Heartmate II DTtrial at a prespecified interim analysis suggests thatthis continuous-flow VAD may indeed be superior tothe Heartmate XVE. Trials of the Ventrassist pumpremain ongoing but hold similar promise. The use ofa preoperative risk score can now stratify potentialrecipients into low, medium, high, and very high riskcategories for post-VAD mortality.21 Application ofthis multivariable score allows clinicians to reserveDT for those patients with an expected 1-year survivalof at least 75%. For higher risk patients, an initialperiod of stabilization and improved nutrition priorto surgery may allow for eligibility at a later date asguided by this score.

VENTRICULAR ASSIST DEVICES: THEPROMISE OF RECOVERY

Until very recently, the process of left ventricularremodeling was believed to progress inexorablytoward a globular, dysfunctional heart prone tomechanical and electrical failure. Medical therapywith an ACE inhibitor or beta-blocker could tem-porarily delay the remodeling process but could notreverse it. We now recognize that the volume andpressure unloading afforded by VADs can reversesome of the detrimental changes in the remodeledleft ventricle. One month after VAD implantation,there is a beneficial reduction in left ventricularend-diastolic diameter and mass.22 Hypertrophiedmyocytes regress back toward a normal pheno-type, and cardiac mechanics improve, particularlyin those patients additionally treated with an ACEinhibitor.23,24 Although the net result of these changesis favorable, in most instances, they are insufficientto produce enough recovery of function to allowdevice removal and obviate transplantation. A recentreport from Harefield, England has engendered hopethat recovery may be attainable in more patients thanoriginally thought possible.25 In combination withan intensive medical regimen including the beta-2agonist clenbuterol, 11 of 15 patients enrolled intheir recovery protocol were able to safely undergodevice removal. All enjoyed a dramatic improvementin their quality of life and freedom from heart fail-ure symptoms. For recovery to become a reality forthe majority of heart failure patients, we must better

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understand myocyte biology and the signals involvedin myocardial remodeling so as to be able to reverse-engineer the myocyte, allowing it to sustain functionin the absence of mechanical support.

VENTRICULAR ASSIST DEVICES:FUTURE APPLICATIONS

Although VADs may allow for reverse remodeling ofthe left ventricle, they may also be able to provide astable platform to re-engineer the heart. Much excite-ment has been engendered by the promise of usingstem cells to regenerate myocardium, in essenceregrowing the heart. In the future, patients may firstreceive a VAD to deliver a sufficient cardiac output topreserve end-organ function, which will be followedby an infusion of stem cells. A similar strategy maybe employed by the combination of device therapyand gene therapy. A multicenter trial is currentlyunderway to determine whether an adenovirus cansuccessfully deliver to failing myocytes a gene encod-ing for sarco(endo)plasmic reticulum Ca2+ ATPase(SERCA), a protein pump involved in the handlingof intracellular calcium. In failing hearts, SERCA isdown-regulated and leads to impaired myocyte con-tractility. Although CUPID (Calcium Upregulation byPercutaneous Administration of Gene Therapy in Car-diac Disease) is not enrolling VAD patients, if it issuccessful, its results may further the promise ofrecovery for VAD recipients.

Perhaps the most exciting prospect for VADsis their becoming standard of care for patients withadvanced heart failure. In order for this to occur,our concept of mechanical support needs to evolve.Our language and thinking are currently constrainedby terms such as destination and bridge that payersemploy. There is enough crossover between theselabels to render them pointless. Some patients whoreceive a destination VAD improve to the point thatthey are eligible for transplantation, their device thusbecoming a bridging VAD. Others who receive abridging device develop complications that precludetransplant, so the VAD becomes DT. The labelsdistract us from the more important measurementof total patient outcomes. Consider too that patientswith chronic kidney disease are evaluated for renalreplacement when their disease has advanced tostage 4 or 5. These candidates are not offered dialysisas a bridge to transplantation, nor does one refer tohemodialysis as DT for those who are ineligible fortransplant. This logic should be applied to advancedheart failure. Advanced heart failure itself–notpostoperative expectations of transplantation–shouldbe the indication needed for receiving a device.

CONCLUSION

The past few years have borne witness to theevolution of a new generation of VADs that haveimproved and extended the lives of patients withstage D heart failure. Although outcomes with cardiactransplantation continue to improve, the low rates oforgan donation will continue to limit this therapy to afortunate few. Bridging the gap between supply anddemand will be VADs, which are poised to becomethe standard of care for patients with stage D heartfailure. In order for that to occur, we as cliniciansmust first understand the long-term biology of VADsupport as we try to unlock the mechanisms that leadto myocardial recovery. By March 2009, Medicarepatients will be required to seek treatment at medicalcenters that have Joint Commission accreditation forVADs, a designation given to programs that havethe multidisciplinary teams and experience neededto ensure the best perioperative results. As ourexperience and understanding of VADs grow, morepatients with advanced heart failure will enjoy thebenefits of these restorative devices.

DISCLOSURES

Potential conflict of interest: Nothing to report.

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DOI:10.1002/MSJ

The Management of Stage D Heart Failure

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