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Left Ventricular Assist Devices as Bridge to Heart Transplantation in Congestive Heart Failure with Pulmonary Hypertension

Haddad, Haissam*; Elabbassi, Wael*; Moustafa, Sherif*; Davies, Ross*; Mesana, Thierry; Hendry, Paul; Masters, Roy; Mussivand, Tofy

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doi: 10.1097/01.mat.0000169125.21268.d7
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Abstract

Left heart failure or congestive heart failure (CHF) is a common cause of secondary pulmonary hypertension (PH). This is growing in importance as the prevalence of CHF continues to rise in the Western world.1 Despite major advances in the medical therapy for CHF, morbidity and mortality remain very substantial. The 5-year survival rate is estimated to be around 50%. The placebo groups of several recent CHF trials have had an annual mortality around 10%.2 For patients with end-stage heart disease, heart transplantation remains a viable option. However, severe PH is a contraindication to heart transplantation because of the unacceptably high risk of donor right heart failure and recipient mortality after transplantation.3,4

Pulmonary Hypertension in Patients with Congestive Heart Failure

In 1998, the World Health Organization5 diagnosed primary PH as a systolic pulmonary artery pressure (PAP) of at least 40 mm Hg. Echocardiographically, a tricuspid regurgitant velocity of 3.0–3.5 m/s was required to make the same diagnosis. In patients with CHF, the same definition is generally accepted; however, it is recognized that the morbidity and mortality risk imparted is a continuous risk that increases with further elevations in PAP.

Pulmonary hypertension is a diverse disease that is a result of the activation of many simultaneous pathophysiologic processes in patients who may or may not have a genetic predisposition, thereby causing pulmonary vascular damage and elevated pulmonary pressure.5 The etiology of PH in CHF patients relates to diastolic left ventricular dysfunction and to mitral regurgitation. Enriquez-Sarano et al.6 were among the first to note that mitral deceleration time (a measure of diastolic function) and the degree of mitral regurgitation, estimated echocardiographically as the effective regurgitant orifice, were both independently correlated with systolic PAP. The pathophysiological origin of PH is multifactorial. Left atrial (LA) hypertension translates into increased postcapillary pressure in the pulmonary circulation. This enhances pulmonary endothelial dysfunction. At the level of endothelial cells, there is decreased availability of nitric oxide and prostacyclin, while there is increased production of thromboxane A2 and endothelin-1. There is also enhanced activity of serine elastase in the subendothelium, which promotes glycoprotein deposition and smooth muscle cell hypertrophy and hyperplasia. Intermittent hypoxia further stimulates vasoconstriction in the lung vasculature. Added to this are enhanced coagulation profile and heightened platelet aggregation.7

It is quite clear that the histopathologic response of the pulmonary microcirculation to diverse etiologic and pathogenetic factors is almost uniform. In fact, primary PH, the associated forms of precapillary PH, and the secondary forms caused by congenital left to right shunts, share the same pathologic picture defined as pulmonary plexogenic arteriopathy. An array of pathologic lesions have been described in this subset ranging from moderate to severe: (1) isolated medial hypertrophy; (2) medial hypertrophy and intimal proliferative changes (concentric and/or eccentric) of any degree leading to progressive luminal obstruction; and, (3) plexiform lesions and necrotizing arteritis, which are considered to be the more severe expression of this form of pulmonary arteriopathy. Thrombosis in situ, typically involving the small arteries or veins, can coexist with any of the previous findings. Additionally, an increased thickness of the adventitia is often present in the small arteries and arterioles. Pulmonary hypertension, together with elevated pulmonary vascular resistance (PVR), is a protective mechanism: the lung capillary bed is protected from passive congestion and hence acute pulmonary edema.8

Although it is hard to predict the prevalence of PH in the CHF population, it is known that its incidence correlates with the severity of the heart failure. Abramson et al.4 noted that 26% of an outpatient cohort they followed up for dilated cardiomyopathy had a systolic PAP of 40 mm Hg or more. In another cohort of 320 patients, up to 36% of the patients had moderate to severe elevation in PVR (PVR ≥ 2.5 Wood units).9

Assessment of Pulmonary Hypertension in Candidates for Cardiac Surgery or Heart Transplantation

Rabinovitch et al.7 used combined or “hybrid” technique to assess the reversibility of PH in children with congenital cardiac defects and PH to determine who could benefit from corrective surgery. They measured pulmonary hemodynamic parameters via right heart catheterization and obtained a lung biopsy specimen to define the extent of pulmonary vascular changes. In their report, the histological grade of PH correlated positively with mean pulmonary artery pressure (MPAP) 1 day after corrective surgery and with PVR, 1 year after surgical correction. The presence of specific histological lesions predicted the persistence of PH after surgery.

In patients with PH being assessed for heart transplantation, the first step is to evaluate its reversibility to vasoreactive challenges such as oxygen, nitric oxide, nitroprusside, or milrinone.10–14 In addition to the systolic PAP, PVR and transpulmonary gradient (defined as MPAP – LA pressure or, less preferably, MPAP – Left ventricular end diastolic pressure or postcapillary wedge pressure) are two parameters that can be used in the assessment of the degree of PH.15,16 A decline of 20% or more in any of these parameters is considered as reversible PH such that patients are suitable candidates for orthotropic heart transplantation (OHT).11,15 Most transplant centers will not offer OHT to a patient with PVR that remains elevated above 4 Wood units, or with a transpulmonary gradient above 15 mm Hg despite vasodilator challenge.

Heart Transplant Options in Patients with Pulmonary Hypertension

Donor availability is currently a major factor limiting the use of heart transplantation as a treatment for severe heart failure. Heterotopic heart transplantation (HHT) addresses this issue by allowing the use of smaller donor organs and donor organs with prolonged ischemic time. In select cases, this mode of transplantation is also used for recipients with fixed PH.17,18 In such a case, the donor heart acts as a biological assist device to the native left ventricle (LV) or to both ventricles. The earliest experience came from Groote Schuur Hospital,19 where 11 out of 132 cases received HHT; 5 out of the 11 patients had fixed severe PH (mean PVR = 4.9 Wood units). A repeat right heart catheterization, 2 months to 2 years after the operation, showed that the mean PVR dropped from 4.9 to 2.4 Wood units (Table 1). Bleasdale et al.18 compared the survival of 42 consecutive cases that underwent HHT to 303 that underwent OHT. Their mean PVR was 3.3 Wood units. In their regression analysis, size mismatch was a major independent risk factor for decreased 1-year survival. However, PVR was significantly higher in those who underwent HHT, reflecting the fact that increased PVR was an indication for using the heterotopic technique; it did not affect mortality in this group, suggesting that heterotopic transplantation can be used in patients with increased PVR provided a size-matched graft is used (Table 1).

Table 1
Table 1:
Heart Transplant Options in Patients with Pulmonary Hypertension

More evidence comes from the “domino” heart transplant program used at Harefield Hospital.20 Patients with significant lung disease (mostly cystic fibrosis and primary PH), who are candidates for combined heart-lung transplantation, are evaluated as possible donors of their conditioned hearts to be transplanted preferentially to recipients with elevated pulmonary pressures. The mean recipient PVR was 3.1 (standard deviation, 2.2) Wood units, with 25% of patients having PVR ≥ 4 Wood units. Anyanwu et al.20 report on 131 cases of domino heart transplantations. The survival rate was lower during the first year but then equalized to that reported by the International Society for Heart & Lung Transplantation for regular orthotopic transplantation. In the subgroup of patients with pretransplant PVR > 4 Wood units, the mortality was not significantly different Table 1.

Kawaguchi et al.21 reported on transplanting hearts from oversized donors to recipients with PH (mean donor size 109% vs. 79% mean recipient size). In the orthotopically transplanted hearts (n = 38), the mean PVR declined from 4.8 to 1.5 Wood units within 30 days. Ten other recipients with PH received a heterotopically transplanted heart. Their PVR decreased from a mean of 6.5 Wood units to 1.6 Wood units within 30 days as well. Of the whole cohort, 13 patients underwent pretransplant vasoreactivity testing and only six patients had reversible PH (Table 1).

The Role of Left Ventricular Assist Devices in Patients with Pulmonary Hypertension due to Congestive Heart Failure

The left ventricular assist device (LVAD) works as a replacement for the LV. It receives its preload from the native ventricle in systole (only if it is in the synchronous mode; however, most of the LVADs are run in asynchronous mode to optimize filling and output), and pumps it back to the systemic circulation in diastole. This aids in improving coronary blood flow in the process. Unloading the LV alleviates LA hypertension and decreases postcapillary wedge pressure, and therefore induces a decline in the PAP. As the patient’s cardiac output improves, there is less hypoxia at the tissue level, and this also reduces an important stimulant of pulmonary vasoconstriction.22

There have been sporadic reports in the surgical literature concerning the use of the LVAD as a treatment strategy for heart transplant candidates who have moderate to severe PH. These patients then went on to receive successful OHT. Baldovinos et al.23 reported to have orthotopically transplanted seven patients with significant PH (mean PVR of 4.8 which decreased to 3.7 Wood units with nitroprusside challenging). One-year after transplant, five patients were still alive and had decreased pulmonary resistance (mean PVR 1.25 Wood units) (Table 2).

Table 2
Table 2:
Role of Left Ventricular Assist Devices in Patients with Pulmonary Hypertension due to Congestive Heart Failure

In the earliest published experience with LVAD, Gallagher et al.22 implanted Novacor LVAD devices in 16 patients who had a mean PVR of 3.8 Wood units. These patients went on to have OHT. In all patients, PVR decreased to within normal levels within 1 week of the transplantation (PVR 3.8 to 1.5 Wood units). Four of these patients had very high PVR to start with (7.2 Wood units), and these patients also responded favorably to the intervention by LVAD (Table 2).

Smedira et al.24 retrospectively reviewed 63 patients supported with TCI HeartMate, including 47 patients with mean PAP > 30 mm Hg and/or PVR > 4 Woods units. The results suggested that PH is not associated with an increased need for right ventricular support or reduced survival after LVAD implantation (Table 2). Adamson et al.25 published a case report on the use of LVAD in a patient with a PVR of 6.6 Wood units that was unresponsive to vasoreactive challenge. Within 10 weeks, the PVR dropped to 2.8 Wood units. Twelve weeks after he received the LVAD, the patient was able to successfully receive an OHT. The patient was alive with mild residual PH 24 months after transplantation (Table 2). Nguyen et al.26 reported on three patients with end-stage ischemic cardiomyopathy who had severe PH which was unresponsive to prostaglandins, nitroprusside, milrinone and dobutamine all of whom were successfully transplanted following LVAD implantation. This study concluded LVAD support improved pulmonary venous congestion leading to significant reduction in PH (Table 2). Petrovski et al.27 published a case report of a patient with congenital heart disease and PH (PVR = 12.2 Woods) who was unresponsive to vasoreactive challenge. The patient then received a Thoratec BiVAD, and his PVR decreased to 3.1 Wood units within 24 hours. After 79 days, he was able to receive an OHT (Table 2). Alkhaldi et al.28 reported on the use of an LVAD (Novacor) in a 95-kg patient with end-stage ischemic cardiomyopathy and severe PH (PAP = 90/46 mm Hg with mean of 60 mm Hg, PVR 7.1 Wood units unresponsive to oxygen, milrinone, sodium nitroprusside, and nitric oxide challenges). Pulmonary pressure was reported to have dropped to 40/20 mm Hg (mean, 27 mm Hg) by the end of the LVAD implantation procedure with a subsequent reduction in PVR to 1.2 Wood units and successful OHT 11 months after LVAD implantation (Table 2).

The only preliminary prospective trial comes from Albert-Ludwigs-University Medical Center in Germany29 where six patients with severe fixed PH (PVR of 5.7 Wood units that could not be brought to ≤ 2.5 Wood units with oxygen inhalation, nitrates, or alprostadil infusion; MPAP was 64 mm Hg) received a TCI HeartMate (four patients), Novacor (one patient), or Jarvik 2000 (one patient). After a mean of 191 days, mean PVR dropped to 2.0 Wood units with subsequent drop of the MPAP to 21, and all patients received an OHT. Five patients are reported alive after a mean of 16.2 months after transplantation (Table 2).

Complications of the Left Ventricular Assist Devices

Although the technology and clinical results continue to improve, the surgical implantation of LVADs in patients with chronic heart failure is associated with well-recognized early and late complications. LVAD-associated complications can be broadly divided by their temporal occurrence. Early complications include perioperative hemorrhage, air embolism, and right ventricular failure. Beyond the perioperative period, late complications consist primarily of infection, thromboembolism, and primary device failure. An improved understanding of the mechanisms involved should aid the clinician in further reducing the incidence of these occurrences. Future design modifications along with a better understanding by clinicians of the mechanisms involved should serve to maintain the incidence of these occurrences at an acceptably low rate.30

Left Ventricular Assist Device Implantation: Are They Cost–Effective?

Implantation of LVADs is associated with longer length of stay and higher cost for initial hospitalization compared with heart transplantation. LVAD patients have higher readmission rates compared with heart transplantation but similar costs and length of stay. Heart transplantation is associated with a greater number of outpatient services. Reimbursements for LVAD therapy are relatively low, resulting in significant lost revenue. If LVAD therapy is to become a viable alternative for large numbers of patients in the future, improvements in cost–effectiveness and reimbursement will be necessary.31 The costs of LVAD therapy will change after the first year of implantation, and device reliability and longevity will be important factors in determining these costs. Should the costs of LVAD therapy continue to track those of cardiac transplantation, devices will be cost–effective only if they offer similar efficacy to cardiac transplantation.32

Left Ventricular Assist Device Implantation: A Bridge to Transplantation or Destination Therapy

Oz et al.33 showed that their medium-term experience with implantable LVAD support is encouraging. Although additional areas of investigation exist, improvements in patient selection and management together with device alterations that have reduced the thromboembolic incidence and facilitated patient rehabilitation led them to believe that a prospective, randomized trial is indicated to study the role that LVADs may have as an alternative to medical management.33

The REMATCH Study Group34 established the LVAD as a new long-term myocardial replacement therapy, joining cardiac transplantation in the treatment options for end-stage heart failure. Although transplantation has never been compared with medical therapy in a randomized trial, the 1-year survival rate of more than 80% and the 10-year survival rate of nearly 50% for transplantation far exceeded the survival rate for LVAD in their study. However, the outcomes of transplantation do not include the substantial mortality rates among patients who are awaiting transplantation. The combination of the availability of LVAD and the encouraging 1-year survival rate of 74% in their patients who were younger than 60 years suggests that a comparison of the long-term use of these devices and transplantation may soon be appropriate. Many new devices that may be equivalent or superior to the device used are now in early clinical trials. Such devices include a fully implantable pulsatile and a smaller, nonpulsatile LVAD and a fully implantable artificial heart. They believe that their findings establish new standards for survival, quality of life, and adverse events.34

Conclusions

There is an accumulating body of evidence that there are some patients previously thought to have irreversible PH can improve following heart transplantation and in particular can successfully be bridged to heart transplantation using a LVAD. Further work needs to be performed to better define who may benefit from this therapy. This will also help refine the indications and improve our experience with the use of LVADs as bridge to heart transplantation in CHF with PH. The use of a LVAD in patients with advanced heart failure resulted in a clinically meaningful survival benefit and an improved quality of life. LVAD is an acceptable alternative therapy in selected patients who are not candidates for cardiac transplantation.

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