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Making the Call: Pulmonary Hypertension in Cardiac Transplant Candidates


Brian A. Houston
Bahoust@gmail.com

Ryan J. Tedford
Ryan.Tedford@jhmi.edu
Johns Hopkins University
Baltimore, MD, USA



I hang up the phone and sigh. I've just gotten the call that every transplant cardiologist dreads. "We're coming out with an RVAD," our surgeon told me, sounding as weary as expected given the operative implications of that statement. The patient who had smiled so broadly today after I told her that a donor heart was available now is now suffering from acute RV failure after orthotopic heart transplant (OHT) and faces a much more difficult road to complete recovery. Even in the current era, acute right ventricular failure accounts for a significant proportion of the morbidity and mortality after OHT. While many factors play a role in the development of acute RV failure (donor organ selection and preservation, ischemic time, donor-recipient size matching), the most prominent is the pre-existence of pulmonary hypertension (PH) in the recipient.

In the early 1950s, Dr. Arthur Guyton informed our understanding of right ventricular afterload sensitivity by varying pulmonary artery constriction in dogs, demonstrating rapid right ventricular failure and systemic circulatory collapse with relatively small acute elevations in RV afterload [1]. These findings were taken together with several early post-transplant deaths due to acute right heart failure in the 1960s to arrive at the notion that the donor right heart is unable to acutely compensate for an acute increase in its afterload when transplanted into a recipient with PH. In 1971, Drs. Shumway and Griepp reported on 26 patients who had undergone OHT at Stanford, finding that the subset of patients with significant PH were at high risk of dying early from acute RV failure [2]. This finding was confirmed and the relative risk of PH in OHT recipients refined in multiple successive cohorts. These studies inform the current ISHLT guidelines which list a PVR >5 Wood units, PVRI >6, or transpulmonary gradient (TPG) >15mmHg as relative contraindications to heart transplantation [3]. Interestingly, pre-transplant diastolic pulmonary gradient (DPG), a recently proposed marker for pre-capillary PH, did not predict post-transplant outcome in large analysis of the UNOS database [4]. Importantly, there is no value of PVR or TPG which predicts freedom from post-OHT RV failure - there is incremental risk with any degree of elevation in RV load.

For patients with left heart failure (the most common indication for OHT), PH develops for three broad pathophysiologic reasons that are believed to develop in temporal succession. First, elevations in left atrial and pulmonary venous pressure can cause passive congestion of the pulmonary vasculature and elevated pulmonary arterial pressures. Furthermore, as pulmonary venous pressure rises, the pulmonary vasculature become less compliant ("more stiff") leading to an increase in pulsatile load for any given resistance and causing further elevations in systolic and mean pulmonary arterial pressures. Pulmonary edema itself may also elevate PVR. This passive, or post-capillary, PH is often remedied by diuretics, or the administration of inotropes or vasodilators which unload the left heart and subsequently the pulmonary vasculature. However, the pulmonary vasculature undergoes more substantive physiologic and pathologic changes with prolonged exposure to elevated pressure. Early in the course, pulmonary vasoconstriction occurs due to a reduction in nitric oxide levels and increases in endothelin-1. Later though, pulmonary vascular smooth muscle hypertrophy and changes in vascular wall thickness arise. Often in the setting of a patient with PH being considered for OHT, pharmacologic challenges are performed in an attempt to differentiate those with reactive or "reversible" PH (thought due to pulmonary vasoconstriction/ congestion) from those with "irreversible" PH. Various agents have been studied and are employed for these challenges (sodium nitroprusside, milrinone, and prostaglandin E1 being the most common) with little consensus on which is most effective in reducing pulmonary pressures or (more importantly) provides the best prediction of post-transplant outcomes. However, even patients with fully reversible PH (defined by the ISHLT as achieving a PVR <2.5 while maintaining a systemic systolic blood pressure >85mmHg) still may have a poorer post-transplant prognosis than those without PH [5].

Mechanical circulatory support has expanded the treatment algorithm in OHT candidates with PH, and has challenged the concept of "irreversible" PH. For patients with PH that do not respond to aggressive medical care and/or vasodilator challenges, multiple studies have found that pulmonary pressures and PVR decline with the prolonged effective unloading provided by left ventricular assist devices [6]. In a select cohort of 60 patients, we found that all measures of RV load improve over the first 6 months of LVAD support, and continue to improve over the ensuing 2 years. However, a subset of LVAD-supported patients continue to have elevated pulmonary pressures precluding OHT. In these patients, we have found that the use of sildenafil is associated with meaningful and more rapid reduction in PVR and pulmonary artery pressures [7]. The upcoming SOPRANO trial will investigate the role of macitentan, an endothelin receptor antagonist, in LVAD-supported patients with persistent PH [8].

For patients with pre-existing PH and post-OHT RV dysfunction, aggressive inotropic and potentially temporary mechanical support of the RV is required. With the reduction in pulmonary venous pressures provided by a functional left ventricle and reversal of the ischemic and preservation injury over time, the RV load may improve and RV dysfunction resolve. Multiple centers have reported on the use of oral sildenafil, systemic prostaglandins, or inhaled prostacyclins in this setting with varying success [9].

In conclusion, the assessment of PH in the heart transplant candidates is as crucial as it is nuanced. The failure to appreciate the importance of pulmonary vascular load or to appropriately delineate the underlying pathophysiology of PH in these patients may set patients up for RV failure and death early post-transplant. Conversely, an appropriate diagnostic evaluation and therapeutic approach to PH may allow the successful provision of the life-saving gift of cardiac transplantation in these patients. To avoid getting the dreaded transplant RV failure call after transplant, transplant cardiologist and surgeons have to be sure to make the right call before transplant for patients with PH. ■

Disclosure Statement: The authors have no conflicts of interest to disclose.


References:

  1. Guyton AC, Lindsey AW, Gilluly JJ. The limits of right ventricular compensation following acute increase in pulmonary circulatory resistance. Circ Res. 1954 Jul;2(4):326-32.
  2. Griepp RB, Stinson EB, Dong E Jr, Clark DA, Shumway NE. Determinants of operative risk in human heart transplantation. Am J Surg. 1971 Aug;122(2):192-7.
  3. Mehra MR, Kobashigawa J, Starling R, Russell S, Uber PA, Parameshwar J, Mohacsi P, Augustine S, Aaronson K, Barr M. Listing criteria for heart transplantation: International Society for Heart and Lung Transplantation guidelines for the care of cardiac transplant candidates--2006. J Heart Lung Transplant. 2006 Sep;25(9):1024-42.
  4. Tedford RJ, Beaty CA, Mathai SC, Kolb TM, Damico R, Hassoun PM, Leary PJ, Kass DA, Shah AS. Prognostic value of the pre-transplant diastolic pulmonary artery pressure-to-pulmonary capillary wedge pressure gradient in cardiac transplant recipients with pulmonary hypertension. J Heart Lung Transplant. 2014 Mar;33(3):289-97.
  5. Butler J, Stankewicz MA, Wu J, et al. Pretransplant reversible pulmonary hypertension predicts higher risk for mortality after cardiac transplantation. J Heart Lung Transplant 2005;24:170-7.
  6. Mikus E, Stepanenko A, Krabatsch T, Loforte A, Dandel M, Lehmkuhl HB, Hetzer R, Potapov EV. Reversibility of fixed pulmonary hypertension in left ventricular assist device support recipients. Eur J Cardiothorac Surg. 2011 Oct;40(4):971-7.
  7. Tedford RJ, Hemnes AR, Russell SD, Wittstein IS, Mahmud M, Zaiman AL, Mathai SC, Thiemann DR, Hassoun PM, Girgis RE, Orens JB, Shah AS, Yuh D, Conte JV, Champion HC. PDE5A inhibitor treatment of persistent pulmonary hypertension after mechanical circulatory support. Circ Heart Fail. 2008 Nov;1(4):213-9.
  8. Clinicaltrials.gov: https://clinicaltrials.gov/ct2/show/NCT02554903
  9. Natale ME1, PiƱa IL. Evaluation of pulmonary hypertension in heart transplant candidates. Curr Opin Cardiol. 2003 Mar;18(2):136-40.



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