Peter Chiu

Heart and Combined Heart–Kidney Transplantation in Patients With Concomitant Renal Insufficiency and End‐Stage Heart Failure

In patients with end‐stage heart failure (ESHF) who are candidates for isolated heart transplant (HRT), dialysis dependence (DD) is considered an indication for combined heart–kidney transplantation (HKT). HKT remains controversial in ESHF transplant candidates with nondialysis‐dependent renal insufficiency (NDDRI). Using United Network for Organ Sharing data, we examined the cumulative incidences of transplant and mortality in patients with DD and NDDRI waitlisted for HKT or HRT. In all groups, 3‐month waitlist mortality was dismal: 31% and 21% for HRT‐ and HKT‐listed patients with DD and 12% and 7% for HRT‐ and HKT‐listed patients with NDDRI. Five‐year posttransplant survival was improved in HKT recipients compared with HRT recipients for both patients with DD (73% vs. 51%, p < 0.001) and NDDRI (80% vs. 69%, p < 0.001). Likewise, multivariable analysis associated HKT with better outcomes than HRT in HKT‐listed patients, although both improved survival. These data argue strongly for HKT in ESHF transplant candidates with DD. However, in patients with NDDRI, HKT must be weighed against the possibility of renal recovery with isolated HRT. Whether HRT (followed by a staged kidney transplant in patients who do not recover renal function after HRT), as opposed to HKT, maximizes organ benefit for patients with NDDRI and ESHF requires assessment. Nevertheless, given their dismal waitlist outcomes and excellent posttransplant results, we suggest that patients with DD and NDDRI with ESHF be considered for early listing and transplant.

Mechanical or Biologic Prostheses for Aortic-Valve and Mitral-Valve Replacement

BACKGROUND In patients undergoing aortic‐valve or mitral‐valve replacement, either a mechanical or biologic prosthesis is used. Biologic prostheses have been increasingly favored despite limited evidence supporting this practice. METHODS We compared long‐term mortality and rates of reoperation, stroke, and bleeding between inverse‐probability‐weighted cohorts of patients who underwent primary aortic‐valve replacement or mitral‐valve replacement with a mechanical or biologic prosthesis in California in the period from 1996 through 2013. Patients were stratified into different age groups on the basis of valve position (aortic vs. mitral valve). RESULTS From 1996 through 2013, the use of biologic prostheses increased substantially for aortic‐valve and mitral‐valve replacement, from 11.5% to 51.6% for aortic‐valve replacement and from 16.8% to 53.7% for mitral‐valve replacement. Among patients who underwent aortic‐valve replacement, receipt of a biologic prosthesis was associated with significantly higher 15‐year mortality than receipt of a mechanical prosthesis among patients 45 to 54 years of age (30.6% vs. 26.4% at 15 years; hazard ratio, 1.23; 95% confidence interval [CI], 1.02 to 1.48; P=0.03) but not among patients 55 to 64 years of age. Among patients who underwent mitral‐valve replacement, receipt of a biologic prosthesis was associated with significantly higher mortality than receipt of a mechanical prosthesis among patients 40 to 49 years of age (44.1% vs. 27.1%; hazard ratio, 1.88; 95% CI, 1.35 to 2.63; P<0.001) and among those 50 to 69 years of age (50.0% vs. 45.3%; hazard ratio, 1.16; 95% CI, 1.04 to 1.30; P=0.01). The incidence of reoperation was significantly higher among recipients of a biologic prosthesis than among recipients of a mechanical prosthesis. Patients who received mechanical valves had a higher cumulative incidence of bleeding and, in some age groups, stroke than did recipients of a biologic prosthesis. CONCLUSIONS The long‐term mortality benefit that was associated with a mechanical prosthesis, as compared with a biologic prosthesis, persisted until 70 years of age among patients undergoing mitral‐valve replacement and until 55 years of age among those undergoing aortic‐valve replacement. (Funded by the National Institutes of Health and the Agency for Healthcare Research and Quality.)

What is high risk? Redefining elevated pulmonary vascular resistance index in pediatric heart transplantation

BACKGROUND Currently, pulmonary vascular resistance index (PVRI) >6 WU × m(2) (indexed units) is generally considered a contraindication to isolated orthotopic heart transplantation (OHT). However, this has been questioned in the literature. METHODS A retrospective review was performed on all patients <18 years old who underwent primary OHT for cardiomyopathy. Data were collected with regard to demographics, pre-operative hemodynamics, need for pre-operative mechanical circulatory support, vasodilator reactivity and 30-day mortality (30dM). A receiver operating characteristic (ROC) curve was used to establish an optimal threshold. Uni- and multivariate logistic regressions were performed to assess the influence of PVRI on 30dM. RESULTS Complete data were available for 158 cardiomyopathy patients <18 years of age, who underwent primary OHT between June 1984 and November 2010. The ROC curve yielded a threshold of 9.290 indexed units. Four of 19 patients (21.1%) with PVRI >9 died in the first 30 days. In patients with PVRI <9, there was only 1 death among 139 patients (0.7%). Odds of mortality increased incrementally with PVRI as a continuous variable, with an odds ratio (OR) of 1.35 per indexed unit (95% confidence interval 1.12 to 1.63). PVRI was dichomotomized (PVRId) using the previously established threshold and revealed an increasing risk of mortality, OR 36.80 (95% confidence interval 3.86 to 350.90), with a PVRI of >9 indexed units. CONCLUSIONS Using a PVRI >6 as a contraindication to isolated OHT may be too restrictive. Patients with PVRI ≤9 do not appear to be at increased risk of early mortality. In patients with PVRI >9, 30-day survival was 78.9% in this study. This represents a viable alternative to heart-lung transplantation.

Evolution of surgical therapy for Stanford acute type A aortic dissection

Acute type A aortic dissection (AcA-AoD) is a surgical emergency associated with very high morbidity and mortality. Unfortunately, the early outcome of emergency surgical repair has not improved substantially over the last 20 years. Many of the same debates occur repeatedly regarding operative extent and optimal conduct of the operation. The question remains: are patients suffering from too large an operation or too small? The pendulum favoring routine aortic valve resuspension, when feasible, has swung towards frequent aortic root replacement. This already aggressive approach is now being challenged with the even more extensive valve-sparing aortic root replacement (V-SARR) in selected patients. Distally, open replacement of most of the transverse arch is best in most patients. The need for late aortic re-intervention has not been shown to be affected by more extensive distal operative procedures, but the contemporary enthusiasm for a distal frozen elephant trunk (FET) only seems to build. It must be remembered that the first and foremost goal of the operation is to have an operative survivor; additional measures to reduce late morbidity are secondary aspirations. With increasing experience, true contraindications to emergency surgical operation have dwindled, but patients with advanced age, multiple comorbidities, and major neurological deficits do not fare well. The endovascular revolution, moreover, has spawned innovative options for modern practice, including ascending stent graft and adaptations of the old flap fenestration technique. Despite the increasingly complex operations and ever expanding therapies, this life-threatening disease remains a stubborn challenge for all cardiovascular surgeons. Development of specialized thoracic aortic teams and regionalization of care for patients with AcA-AoD offers the most promise to improve overall results.

Lung Quality and Utilization in Controlled Donation After Circulatory Determination of Death Within the United States

Although controlled donation after circulatory determination of death (cDCDD) could increase the supply of donor lungs within the United States, the yield of lungs from cDCDD donors remains low compared with donation after neurologic determination of death (DNDD). To explore the reason for low lung yield from cDCDD donors, Scientific Registry of Transplant Recipient data were used to assess the impact of donor lung quality on cDCDD lung utilization by fitting a logistic regression model. The relationship between center volume and cDCDD use was assessed, and the distance between center and donor hospital was calculated by cDCDD status. Recipient survival was compared using a multivariable Cox regression model. Lung utilization was 2.1% for cDCDD donors and 21.4% for DNDD donors. Being a cDCDD donor decreased lung donation (adjusted odds ratio 0.101, 95% confidence interval [CI] 0.085–0.120). A minority of centers have performed cDCDD transplant, with higher volume centers generally performing more cDCDD transplants. There was no difference in center‐to‐donor distance or recipient survival (adjusted hazard ratio 1.03, 95% CI 0.78–1.37) between cDCDD and DNDD transplants. cDCDD lungs are underutilized compared with DNDD lungs after adjusting for lung quality. Increasing transplant center expertise and commitment to cDCDD lung procurement is needed to improve utilization.

Combined Heart–Liver Transplantation in the MELD Era: Do Waitlisted Patients Require Exception Status?

Combined heart–liver transplant (HLT) is a viable therapy for patients with concomitant end‐stage heart and liver failure. Using data from the United Network for Organ Sharing database, we examined the cumulative incidences of transplant and mortality in waitlisted candidates for HLT, isolated heart transplant (HRT) and isolated liver transplant (LIV) in the Model for End‐Stage Liver Disease era. The incidence of waitlist mortality was higher in HLT candidates than in HRT candidates (p = 0.001, 26% vs. 12% at 1 year) or LIV candidates (p = 0.005, 26% vs. 14% at 1 year). These differences persisted after stratifying by disease severity. Posttransplant survival was not significantly different between HLT and HRT recipients or between HLT and LIV recipients. In a multivariable model, undergoing HLT was associated with enhanced survival for HLT candidates (hazard ratio, 0.41; confidence interval, 0.21–0.79; p = 0.008), but undergoing HRT alone was not. Interestingly, 90% of HLT recipients were allocated an organ locally, compared to 60% of HRT candidates and 73% of LIV candidates (both p < 0.001). These data suggest that the current cardiac and liver allocation systems may underestimate the risk of death for patients with concomitant end‐stage heart and liver failure on the HLT waitlist.

Influence of durable mechanical circulatory support and allosensitization on mortality after heart transplantation

BACKGROUND Allosensitization has been shown to negatively affect post-heart transplant (HTx) survival even with a negative crossmatch. Whether allosensitization related to mechanical circulatory support (MCS) is associated with worse post-HTx survival remains controversial. METHODS Adult HTx recipients listed in the United Network for Organ Sharing database (July 2006-December 2012) were identified. Multivariate Cox regression assessed the effect of allosensitization on survival. Propensity matching was performed to compare patients who were and were not allosensitized. Kaplan-Meier survival analysis compared matched and unmatched patients in the MCS and medically managed cohorts. RESULTS We identified 11,840 HTx recipients, of whom 4,167 had MCS. MCS was associated with allosensitization in multivariate logistic regression. Each different MCS device was associated with worse post-HTx survival in multivariate Cox regression. Allosensitization did not predict post-HTx mortality in MCS patients (hazard ratio, 1.07; 95% confidence interval, 0.89-1.28; p = 0.48. Among patients without MCS, allosensitization was associated with post-HTx mortality (hazard ratio, 1.19; 95% confidence interval, 1.03-1.39; p = 0.02). Kaplan-Meier analysis revealed equivalent survival in unmatched and matched cohorts when MCS patients who were allosensitized were compared with non-allosensitized MCS patients. Among non-MCS patients, allosensitization was associated with worse survival in unmatched and matched analysis. CONCLUSIONS MCS was associated with allosensitization. For MCS patients, allosensitization did not independently predict worse post-HTx outcome. Among non-MCS patients, allosensitization was associated with worse post-HTx survival. Allosensitization appears to be a heterogeneous process influenced by presence of MCS.

Elevated pretransplant pulmonary vascular resistance index does not predict mortality after isolated orthotopic heart transplantation in children: A retrospective analysis of the UNOS database

OHT is the definitive therapy in end‐stage heart failure. Elevated PVRI is considered a relative contraindication to isolated OHT; this assumption is re‐evaluated using data from the UNOS database. A retrospective review of de‐identified data from the UNOS dataset was performed. There were 1943 pediatric OHT recipients between 10/87 and 12/11 with sufficient data for analysis. Cox regression was performed to examine the effect of baseline characteristics on post‐transplant survival. Patients were propensity matched, and Kaplan–Meier survival analysis was performed comparing cohorts of patients using thresholds of 6 and 9 WU × m2. PVRI was not a significant predictor of post‐transplant outcomes in either univariate or multivariate Cox regression. Kaplan–Meier analysis revealed no difference in survival between both unmatched and propensity‐matched OHT recipients. In conclusion, elevated PVRI was not associated with post‐transplant mortality in pediatric OHT recipients. A prospective study assessing the current use of PVRI ≥6 as a threshold to contraindicate isolated OHT should be undertaken. Removing this potentially unnecessary restriction on transplant candidacy may make this life‐saving therapy available to a greater number of patients.

Long‐term miR‐29b suppression reduces aneurysm formation in a Marfan mouse model

Aortic root aneurysm formation and subsequent dissection and/or rupture remain the leading cause of death in patients with Marfan syndrome. Our laboratory has reported that miR‐29b participates in aortic root/ascending aorta extracellular matrix remodeling during early aneurysm formation in Fbn1C1039G/+ Marfan mice. Herein, we sought to determine whether miR‐29b suppression can reduce aneurysm formation long‐term. Fbn1C1039G/+ Marfan mice were treated with retro‐orbital LNA‐anti‐miR‐29b inhibitor or scrambled‐control‐miR before aneurysms develop either (1) a single dose prenatally (pregnant Fbn1C1039G/+ mice at 14.5 days post‐coitum) (n = 8–10, each group) or (2) postnatally every other week, from 2 to 22 weeks of age, and sacrificed at 24 weeks (n = 8–10, each group). To determine if miR‐29b blockade was beneficial even after aneurysms develop, a third group of animals were treated every other week, starting at 8 weeks of age, until sacrificed (n = 4–6, each group). miR‐29b inhibition resulted in aneurysm reduction, increased elastogenesis, decreased matrix metalloproteinase activity and decreased elastin breakdown. Prenatal LNA‐anti‐miR‐29b inhibitor treatment decreased aneurysm formation up to age 32 weeks, whereas postnatal treatment was effective up to 16 weeks. miR‐29b blockade did not slow aortic growth once aneurysms already developed. Systemic miR‐29b inhibition significantly reduces aneurysm development long‐term in a Marfan mouse model. Drug administration during aortic wall embryologic development appears fundamental. miR‐29b suppression could be a potential therapeutic target for reducing aneurysm formation in Marfan syndrome patients.

Limited Root Repair in Acute Type A Aortic Dissection is Safe but Results in Increased Risk of Reoperation

Objective Management of the aortic root is a challenge for surgeons treating acute type A aortic dissection. Methods We performed a retrospective review of the acute type A aortic dissection experience at Stanford Hospital between 2005 and 2015 and identified patients who underwent either limited root repair or aortic root replacement. Differences in baseline characteristics were balanced with inverse probability weighting to estimate the average treatment effect on the controls. Weighted logistic regression was used to evaluate in‐hospital mortality. Weighted Cox proportional hazards regression was used to evaluate differences in the hazard for mid‐term death. Reoperation was evaluated with death as a competing risk with the Fine‐Gray subdistribution hazard. Results After we excluded patients managed either nonoperatively or with definitive endovascular repair, there were 293 patients without connective tissue disease who underwent either limited root repair or aortic root replacement. There was no difference in weighted perioperative mortality, odds ratio 0.89 (95% confidence interval [CI], 0.44‐1.76, P = .7), and there was no difference in weighted survival, hazard ratio 1.12 (95% CI, 0.54‐2.31, P = .8). Risk of reoperation was greater in limited root repair (11.8%, 95% CI, 0.0%‐23.8%) than for root replacement (0%), P < .001. Conclusions Limited root repair was associated with increased risk of late reoperation after repair of acute type A aortic dissection. Surgeons with adequate experience may consider aortic root replacement in well‐selected patients. However, given good outcomes after limited root repair, surgeons should not feel compelled to perform this more‐complex operation.