Recipient and surgical factors trigger severe primary graft dysfunction after heart transplant.

BACKGROUND: Primary graft dysfunction (PGD) is a major cause of early mortality following heart transplant (HT). The International Society for Heart and Lung Transplantation (ISHLT) subdivides PGD into 3 grades of increasing severity. Most studies have assessed risk factors for PGD without distinguishing between PGD severity grade. We sought to identify recipient, donor and surgical risk factors specifically associated with mild/moderate or severe PGD. METHODS: We identified 734 heart transplant recipients at our institution transplanted between January 1, 2012 and December 31, 2018. PGD was defined according to modified ISHLT criteria. Recipient, donor and surgical variables were analyzed by multinomial logistic regression with mild/moderate or severe PGD as the response. Variables significant in single variable modeling were subject to multivariable analysis via penalized logistic regression. RESULTS: PGD occurred in 24% of the cohort (n = 178) of whom 6% (n = 44) had severe PGD. One-year survival was reduced in recipients with severe PGD but not in those with mild or moderate PGD. Multivariable analysis identified 3 recipient factors: prior cardiac surgery, recipient treatment with ACEI/ARB/ARNI plus MRA, recipient treatment with amiodarone plus beta-blocker, and 3 surgical factors: longer ischemic time, more red blood cell transfusions, and more platelet transfusions, that were associated with severe PGD. We developed a clinical risk score, ABCE, which provided acceptable discrimination and calibration for severe PGD. CONCLUSIONS: Risk factors for mild/moderate PGD were largely distinct from those for severe PGD, suggesting a differing pathophysiology involving several biological pathways. Further research into mechanisms underlying the development of PGD is urgently needed.

Hypothermia promotes mitochondrial elongation In cardiac cells via inhibition of Drp1.

Hypothermia is a valuable clinical tool in mitigating against the consequences of ischemia in surgery, stroke, cardiac arrest and organ preservation. Protection is afforded principally by a reduction of metabolism, manifesting as reduced rates of oxygen uptake, preservation of ATP levels, and a curtailing of ischemic calcium overload. The effects of non-ischemic hypothermic stress are relatively unknown. We sought to investigate the effects of clinically mild-to-severe hypothermia on mitochondrial morphology, oxygen consumption and protein expression in normoxic hearts and cardiac cells. Normoxic perfusion of rat hearts at 28-32 °C was associated with inhibition of mitochondrial fission, evidenced by a reduced abundance of the active phosphorylated form of the fission receptor Drp1 (pDrp1S616). Abundance of the same residue was reduced in H9c2 cells subjected to hypothermic culture (25-32 °C), in addition to a reduced abundance of the Drp1 receptor MFF. Hypothermia-treated H9c2 cardiomyocytes exhibited elongated mitochondria and depressed rates of mitochondrial-associated oxygen consumption, which persisted upon rewarming. Hypothermia also promoted a reduction in mRNA expression of the capsaicin receptor TRPV1 in H9c2 cells. When normothermic H9c2 cells were transfected with TRPV1 siRNA we observed reduced pDrp1S616 and MFF abundance, elongated mitochondria, and reduced rates of mitochondrial-associated oxygen consumption, mimicking the effects of hypothermic culture. In conclusion hypothermia promoted elongation of cardiac mitochondria via reduced pDrp1S616 abundance which was also associated with suppression of cellular oxygen consumption. Silencing of TRPV1 in H9c2 cardiomyocytes reproduced the morphological and respirometric phenotype of hypothermia. This report demonstrates a novel mechanism of cold-induced inhibition of mitochondrial fission.

Combining Stem Cell Therapy for Advanced Heart Failure and Ventricular Assist Devices: A Review.

The use of stem cell therapy in combination with a left ventricular assist device (LVAD) for patients with advanced heart failure (HF) is an attractive concept with the potential to alter the natural history of HF. Cell therapy trials for HF have demonstrated excellent safety and encouraging results, but current rates of myocardial recovery after LVAD implantation are limited. Early trials combining these 2 therapies to increase the likelihood of recovery and to potentially obviate the need for subsequent transplantation appear promising. Additionally, the application of cell therapy to patients undergoing LVAD implantation as a bridge to cardiac transplantation creates an opportunity to examine cardiac tissue before and after treatment and to study the mechanism of benefit. Despite the promise, there is a paucity of data for the combination of stem cell therapy with LVAD insertion in patients with HF. Of 11 case series or clinical trials, the largest enrolled 30 patients. We highlight clinical trials using stem cell therapy for end-stage HF most relevant to an LVAD patient population and comprehensively review the preclinical and clinical studies of combined stem cell therapy and long-term mechanical circulatory support. Based on the available clinical trials, the combination of stem cell therapy and LVAD support is a promising approach but requires further clinical refinement, with additional clinical data and larger numbers of patients required to support its clinical application.

Left Ventricular Reconstruction for Postinfarction Left Ventricular Aneurysm: Review of Surgical Techniques.

Different surgical techniques, each with its own advantages and disadvantages, have been used to reverse adverse left ventricular remodeling due to postinfarction left ventricular aneurysm. The most appropriate surgical technique depends on the location and size of the aneurysm and the scarred tissue, the patient's preoperative characteristics, and surgeon preference. This review covers the reconstructive surgical techniques for postinfarction left ventricular aneurysm.

Role of Thromboelastography Platelet Mapping and International Normalized Ratio in Defining "Normocoagulability" During Anticoagulation for Mechanical Circulatory Support Devices: A Pilot Retrospective Study.

Thromboembolic (TE) events and hemorrhagic complications continue to remain as frequent adverse events and causes of death after mechanical circulatory support device (MCSD) implantation. To counterbalance this postimplant multifactorial hypercoagulable state, antithrombotic therapy given postimplant must be individually tailored to keep patient adequately anticoagulated yet normocoagulable. Prior studies describing different anticoagulation protocols do not define normocoagulability for patients on MCSDs. We evaluated the role of thromboelastography platelet mapping (TEG PM) in defining "normocoagulability" for MCS patients on anticoagulant (warfarin) and antiplatelet agents. Ninety-eight MCSD patients who underwent TEG PM assay at our institution from 2012 to 2014 were included for retrospective analysis. Eleven (11.2%) subjects developed at least one TE event during the study period. Of the 13 TE events, 8 occurred in patients with total artificial heart (TAH). TEG parameters closest to the event or when patient was clinically adequately anticoagulated and corresponding international normalized ratio (INR) were measured. Thromboelastography coagulation index (CI) appears to be the single most statistically significant parameter that can be used to designate a patient as normocoagulable. Based on our results, patients with HeartMate II (HM II) and Heart Ware (HW) devices should be maintained at a CI value of less than or equal to 1.5 whereas patients with TAH devices should be maintained at a CI less than or equal to 1.2. The CI should be correlated with the degree of Vitamin K-dependent coagulation factor inhibition that is achieved using device-specific goal INR ranges. A recent modification, TEG PM assesses the effects of antiplatelet drug. Maximal amplitude arachidonic acid (MA-AA) < 50 and maximal amplitude adenosine diphosphate (MA-ADP) < 50 are desired for normocoagulable state.

Pathology of Chronic Chagas Cardiomyopathy in the United States: A Detailed Review of 13 Cardiectomy Cases.

OBJECTIVES: The pathologic features of chronic Chagas cardiomyopathy may not be widely appreciated in the United States. We sought to describe the gross, microscopic, immunohistochemical, and molecular pathology features useful to diagnose chronic Chagas cardiomyopathy. METHODS: The features from a case series of cardiectomy specimens of patients undergoing heart transplantation (12 patients) or mechanical circulatory support device implantation (one patient) for chronic Chagas cardiomyopathy at three institutions in the United States are reported and analyzed. RESULTS: Gross findings included enlarged and dilated ventricles (100% of cases), mural thrombi (54%), epicardial plaques (42%), and left ventricular aneurysm (36%). Microscopic evaluation revealed myocarditis (100% of cases) characterized by mononuclear cell infiltration, fibrosis (100%), nonnecrotizing granulomas (62%), and giant cells (38%). Two specimens (15%) showed rare intracellular amastigotes. Immunohistochemical assays for Trypanosoma cruzi organisms were negative in all cardiectomy specimens, whereas tissue polymerase chain reaction was positive in six (54%) of 11 cases. CONCLUSIONS: The gross and microscopic features of chronic Chagas cardiomyopathy in the United States appear similar to those reported in endemic countries. Importantly, tissue polymerase chain reaction may be useful to confirm the diagnosis.

Prevalence of Warfarin Genotype Polymorphisms in Patients with Mechanical Circulatory Support.

Polymorphisms for VKORC1 and CYP2C9 are associated with increased warfarin sensitivity. The prevalence of these polymorphisms in patients with mechanical circulatory support (MCS) is unknown. Polymorphisms for VKORC1 and CYP2C9 were determined in 65 patients undergoing MCS surgery. Postoperative warfarin dose, international normalized ratio (INR), and bleeding events were measured until discharge, 6 months, or composite end point (in-hospital MCS recovery, heart transplant, or death). A total of 67.7% (44/65) had at least one polymorphism: VKORC1 (44.6%), CYP2C9*2 (7.7%), CYP2C9*3 (4.6%), CYP2C9*2 and VKORC1 (3.1%), or CYP2C9*3 and VKORC1 (7.7%). At discharge or before composite end point, patients with any polymorphism received a lower mean warfarin dosage than patients having no polymorphism (3.21 ± 1.47 vs. 5.57 ± 3.72 mg, p = 0.015) and achieved a similar mean INR (2.20 ± 0.67 vs. 2.19 ± 0.69, p = 0.96). There was no significant difference in bleeding rates within 6 months or before composite end point (6.13 vs. 8.02 events/patient-year, p = 0.13). One or more polymorphisms for VKORC1 or CYP2C9 (associated with warfarin sensitivity) were found in 67.7% of MCS patients. By using a warfarin genotype-guided approach, MCS patients with polymorphisms received a lower warfarin dosage to achieve a similar INR, with similar bleeding rates, in comparison with no polymorphisms. A warfarin genotype-guided approach avoided excessive anticoagulation and its attendant bleeding risks.

Human cardiosphere-derived cells from advanced heart failure patients exhibit augmented functional potency in myocardial repair.

OBJECTIVES: This study sought to compare the regenerative potency of cells derived from healthy and diseased human hearts. BACKGROUND: Results from pre-clinical studies and the CADUCEUS (CArdiosphere-Derived aUtologous stem CElls to reverse ventricUlar dySfunction) trial support the notion that cardiosphere-derived cells (CDCs) from normal and recently infarcted hearts are capable of regenerating healthy heart tissue after myocardial infarction (MI). It is unknown whether CDCs derived from advanced heart failure (HF) patients retain the same regenerative potency. METHODS: In a mouse model of acute MI, we compared the regenerative potential and functional benefits of CDCs derived from 3 groups: 1) non-failing (NF) donor: healthy donor hearts post-transplantation; 2) MI: patients who had an MI 9 to 35 days before biopsy; and 3) HF: advanced cardiomyopathy tissue explanted at cardiac transplantation. RESULTS: Cell growth and phenotype were identical in all 3 groups. Injection of HF CDCs led to the greatest therapeutic benefit in mice, with the highest left ventricular ejection fraction, thickest infarct wall, most viable tissue, and least scar 3 weeks after treatment. In vitro assays revealed that HF CDCs secreted higher levels of stromal cell-derived factor (SDF)-1, which may contribute to the cells' augmented resistance to oxidative stress, enhanced angiogenesis, and improved myocyte survival. Histological analysis indicated that HF CDCs engrafted better, recruited more endogenous stem cells, and induced greater angiogenesis and cardiomyocyte cell-cycle re-entry. CDC-secreted SDF-1 levels correlated with decreases in scar mass over time in CADUCEUS patients treated with autologous CDCs. CONCLUSIONS: CDCs from advanced HF patients exhibit augmented potency in ameliorating ventricular dysfunction post-MI, possibly through SDF-1­mediated mechanisms.

Combined heart and kidney transplantation: what is the appropriate surgical sequence?

Combined heart and kidney transplantation is increasing in frequency but there are no guidelines to establish the indications, contraindications and sequence for this surgical procedure. We report our single-centre experience on 30 consecutive patients who underwent combined heart and kidney transplant in comparison with heart transplant alone. Patients had similar preoperative characteristics in both groups. Combined heart and kidney transplant is associated with the same long-term survival rate, low cellular rejection and antibody-mediated rejection rates when compared with heart transplant alone. We did not observe any difference in the outcomes related to preoperative patient characteristics. We suggest the staged surgical approach as the preferred method for transplant.

Intrinsic cardiac origin of human cardiosphere-derived cells.

AIMS: Cardiosphere-derived cells (CDCs) are in clinical development as a regenerative cell product which can be expanded ex vivo from patient cardiac biopsies. Cardiosphere-derived cells are clonogenic, exhibit multilineage differentiation, and exert functional benefits in preclinical models of heart failure. The origin of CDCs remains unclear: are these cells endogenous to the heart, or do they arise from cells that populate the heart via blood-borne seeding? METHODS AND RESULTS: Right ventricular endomyocardial biopsies were obtained from cardiac transplant recipients (n = 10, age 57 ± 15 years), and CDCs expanded from each biopsy. Donor-recipient mismatches were used to probe the origin of CDCs in three complementary ways. First, DNA analysis of short-tandem nucleotide repeats (STRs) was performed on genomic DNA from donor and recipient, then compared with the STR pattern of CDCs. Second, in two cases where the donor was male and the recipient female, CDCs were examined for the presence of X and Y chromosomes by fluorescence in situ hybridization. Finally, in two cases, quantitative PCR (qPCR) was performed for individual-specific polymorphisms of a major histocompatability locus to quantify the contribution of recipient cells to CDCs. In no case was recipient DNA detectable in the CDCs by STR analysis. In the two cases in which a female patient had received a male heart, all CDCs examined had an X and Y chromosome, similarly indicating exclusively donor origin. Likewise, qPCR on CDCs did not detect any recipient DNA. CONCLUSION: Cardiosphere-derived cells are of endogenous cardiac origin, with no detectable contribution from extra-cardiac seeding.

Significant reduction of ATP production in PHA-activated CD4+ cells in 1-day-old blood from transplant patients.

BACKGROUND: Global immunosuppression can be measured by assessing adenosine triphospate (ATP) levels in mitogen-stimulated CD4+ T cells. METHODS: We investigated the effect of storage time on ATP levels in 234 blood samples from 18 healthy individuals and 152 transplant patients. The difference between day 0 (<13 hours post-blood draw) and day 1 (24-37 hours) measurements was analyzed and compared with various factors; a subset of samples was also analyzed in 6-hour intervals. RESULTS: The ATP levels were significantly lower on day 1 compared with that on day 0 in healthy individuals (279±159 vs 414±159 ng/mL, P<0.001) and patients (356±209 vs 455±221 ng/mL, P<0.0001). Of the 18 healthy individuals, 17 showed ATP reduction, whereas 192 (89%) of 216 patients did so on day 1 (24.8±24.1%). In the time course analysis, ATP levels decreased with the blood storage time in healthy and patient samples, and the reduction began as early as 7 hours post-blood draw. The reduction rate was significantly higher in patient samples with low day 0 ATP levels compared with samples with moderate or high levels (44.7±31.3% vs 23.2±23.6% or 18.7±15.7%; P<0.001). The reduction rate in patients treated with alemtuzumab induction was slightly higher than that in daclizumab-treated patients (28.8±24.6% vs 21.3±21.3%, P=0.09). CD4+ cell number did not change within 24 hours post-blood draw, but CD4 expression decreased 2.0±2.8% (P<0.05). CONCLUSIONS: The ATP levels are significantly lower in 1-day-old blood compared with fresh blood, suggesting that fresh blood should be used for assessing the T cell immune function to obtain the most accurate results.

Impact of virtual cross match on waiting times for heart transplantation.

BACKGROUND: Heart transplantation for sensitized patients has been a significant challenge. In this study, outcome of heart transplantation in sensitized patients with virtual cross match was compared with prospective cross match. METHODS: Prior to July 2007, prospective cross match was used and afterward, virtual cross match with Luminex (One Lambda, Inc, Canoga Park, CA) based antibody analysis was used for potential heart transplant recipients. Prospectively collected data for the 3 years before and after July 2007, in sensitized (panel reactive antibody greater than 10%) and nonsensitized heart transplant recipients were reviewed. RESULTS: One hundred sixty-eight patients met inclusion criteria for analysis (78 patients for prospective cross match and 90 patients for virtual cross match). Multiple parameters were compared for the prospective cross match and virtual cross match eras. Three-year survivals in nonsensitized patients were 84.6% and 77.2% and in sensitized patients were 76.9% and 77.4% (p = 0.49) for prospective cross match and virtual cross match eras, respectively. Freedom from 3A (2R) cellular rejection in nonsensitized patients was 96.9% and 95.3%, and in sensitized patients was 90.9% and 100% (p = 0.83). Freedom from antibody-mediated rejection in nonsensitized patients was 95.3% and 96.8%, and in sensitized patients was 90.9% and 90.5% (p = 0.65). Mean waiting time was 129 ± 246 days (mean ± SD) for the period before virtual cross match and 59 ± 78 days with virtual cross match (p = 0.018). Donor geographic area was similar for prospective and virtual cross match. CONCLUSIONS: In sensitized heart transplant candidates, virtual cross match may shorten waiting time to heart transplantation without increasing subsequent occurrence of cellular rejection, antibody mediated rejection, and mortality after heart transplantation.

Is robotic mitral valve repair a reproducible approach?

OBJECTIVE: We sought to review the surgical outcomes of our initial 120 robotic mitral valve repairs from June 2005 through April 2009. METHODS: The initial 74 repairs were performed with the first-generation da Vinci robot (Intuitive Surgical, Inc, Sunny Vale, Calif), and the last 46 were performed with the da Vinci Si HD model. All patients received an annuloplasty band and 1 or more of the following: leaflet resection; annuloplasty; basal chord transposition, polytetrafluoroethylene neochordal replacement, or both; and edge-to-edge repair. RESULTS: The overall mean age was 58.4 +/- 10.5 years, and 64% were male. There was 1 (0.8%) hospital mortality. Five patients required mitral valve replacement for a failed repair. Another patient had mitral valve rerepair on postoperative day 2. Except for 2 early reoperations for postoperative bleeding, all of the complications and failed repairs requiring operative revision occurred with the original robot. Postdischarge transthoracic echocardiographic follow-up was available on 107 (93%) of 115 patients, with a median follow-up of 321 days. None to mild mitral regurgitation was seen in 102 (89%) patients, moderate mitral regurgitation was seen in 9 (8.4%) patients, and severe mitral regurgitation was seen in 3 (2.8%), with 1 patient undergoing mitral valve replacement and 2 patients being medically managed. CONCLUSIONS: The majority of complications and all the repeat operations for failed mitral valve repair occurred with the older-model da Vinci robot. The newer da Vinci Si HD system, with the addition of an adjustable left atrial roof retractor, improves mitral valve exposure, enhancing the surgeon's ability to repair and test the valve. We have progressed to successful repair of all types of degenerative mitral valve pathology and have found the approach reproducible.

Heart transplantation using bivalirudin as anticoagulant.

We present the case of a man with heparin-induced thrombocytopenia (HIT) and acute idiopathic decompensated cardiomyopathy who underwent successful heart transplantation with the use of bivalirudin as anticoagulant.

Coronary revascularization alone or with mitral valve repair: outcomes in patients with moderate ischemic mitral regurgitation.

We sought to evaluate retrospectively the outcomes of patients at our hospital who had moderate ischemic mitral regurgitation and who underwent coronary artery bypass grafting (CABG) alone or with concomitant mitral valve repair (CABG+MVr).A total of 83 patients had a reduced left ventricular ejection fraction and moderate mitral regurgitation: 28 patients underwent CABG+MVr, and 55 underwent CABG alone. Changes in mitral regurgitation, functional class, and left ventricular ejection fraction were compared in both groups.The mean follow-up was 5.1 +/- 3.6 years (range, 0.1-15.1 yr). Reduction of 2 mitral-regurgitation grades was found in 85% of CABG+MVr patients versus 14% of CABG-only patients (P < 0.0001) at 1 year, and in 56% versus 14% at 5 years, respectively (P = 0.1), as well as improvements in left ventricular ejection fraction and functional class. One- and 5-year survival rates were similar in the CABG+MVr and CABG-only groups: 96% +/- 3% versus 96% +/- 4%, and 87% +/- 5% versus 81% +/- 8%, respectively (P = NS). Propensity analysis showed similar results. Recurrent (3+ or 4+) mitral regurgitation was found in 22% and 47% at late follow-up, respectively.In patients with moderate ischemic mitral regurgitation, either surgical approach led to an improvement in functional class. Early and intermediate-term mortality rates were low with either CABG or CABG+MVr. However, an increased rate of late recurrent mitral regurgitation in the CABG+MVr group was observed.

An unusual case of allograft neutrophilic myocarditis mimicking acute myocardial infarction in a post-heart transplant patient.

The clinical presentation of myocarditis is variable and can mimic myocardial infarction. The diagnosis of acute myocarditis is frequently empiric, and is made on the basis of the clinical presentation, electrocardiographic changes, elevated cardiac enzymes, and lack of epicardial coronary artery disease and lymphocytic infiltration on myocardial biopsy. We present an unusual case of a young patient with history of heart transplantation who presented with fever and polyarthritis and developed chest pain along with electrocardiographic changes and troponin elevation with no evidence of coronary artery disease. His myocardial biopsy revealed marked neutrophilic infiltration and no evidence of rejection. The clinical picture was compatible with a rare finding of neutrophilic myocarditis in the allograft, possibly related to a systemic inflammatory process.