Impact of donor smoking history on post heart transplant outcomes: A propensity-matched analysis of ISHLT registry.

PURPOSE: Smoking is a major public health issue, and its effect on cardiovascular outcomes is well established. This study evaluates the impact of donor smoking on heart transplant (HT) outcomes. METHODS: HT recipients between January 1, 2005, and December 31, 2016, with known donor smoking status were queried from the International Society of Heart and Lung Transplantation (ISHLT) registry. The primary outcome was all-cause mortality, and secondary endpoints were graft failure, acute rejection, and cardiac allograft vasculopathy. We utilized propensity-score matching to identify cohorts of recipients with and without a history of donor smoking. Hazard ratios for post-transplant outcomes for the matched sample were estimated from separate Cox proportional hazard models. RESULTS: Of 26 390 patients in the cohort, 18.9% had history of donor smoking. Donors with history of smoking were older, predominantly male and had higher incidence of diabetes, hypertension, cocaine use, and "high-risk" status. In propensity-matched analysis, recipients with a history of donor smoking had increased risk of death (HR 1.11, 95% CI 1.03-1.20) and higher risk of graft failure (HR 1.11, 95% CI 1.03-1.20). CONCLUSION: Donor smoking was associated with increased mortality and higher incidence of graft failure following HT. Consideration of donor smoking history is warranted while evaluating donor hearts.

The effect of donor alcohol abuse on outcomes following heart transplantation.

BACKGROUND: Current guidelines recommend against the use of hearts from donors that abuse alcohol. We explored the effect of donor alcohol abuse (AA) on cardiac allograft function and outcomes in heart transplant (HTx) recipients. METHODS: Overall, 370 HTx recipients were divided into two groups: (a) the alcoholic donor group (AD, n = 58) and (b) the non-alcoholic donor group (NAD, n = 312). RESULTS: Recipients in the AD group had a slower heart rate (86 ± 13 vs 93 ± 13, P = 0.004) and an increased incidence of early atrial fibrillation (AF) (30% vs 11%, P = 0.003). Echocardiographic left ventricular mass was higher among alcoholic donors (171.7 ± 66.7 vs 151.6 ± 54.7, P = 0.02). This difference remained present 1 year following HTx (185 ± 43 vs 166 ± 42, P = 0.007). E/E' was higher in the AD group (9.5 ± 3.9 vs 8.4 ± 2.9, P = 0.04) and a larger number of AD recipients had a ventilatory equivalent for VCO2  > 34 (50% vs 31%, P = 0.04) on cardiopulmonary exercise test. There was no significant difference in rejection, cardiac allograft vasculopathy (CAV), or survival between the groups. CONCLUSIONS: Our data suggest that donor AA does not impact rejection, CAV, or intermediate-term survival, but may cause increased incidence of post-HTx AF and impaired cardiac allograft diastolic function.

Early Hemodynamic Changes during Head-Up Tilt Table Testing Can Predict a Neurocardiogenic Response in an African-American Patient Population.

BACKGROUND: Head-up tilt table testing (HUTT) is time-consuming and associated with increased patient morbidity. Hemodynamic changes that occur during the early phase of HUTT may be predictive of neurocardiogenic syncope. METHODS: A retrospective chart review was performed in 119 consecutive African Americans ( 57 ± 19) who underwent HUTT for evaluation of syncope of unknown etiology. Positive responses were defined as the development of symptoms linked with a systolic blood pressure (BP) <90 mm Hg, heart rate <50 b.p.m. or sinus arrest >3 s. Hemodynamic variables during the passive phase of HUTT were analyzed and results were then classified as a function of various predictors. RESULTS: Sixty-two subjects (52%) had positive HUTT, and 57 (48%) had negative HUTT. Early changes in BP variables from baseline significantly predicted HUTT responses (p < 0.05). There was also a significant interaction between age and BP. An algorithm based on age and BP was developed which had positive and negative predictive values of 67.7 and 93%, respectively, with an accuracy of 79.8%. CONCLUSION: A novel algorithm utilizing the patients' age and changes in both systolic and diastolic BP during the early phase of HUTT enables the prediction of HUTT results without the use of vasoactive stimulation, allowing for rapid diagnosis, decreased patient morbidity and reduction in costs.

Resolution of neurological deficits secondary to spontaneous intracranial haemorrhage and posterior reversible encephalopathy syndrome (PRES) in a patient with hepatitis C-associated cryoglobulinaemia: a role for plasmapheresis.

Essential mixed cryoglobulinaemia or type II cryoglobulinaemia is an important extrahepatic manifestation of chronic hepatitis C. Cryoglobulinaemia results in the deposition of immune complexes in small or medium-sized blood vessels leading to palpable purpura, arthralgia, renal disease and peripheral neuropathy. Posterior reversible encephalopathy syndrome (PRES) is a distinct phenomenon characterised by vasogenic oedema in the posterior circulation of brain. Cryoglobulinaemic vasculitis leading to spontaneous intracranial haemorrhage and PRES syndrome is rarely reported in the medical literature. In this report, we present an unusual case of spontaneous intracranial haemorrhage and PRES secondary to hepatitis C-associated cryoglobulinaemia presenting as right dense hemiplegia. Prompt institution of plasmapheresis resulted in successful resolution of symptoms in our patient, followed by full neurological recovery. To the best of our knowledge, this case describes the first successful use of plasmapheresis in alleviating neurological complications resulting from cryoglobulinaemic vasculitis and PRES secondary to chronic hepatitis C.

Hepatitis C virus induced miR200c down modulates FAP-1, a negative regulator of Src signaling and promotes hepatic fibrosis.

Hepatitis C virus (HCV) induced liver disease is the leading indication for liver transplantation (LTx). Reinfection and accelerated development of fibrosis is a universal phenomenon following LTx. The molecular events that lead to fibrosis following HCV infection still remains poorly defined. In this study, we determined microRNA (miRNA) and mRNA expression profiles in livers from chronic HCV patients and normals using microarrays. Using Genego software and pathway finder we performed an interactive analysis to identify target genes that are modulated by miRNAs. 22 miRNAs were up regulated (>2 fold) and 35 miRNAs were down regulated (>2fold) compared to controls. Liver from HCV patients demonstrated increased expression of 306 genes (>3 fold) and reduced expression of 133 genes (>3 fold). Combinatorial analysis of the networks modulated by the miRNAs identified regulation of the phospholipase C pathway (miR200c, miR20b, and miR31through cellular proto-oncogene tyrosine-protein kinase Src (cSrc)), response to growth factors and hormones (miR141, miR107 and miR200c through peroxisome proliferator-activated receptor alpha and extracellular-signal-regulated kinases, and regulation of cellular proliferation (miR20b, miR10b, and miR141 through cyclin-dependent kinase inhibitor 1 or CDK-interacting protein 1 p21). Real time PCR (RT-PCR) validation of the miRNA in HCV infected livers demonstrated a 3.3 ±0.9 fold increase in miR200c. In vitro transfection of fibroblasts with miR200c resulted in a 2.2 fold reduction in expression of tyrosine-protein phosphatase non-receptor type 13 or FAS associated phosphatase 1 (FAP-1) and 2.3 fold increase in expression of cSrc. miR200c transfection resulted in significant increases in expression of collagen and fibroblast growth factor (2.8 and 3.4 fold, p<0.05). Therefore, we propose that HCV induced increased expression of miR200c can down modulate the expression of FAP1, a critical regulator of Src and MAP kinase pathway that play an important role in the production of fibrogenic growth factors and development of fibrosis.

Sweet's syndrome as a dermatological manifestation of underlying coronary artery disease.

We report an unusual case of a 50-year-old female with no significant past medical history who reported with a sudden eruption of painful erythematous papules accompanied by fever. Clinical and pathological findings were consistent with acute febrile neutrophilic dermatosis (or Sweet's syndrome). Two weeks later, she complained of chest pain and was diagnosed with non-ST elevation myocardial infarction. Coronary angiogram demonstrated stenosis of right coronary artery and left Circumflex artery. Subsequent workup to identify underlying malignant or autoimmune disorders was negative. She refused to undergo percutaneous coronary intervention and was treated conservatively with steroids, resulting in dramatic resolution of skin lesions. Six months later, the patient was readmitted with similar complaints including fever, generalized rash, and chest pain. Electrocardiography demonstrated old infero-lateral wall infarction. Cardiac enzymes were not elevated. Repeat workup failed to identify underlying systemic disorder except coronary artery disease (CAD). She recovered following administration of steroids and continued to receive medical therapy for CAD. This case demonstrates an unusual association between Sweet's syndrome and CAD in an adult female. Sweet's syndrome is considered to be a reactive phenomenon of underlying systemic disorders. Therefore, patients presenting with Sweet's syndrome should be evaluated for CAD, especially in the absence of underlying malignant or autoimmune disorders.

Ventricular arrhythmias and acute left ventricular dysfunction as a primary and life-threatening manifestation of a mitochondrial crisis: A novel management strategy.

Mitochondrial disorders are genetic diseases that result in a deficiency of energy metabolism (ATP production). A "mitochondrial crisis" can occur in the setting of infection, dehydration, or physiologic stress. The hallmark of a mitochondrial crisis is failure of multiple individual organ systems. The mortality of mitochondrial crisis is high and therapy is supportive but involves a specific strategy of hydration with dextrose-containing IV fluids, avoidance of many medications known to worsen mitochondrial function, and limitations of oxygenation as this can promote free radical production. We report a case of a patient with known mitochondrial disease that presented with a mitochondrial crisis with prominent and life-threatening cardiac manifestations including long QT, ventricular arrhythmias, and acute left ventricular systolic dysfunction in addition to rhabdomyolysis, lactic acidosis, and an acute kidney injury. This patient was managed successfully with a specifically tailored supportive strategy, a high-dose metabolic cocktail, permissive hypoxia, and low-protein diet. At 10 weeks post discharge all electrocardiographic abnormalities resolved and ventricular recovery has been observed. Given the increased survival of this population of patients into adulthood it is important that these adjunctive therapeutic strategies require consideration by clinicians treating this group of patients.

Identification of immunodominant HLA-B7-restricted CD8+ cytotoxic T cell epitopes derived from mammaglobin-A expressed on human breast cancers.

Mammaglobin-A (MGBA), a 10-kD protein, is over expressed in 80% of primary and metastatic human breast cancers. Breast cancer patients demonstrate high frequencies of CD8(+) cytotoxic T lymphocytes (CTL) specific to MGBA. Defining CD8(+) CTL responses to HLA class I-restricted MGBA-derived epitopes assumes significance in the context of our ongoing efforts to clinically translate vaccine strategies targeting MGBA for prevention and/or treatment of human breast cancers. In this study, we define the CD8(+) CTL response to MGBA-derived candidate epitopes presented in the context of HLA-B7, which has a frequency of 17.7% in Caucasian and 15.5% in African American populations. We identified seven MGBA-derived candidate epitopes with high predicted binding scores for HLA-B7 using a computer algorithm. Membrane stabilization studies with TAP-deficient T2 cells transfected with HLA-B7 indicated that MGBA B7.3 (VSKTEYKEL), B7.6 (KLLMVLMLA), B7.7 (NPQVSKTEY), and B7.1 (YAGSGCPLL) have the highest HLA-B7 binding affinities. Further, two CD8(+) CTL cell lines generated in vitro against T2.B7 cells individually loaded with MGBA-derived candidate epitopes showed significant cytotoxic activity against MGBA B7.1, B7.3, B7.6, and B7.7. In addition, the same CD8(+) CTL lines lysed the HLA-B7(+)/MGBA(+) human breast cancer cell line DU-4475 but had no significant cytotoxicity against HLA-B7(-) or MGBA(-) breast cancer cell lines. Cold-target inhibition studies strongly suggest that MGBA B7.3 is an immunodominant epitope. In summary, our results define HLA-B7-restriced, MGBA-derived, CD8(+) CTL epitopes with all of the necessary features for developing novel vaccine strategies against HLA-B7 expressing breast cancer patients.

Characterization of immune responses to cardiac self-antigens myosin and vimentin in human cardiac allograft recipients with antibody-mediated rejection and cardiac allograft vasculopathy.

BACKGROUND: Herein we study the role of donor-specific antibodies (DSA) to mismatched human leukocyte antigen (HLA) and antibodies (Abs) to the cardiac self-antigens myosin (MYO) and vimentin (VIM) in the pathogenesis of acute antibody-mediated rejection (AMR) in the early post-transplant period (EP, <12 months) and cardiac allograft vasculopathy (CAV) in the late post-transplant period (LP, >12 months) after heart transplantation (HTx). METHODS: One hundred forty-eight HTx recipients (65 in EP, 83 in LP) were enrolled in the study. Development of DSA was determined by Luminex. Circulating Abs against MYO and VIM in sera were measured using enzyme-linked immunoassay (ELISA). Frequency of CD4+ T-helper cells (CD4+ Th) secreting interferon (IFN)-γ, interleukin (IL)-17, IL-10 or IL-5 specific to either MYO or VIM were analyzed in vitro using ELISpot assays. RESULTS: AMR patients were more likely DSA positive (AMR-: 15%; AMR+: 70%; p = 0.03) and demonstrated increased Abs to MYO (AMR-: 144 ± 115 µg/ml; AMR+: 285 ± 70 µg/ml; p = 0.033) and VIM (AMR-: 37 ± 19 µg/ml; AMR+: 103 ± 43 µg/ml; p = 0.014). AMR patients demonstrated increased IL-5 CD4+ Th cells specific to MYO (5.2 ± 0.9 fold, p = 0.003) and VIM (7.3 ± 2.9-fold, p = 0.004) and decreased IL-10 CD4+ Th cells specific to MYO (2.2 ± 0.4-fold, p = 0.009) and VIM (1.7 ± 0.2-fold, p = 0.03). CAV patients were more likely DSA positive (CAV-): 25%; CAV+: 79%; p = 0.03) and demonstrated increased Abs to MYO (CAV-: 191 ± 120 µg/ml; CAV+: 550 ± 98 µg/ml; p = 0.025) and VIM (CAV-: 55 ± 25 µg/ml; CAV+: 255 ± 49 µg/ml; p = 0.001). CAV patients demonstrated increased IL-17 CD4+ Th cells specific to MYO (10.5 ± 7.3-fold, p = 0.002) and VIM (7.0 ± 3.9-fold, p = 0.003). CONCLUSIONS: The presence of DSA in AMR and CAV is significantly associated with development of Abs to MYO and VIM in post-HTx patients. Induction of high CD4+ Th cells specific to cardiac self-antigens that secrete predominantly IL-5 and IL-17 plays a significant role in the development of Abs to self-antigens leading to AMR and CAV, respectively.

Hepatopulmonary syndrome - past to present.

Hepatopulmonary syndrome (HPS) is the one of the complication of liver cirrhosis with portal hypertension, irrespective of etiology, age and sex. It has also been observed in non cirrhotic portal hypertension and in acute hepatic conditions. Presence of hypoxemia or abnormal alveolar arterial oxygen tension with intrapulmonary vasodilation in liver cirrhosis is termed as HPS. Contrast echocardiogram is the better screening tool to demonstrate intrapulmonary shunt. Clinicians should be aware of other common chronic pulmonary and cardiac comorbid conditions, in particular COPD, tuberculosis, bronchial asthma and idiopathic pulmonary fibrosis, etc. which may coexist with HPS. There is no specific clinical finding to diagnose but digital clubbing, cyanosis, dyspnoea, platypnoea, and spider naevi are more common among cirrhosis with HPS. The presence of HPS independently worsens prognosis of cirrhosis. Even though number of mechanisms have been proposed to explain arterial hypoxemia in HPS, role of nitric oxide is the major one along with cytokines. Liver transplantation is the choice of treatment though mortality is comparatively high. There is no still effective recommended medical therapy to reverse this condition and anti cytokine/ nitric oxide inhibitors, etc are under preliminary stage.