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Background: Heart failure with preserved ejection fraction is increasing in prevalence, but few effective treatments are available. Elevated left ventricular (LV) diastolic filling pressures represent a key therapeutic target. Pericardial restraint contributes to elevated LV end-diastolic pressure, and acute studies have shown that pericardiotomy attenuates the rise in LV end-diastolic pressure with volume loading. However, whether these acute effects are sustained chronically remains unknown. Methods: Minimally invasive pericardiotomy was performed percutaneously using a novel device in a porcine model of heart failure with preserved ejection fraction. Hemodynamics were assessed at baseline and following volume loading with pericardium intact, acutely following pericardiotomy, and then again chronically after 4 weeks. Cardiac structure was assessed by magnetic resonance imaging. Results: The increase in LV end-diastolic pressure with volume loading was mitigated by 41% (95% CI, 27%–45%, P <0.0001; ΔLV end-diastolic pressure reduced from +9±3 mm Hg to +5±3 mm Hg, P =0.0003, 95% CI, −2.2 to −5.5). The effect was sustained at 4 weeks (+5±2 mm Hg, P =0.28 versus acute). There was no statistically significant effect of pericardiotomy on ventricular remodeling compared with age-matched controls. None of the animals developed hemodynamic or pathological indicators of pericardial constriction or frank systolic dysfunction. Conclusions: The acute hemodynamic benefits of pericardiotomy are sustained for at least 4 weeks in a swine model of heart failure with preserved ejection fraction, without excessive chamber remodeling, pericarditis, or clinically significant systolic dysfunction. These data support trials evaluating minimally invasive pericardiotomy as a novel treatment for heart failure with preserved ejection fraction in humans.

AbstractBackgroundLittle is known about the ablation outcomes of premature ventricular contractions (PVCs) that originate from the periprosthetic aortic valve (PPAV) regions of patients with aortic valve replacement (AVR).Methods and ResultsOur study had 11 patients who underwent catheter ablation for PVCs arising from the PPAV regions (bioprosthetic aortic valve, n = 5; mechanical aortic valve, n = 6). The PVC characteristics, procedure characteristics, and efficacy of ablation were compared with the control group (n = 33). At baseline, the PPAV group had a lower left ventricular ejection fraction (mean [SD], 41% [12%] vs. 51% [8%]; p = .002). The rate of acute ablation success was 90.9% in the PPAV group. Ablation sites were identified above the left coronary cusp (LCC) and right coronary cusp commissure (LRCC) in one PVC, below the prosthetic valve in eight PVCs (four below LCC and four below LRCC), and within the distal coronary sinus in two PVCs. The mean procedure time, fluoroscopy time, and radiation in the PPAV group were all significantly greater than those in the control group (all p < .05). However, the number of radiofrequency ablation energy deliveries was not different. The PPAV group had a long‐term success rate compared with the control group (72.7% vs. 87.9%, p = .48) and an increase of left ventricular ejection fraction from 43% to 49% after successful PVC ablation at follow‐up (p < .001). Echocardiography showed no significant change in valve regurgitation after ablation. No new atrioventricular block occurred.ConclusionPVCs arising from PPAV regions can be successfully ablated in patients with prior AVR, without damaging the prosthetic aortic valve and atrioventricular conduction.

Heparin-induced thrombocytopenia is an immune-mediated disorder caused by antibodies that recognize complexes of platelet factor 4 and heparin. Thrombosis is a central and unpredictable feature of this syndrome. Despite optimal management, disease morbidity and mortality from thrombosis remain high. The hypercoagulable state in heparin-induced thrombocytopenia is biologically distinct from other thrombophilic disorders in that clinical complications are directly attributable to circulating ultra-large immune complexes. In some individuals, ultra-large immune complexes elicit unchecked cellular procoagulant responses that culminate in thrombosis. To date, the clinical and biologic risk factors associated with thrombotic risk in heparin-induced thrombocytopenia remain elusive. This review will summarize our current understanding of thrombosis in heparin-induced thrombocytopenia with attention to its clinical features, cellular mechanisms, and its management.

Abstract Background Orthotopic heart transplant (OHT) is indicated in 1–8% of patients with myocarditis. However, national trends in the utilization of transplantation and outcomes in myocarditis across the United States are not well established. Purpose Our objective was to study the trends and baseline characteristic of myocarditis patients undergoing heart transplant in the United States using Healthcare Cost and Utilization Project (HCUP) National (nationwide) Inpatient Sample (NIS) from 1999 to 2014. Methods Using NIS data, we identified patients older than 18 years with myocarditis using codes ICD9 codes of 422.0 and 422.9. Among these patients, we identified those who underwent cardiac transplantation using ICD9 procedure codes 37.5 and 33.6. We presented categorical data as percentages and continuous data as mean or median as appropriate. Results We identified a total of 62,264 hospitalizations for myocarditis from 1999–2014. 430 (0.69%) myocarditis patients underwent OHT which consisted of 0.82% of all 29990 cardiac transplants identified in the same period. The trends in OHT for myocarditis is as shown in Figure 1. The mean age was 32.9±2.4 years and 51.1% (n=219) were females. 235 (54.6%) were Caucasians and 60 (13.9%) were Hispanic. Majority of the transplants were performed at medium (16%) and large sized hospitals (80.4%). Cardiac transplants were mainly done at teaching hospitals (98.9%). Further, with regards to the geographical distribution of transplant procedure, most were done in the West (37.2%) followed by South (25.3%), Northeast (21.4%) and Mid-west (16%) of the United States. Private insurance was the major payor source which covered 245 (58%) patients followed by Medicaid covering 112 (26%) patients. A total of 26 (6%) myocarditis patients died during the same hospitalization for OHT. In terms of discharge following OHT in myocarditis 85.8% (n=369) were discharged home and 8.1% (n=35) to short term hospitalization. The average length of stay for OHT for myocarditis was 64.3±6.3 days. Also, the mean cost of hospitalization for heart transplant in myocarditis when adjusted for inflation was 789,566±93,108 dollars. In-patient mortality following OHT was not significantly different in large sized hospital compared to small and medium sized hospitals (7.6% vs 5.7%, p=0.54). However, the cost of hospitalization was significantly lesser in small and medium sized hospitals (588,363±154,349 vs 826,864±106,110 dollars, p&lt;0.0001). Conclusions Only a small percentage of OHT is done for myocarditis with high proportion done in female when compared to OHT for other etiologies. Further studies need to be done to compare long term outcomes of heart transplant in myocarditis. Funding Acknowledgement Type of funding source: None

Abstract Background Orthotopic heart transplant (OHT) is indicated for end-stage heart failure due to cardiac sarcoidosis (CS). However, utilization of OHT for CS has been controversial due to concern for involvement of other organs by sarcoidosis affecting long term outcomes. Purpose Our objective was to study the trends in OHT in patients with CS in the United States using Healthcare Cost and Utilization Project (HCUP) National (nationwide) Inpatient Sample (NIS) from 1999 to 2014. Methods Using NIS data, we identified patients older than 18 years with cardiac sarcoidosis using codes ICD 9-CM codes of 135 and 425.8. Among these patients, we identified those who underwent cardiac transplantation using ICD 9-CM procedure codes 37.5 and 33.6. We presented categorical data as percentages and continuous data as mean or median as appropriate. Results A weighted total of 24231 hospitalizations for CS was extracted from 1999 to 2014 of which 248 (1.02%) CS patients underwent OHT. The trends in cardiac transplant for CS is as shown in Figure 1. The mean age of CS patients undergoing OHT was 51.7±1.1 years and 60.4% (n=150) were males. 114 (45.9%) were Caucasians and 27.8% (n=25) were African-American. 100% of the transplants were performed at medium (n=5) or large sized (n=243) teaching hospitals and 97.9% of cardiac transplants were also done at teaching hospitals. Heart transplants were mostly done in the South (36.3%) followed by Midwest (26.2%), West (25%) and Northeast (12.5%). Private insurance was the major payor source which covered 149 (60.1%) patients followed by Medicare covering 65 (26.2%) patients. A total of 10 (3.9%) cardiac sarcoidosis patients died during the same hospitalization for cardiac transplantation. Following OHT, 84.2% (n=209) were discharged home and 11.6% (n=29) to short term hospitalization. The mean cost of hospitalization for OHT in CS when adjusted for inflation was 535144±56060 dollars while the average length of stay for heart transplant for CS was 46.2±6.6 days. Conclusions Cardiac transplant trends in CS have not changed from 1999 to 2014 despite recent studies showing improved outcomes and are associated with substantial cost of hospitalization and length of stay. Majority of cardiac transplant was done in Caucasians despite cardiac sarcoidosis being more common in African-Americans. Funding Acknowledgement Type of funding source: None

Abstract Background Cardiac amyloidosis (CA) remains an underdiagnosed entity. Atrial fibrillation (AF) is common in patients with CA, likely owing to direct amyloid deposition in the left atrium. However, the prevalence of AF in CA and its association with in-hospital outcomes has not been studied in large populations. Purpose Our aim was to study the trends, baseline characteristics, and clinical impact of AF in patients with CA in the United States using the Healthcare Cost and Utilization Project (HCUP) National) Inpatient Sample (NIS) from 1999 to 2014. Methods We queried the NIS and identified CA using ICD-9-CM codes 277.39 and 425.7. AF in CA patients was identified using the ICD-9-CM code of 427.31. Statistical Analysis System (SAS) 9.4 was used for analysis of data. Results There were a total of 145,920 CA hospitalizations between 1999 and 2014 in the United States, of which 37,070 (25.4%) had AF. The prevalence of AF remained consistent from 27.5% in 1999 to 27.4% in 2014. The mean age of patients with AF was 72.9±28.2 years and for patients without AF was 67±31.9 years (p&lt;0.0001). The majority of the patients with AF were male (60.3%) and the study group was predominantly white (62.8% in patients with AF and 56.4% in patients without AF). CA patients with AF suffered more from thyroid-related disease (22.5% vs 16.1%), heart failure (62.9% vs 36.5%) and renal failure (34.7% vs 30.5%) and less from hypertension (29.3% vs 34.0%) and diabetes mellitus (23.2% vs 25.2%) (p&lt;0.0001). There was no significant difference in the Charlson comorbidity score between the groups. Inpatient mortality was significantly higher in CA patients with AF (10.4% vs 6.5%, p&lt;0.001). However, in-patient mortality has been decreasing over the years from 10.3% in 1999 to 7.6% in 2014. Furthermore, cardiogenic shock was significantly higher in CA patients with AF (2.1% vs 1.2%, p&lt;0.001), yet the use of mechanical circulatory support was not significantly different between the groups (0.42% vs 0.35%, p=0.375). Pacemaker implantation was also noted to be higher in CA patients with AF compared to patients without AF (2.8% vs 1.2%, p&lt;0.0001). There was no significant difference between CA patients with and without AF in mean cost of hospitalization ($58222±10752 vs $57695±545, p=0.081) or length of stay (7.9±0.1 vs 7.7±0.1 days, p=0.7089). Conclusion CA with atrial fibrillation is a well-recognized entity, and our large scale retrospective analysis found significant association with worse in-hospital outcomes and cardiogenic shock. Interestingly, trend of in-patient mortality in CA has been decreasing over the years, likely owing to improved imaging modalities for diagnosis. Optimal management of AF in CA is imperative to improve outcomes in this population. Funding Acknowledgement Type of funding source: None

Abstract Background Orthotopic heart transplantation is the most effective long-term therapy for end-stage heart disease. Denervation of transplanted heart with the loss of autonomic modulation, vasculopathy, utilization of immunosuppressant drugs, and risk of allograft rejection may result in change in the prevalence of arrhythmias in transplanted hearts. Purpose To describe the trends, distribution and the clinical impact of arrhythmias in transplanted hearts in a large nationwide population. Methods We queried the National Inpatient Sample with administrative codes. Cardiac transplant patients were identified using procedure ICD-9-CM codes 37.5 and 33.6. Common arrhythmias were extracted using appropriate validated ICD-9-CM codes. Statistical Analysis System (SAS) version 9.4 was used for analysis of data. Results There was a total of 30,020 hospitalizations of heart transplant recipients between 1999 and 2014 in the United States and 16342 (54.4%) of these had arrhythmias. The prevalence of total arrhythmias increased from 53.6% (n=1,158) in 1999 to 67.3% (n=1,575) in 2014. The most common arrhythmia was atrial fibrillation (26.83%) followed by ventricular tachycardia (22.86%) and the prevalence of individual arrhythmias is as shown in Figure 1. Cardiogenic shock was higher in transplanted hearts with arrhythmias when compared with patients without arrhythmias (25.96% vs 18.18%; p&lt;0.001). Transplant recipients with arrhythmias were also associated with an increased use of mechanical circulatory device (18.22% vs 12.67%, p&lt;0.001). The use of implantable cardiac defibrillators and permanent pacemaker was also higher in the arrhythmia group (2.19% vs 0.63% and 40.43% vs 30.24% respectively, p&lt;0.0001). However, there was no significant difference in inpatient mortality between transplant recipients with arrhythmias and without arrhythmias (7.72% vs 6.90%, p=0.225). Further, there was no significant difference in frequency of strokes between the groups (4.98% vs 5.08%; p=0.857). The total hospital cost when adjusted for inflation was significantly higher in the arrhythmic patients, with an average cost of about $570,415±9,590 vs $439,707±8362 in patients without arrhythmias (p&lt;0.0001). The mean length of hospitalization was 44.2±0.8 days in patients with arrhythmias compared to 33.9±0.8 days in patients without arrhythmias (p&lt;0.0001). Conclusion A significant proportion of patients with heart transplant have cardiac arrhythmias and are associated with worse in-hospital outcomes of cardiogenic shock, increased length of stay, and cost of hospitalization. However, they are not associated with worse inpatient mortality. Funding Acknowledgement Type of funding source: None

Abstract Background Takotsubo cardiomyopathy (TC) is a reversible stress-induced myocardial dysfunction with increased sympathetic activity caused by excessive release of catecholamines playing a central role in its pathophysiology. The occurrence of TC in transplanted hearts is rare given the complete denervation done during transplantation. However, it has been demonstrated that 40% of transplant recipients undergo sympathetic re-innervation. There have only been case reports describing TC in post-transplant recipients. Purpose To evaluate the incidence, baseline characteristics and outcomes of TC occurring in heart transplant recipients using Healthcare Cost and Utilization Project (HCUP) National (nationwide) Inpatient Sample (NIS) in United States from 2009 to 2014. Methods Using NIS data, we identified patients who underwent cardiac transplantation using ICD9 procedure codes 37.5 and 33.6. Among these patients, we identified those admitted to the hospital with diagnosis of TC based on ICD-9-CM code 429.83. We presented categorical data as percentages and continuous data as mean or median as appropriate. Results We identified 257 hospitalizations for TC in heart transplant recipient patients. There was an approximately 9-fold increase in admissions from 11 in 2009 to 95 in 2014. Among patients with TC, the mean age was 65.3±1.8 years and majority were female (76.6%). A majority of patients were Caucasians (63%) followed by smaller proportion of African-Americans (13.2%). In-patient mortality in patients admitted with TC following heart transplant was 11.3% (n=29). During the hospitalization, 4.8% of patients had cardiogenic shock and 2.8% required mechanical circulatory support. The average length of stay for patients with TC was 16.6±3.3 days. The mean cost of hospitalization for these patients when adjusted for inflation were 237248±55709 dollars. Conclusion TC can still occur in substantially in heart transplant recipients and should be considered one of the differential diagnosis in transplant patients presenting to the hospital. Funding Acknowledgement Type of funding source: None

Heparin-induced thrombocytopenia (HIT) is a serious reaction to heparin treatment characterized by antibodies that recognize a complex formed between heparin and platelet factor 4 (PF4/H) and are capable of activating platelets and inducing a pro-thrombotic state. Although a high percentage of heparin-treated patients produce antibodies to PF4/H, only a subset of these antibodies are platelet-activating (pathogenic) and capable of causing HIT. We previously reported that we cloned B cells from six patients experiencing HIT and identified two types of PF4/H-binding antibodies: seven platelet-activating (PA) and 48 non-activating (NA). Comparison of the structural features in the PA, NA, and non PF4/H-binding (NB) clones showed that the length and the number of basic amino acid and tyrosine residue in the heavy chain complementarity determining region 3 (HCDR3) were significantly different, and was in the order of PA&gt;NA&gt;NB. Most significantly, the seven platelet-activating antibodies each have one of the two pathogenic motifs: RX1-2 R/KX1-2 R/H and YYYYY in an unusually long HCDR3 (≥ 20 residues). In the current study, we attempt to understand the origin of the B cells that produce the PA and NA antibodies and the nature of the immune response in HIT through analyzing somatic hypermutation and biological property of such antibodies. Longer HCDR3 and more basic Aas and Tyr residues in the HCDR3 are features of autoreactive and polyreactive antibodies. With this in mind, we tested PA and NA clones in a standard antinuclear antibody (ANA) assay and found that these clones were significantly more reactive than NB antibodies, and the plasma of HIT patients were significantly more reactive than normal plasma (Figure1). We then compared reactions of PA, NA and NB clones against a group of self and foreign antigens commonly used in polyreactivity assays: dsDNA, ssDNA, LPS, insulin, and keyhole limpet hemocyanin (KLH). About 90% of PA and NA clones were reactive to at least two antigens, this was true of only 20% of the NB clones, and the latter is consistent with the frequency of polyreactive clones in the IgG+ B cells (Figure2). Taken together, these data indicate that PA and NA antibodies are largely polyreactive. We then investigated the development of the PA and NA B cells through analyzing somatic hypermutation in the antibodies. Through analyzing the HCDR3 nucleotide insertion, trimming and VDJ segment usage, we found that longer HCDR3 typical of PF4/H-binding clones and the RKH and Y5 motifs identified in PA clones were the result of original recombination not somatic hypermutation. Consistently, the average number of nucleotide mutations in the VH genes of the binding clones was lower (PA and NA, 9.4 ± 9.5) compared to that of peripheral blood IgG+ memory B cells in healthy subjects (~18) (Figure3). Total mutation frequency in the VH and Vk CDRs of the PF4/H-binding PA and NA clones was comparable to that of the framework regions. This finding contrasts with findings made in peripheral blood IgG+ memory B cells of healthy subjects showing that the mutation frequencies are much higher in the CDRs than in the FRs of VH. Taken together, these findings suggest that affinity maturation plays a limited role in the evolution PF4/H-binding antibodies during the immune response that leads to HIT. In this study, we showed thay PF4/H-binding PA and NA IgGs are largely polyreactive antibodies and contain lower levels of mutations compared to IgG+ memory B cells. B1 and MZ B cells are innate B cells that are main producers of polyreactive natural antibodies and can respond to toll-like receptor signaling, quickly differentiate into antibody-secreting cells, and undergo IgG class switch extrafollicularly. Polyreactivity identified in the PF4/H-binding PA and NA IgGs supports the possibility that human B cells producing PF4/H-binding antibodies are innate B cells akin to MZ B cells shown to be a source of PF4/H antibodies in mice. A mutation rate lower than that of IgG+ memory cells in the PF4/H-binding IgGs is also consistent with an extrafollicular response typical of innate B cells. These observations would help to improve our understanding of the immunological responses and B cell origin in HIT patients. Disclosures Padmanabhan: Retham Technologies: Current equity holder in private company; Veralox Therapeutics: Membership on an entity's Board of Directors or advisory committees; Versiti Blood Research Institute: Patents & Royalties.