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Background Many patients with American College of Cardiology/American Heart Association Stage D (advanced) heart failure are discharged home on chronic intravenous inotropic support (CIIS) as bridge to surgical therapy or as palliative therapy. This study analyzed the clinical trajectory of patients with advanced heart failure who were on home CIIS. Methods We conducted a single-institution, retrospective cohort study of patients on CIIS between 2010 and 2016 (n = 373), stratified by indication for initiation of inotropic support. Study outcomes were time from initiation of CIIS to cessation of therapy, time to death for patients who did not receive surgical therapy and rates of involvement with palliative care. Results Overall, patients received CIIS therapy for an average of 5.9 months (standard deviation [SD] 7.3). Patients on CIIS as palliative therapy died in an average of 6.2 months (SD 6.6) from the time of initiation of CIIS, and those on CIIS as bridge therapy who did not ultimately receive surgical therapy died after an average of 8.6 months (SD 9.3). Patients who received CIIS as bridge therapy were significantly less likely to receive palliative-care consultation than those on inotropes as palliative therapy, whether or not they underwent surgery. Conclusions In this large cohort of patients with advanced HF, patients who on CIIS as palliative therapy survived for 6.2 months, on average, with wide variation among patients. Patients who were on CIIS as bridge therapy but did not ultimately receive surgical therapy received less palliative care despite the high mortality rate in this subgroup.

Background/purpose The aim of this study is to characterize the pattern and the severity of coronary artery lesions in cardiac amyloidosis . Methods We retrospectively compared patients with heart failure who tested positive (i.e., biopsy or gene tests – HF/CA+) against those who tested negative (HF/CA−) for cardiac amyloidosis. Groups were compared demographically and angiographically for qualitative and quantitative variables to determine patterns of involvement in the major epicardial coronary vessels . Results The study included 110 heart failure patients, of whom 55 patients (88 lesions) were in the HF/CA+ group, and 55 patients (66 lesions) were HF/CA−. Despite the advanced age of HF/CA+ patients (74.5 ± 11.0 years vs. 54.1 ± 15.0 years; p = 0.05), no severe calcification was found in the HF/CA+ group (0.0% vs. 4.5%; p = 0.018). The HF/CA+ group also had fewer ostial lesions (3.4% vs. 15.1%; p = 0.0095) and a higher, albeit not significant, Thrombolysis in Myocardial Infarction frame count (30.4 ± 12.6 vs. 26.6 ± 11 frames; p = 0.06). In the HF/CA+ group, men had a significant number of tandem lesions compared to women (14.5% vs 0.0%, p = 0.02). Conclusions Overall, heart failure patients with cardiac amyloidosis were older but were found to have less calcified lesions, less ostial involvement, and a reduced anterograde coronary blood flow . This is the first report examining coronary lesions in heart failure patients with cardiac amyloidosis.

Background: Outcomes in heart failure with reduced ejection fraction (HFrEF) are influenced by access and adherence to guideline-directed medical therapy. Our objective was to study the association between annual household income and: (1) the odds of having a claim for sacubitril/valsartan among insured patients with HFrEF and (2) medication adherence (measured as the proportion of days covered). We hypothesized that lower annual household income is associated with decreased odds of having a claim for and adhering to sacubitril/valsartan. Methods: Using the Optum de-identified Clinformatics Data Mart, patients with HFrEF and ≥6 months of enrollment for follow-up (2016–2020) were included. Covariates included age, sex, race, ethnicity, educational attainment, US region, number of prescribed medications, and Elixhauser Comorbidity Index. Prescription for sacubitril/valsartan was defined by the presence of a claim within 6 months of HFrEF diagnosis. Adherence was defined as proportion of days covered ≥80%. We fit multivariable-adjusted logistic regression models and hierarchical logistic regression accounting for covariates. Results: Among 322 007 individuals with incident HFrEF, 135 282 had complete data for analysis. Of the patients eligible for sacubitril/valsartan, 4.7% (6372) had a claim within 6 months of HFrEF diagnosis. Following multivariable adjustment, individuals in the lowest annual income category ( Conclusions: Lower household income is associated with decreased likelihood of a sacubitril/valsartan claim and medication adherence within 6 months of HFrEF diagnosis, even after adjusting for sociodemographic and clinical factors. Future analyses are needed to identify additional social factors associated with delays in sacubitril/valsartan initiation and long-term adherence.

Background: Outcomes in heart failure with reduced ejection fraction (HFrEF), are influenced by access and adherence to guideline directed medical therapy. Objective: To study the association between median annual household income and: (1) odds of receiving sacubitril/valsartan, a novel angiotensin receptor/neprilysin inhibitor (ARNI) therapy among insured patients with heart failure with reduced ejection fraction (HFrEF) and (2) medication adherence (measured as the proportion of days covered (PDC)). Hypothesis: lower income is associated with lower odds of receiving and adhering to ARNI among patients with HFrEF. Methods: Using Optum’s deidentified Clinformatics® Data Mart, patients with ≥ 2 diagnoses of HFrEF and ≥ 6 months of enrollment for follow up (2016-2020) were included. Covariates included age, race, ethnicity, sex, educational attainment, household net worth, geographical region and Elixhauser comorbidity index. Prescription for ARNI was defined by presence of a claim within 180 days. Adherence was defined as PDC ≥80%. We fit multivariable-adjusted logistic regression models and hierarchical logistic regression accounting for covariates. We also assessed for race-income interaction. Results: Among 322007 individuals with HFrEF diagnosis, 136,613 had ≥6 months of complete data. Of the patients eligible for ARNI, only 5.4% (7409/136613) received a claim within 180 days of HFrEF diagnosis. After adjusting for social and clinical factors, the odds were elevated for ARNI claim within 180 days of HFrEF diagnosis (OR=1.38, 95% CI: 1.27, 1.49) for the highest income category (>$100K) compared with the lowest ($100K. Conclusions: Higher patient income is associated with increased likelihood of an ARNI claim within 180 days of HFrEF diagnosis, even after adjusting for socioeconomic and clinical factors. Future analyses are needed to determine other social factors associated with delay in ARNI initiation and long-term adherence.

Background Heart failure (HF) and breast cancer are 2 of the leading causes of death in postmenopausal women. The temporal association between HF and breast cancer in postmenopausal women has not been described. Objectives This study sought to examine the temporal association between HF and breast cancer. Methods Postmenopausal women within the WHI (Women’s Health Initiative) cohort were studied. All prevalent HF and prevalent breast cancer at enrollment were self-reported. Incident hospitalized HF and breast cancer diagnoses were adjudicated through 2017. Results Among a cohort of 44,174 women (mean age 63 ± 7 years), 2,188 developed incident invasive breast cancer and 2,416 developed incident hospitalized HF over a median follow-up of 14 and 15 years, respectively. When compared with a breast cancer- and HF-free cohort, there was no association between prevalent HF and incident invasive breast cancer and similarly, there was no association between prevalent breast cancer and incident hospitalized HF. Across the entire cohort, the median survival after incident hospitalized HF was worse compared with an incident invasive breast cancer diagnosis (5 and 19 years, respectively). In women with incident invasive breast cancer, prevalent HF was associated with an increased risk of mortality (hazard ratio: 2.28; 95% confidence interval: 1.31 to 3.95). In women with incident hospitalized HF, prevalent breast cancer was associated with an increased risk of mortality (hazard ratio: 1.66; 95% confidence interval: 1.03 to 2.68). Cause of death after incident HF was different only in women with prevalent and interim breast cancer compared with those without prevalent and interim breast cancer. Conclusions In postmenopausal women, prevalent HF was not associated with a higher incidence of breast cancer and vice versa. However, the presence of incident invasive breast cancer or incident HF in those with prevalent HF or prevalent breast cancer, respectively, was associated with increased mortality., Central Illustration

The PARADIGM-HF (Prospective Comparison of Angiotensin II Receptor Blocker Neprilysin Inhibitor With Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Mor...

Background Patients with cardiac amyloidosis (CA) have increased mortality, which can be explained in part by an increased risk of arrhythmias. The burden of arrhythmias in CA, their predictors, and impact on in‐hospital outcomes remains unclear. The role of implantable cardioverter‐defibrillators (ICD) in this population is also uncertain. Methods We queried the National Inpatient Sample (NIS) using ICD‐9‐CM codes 277.39 and 425.7 to identify CA. Twelve common arrhythmias were extracted using appropriate, validated ICD‐9‐CM codes. ICD implantation was identified using procedure ICD‐9 codes 37.94 to 37.98, 00.51 and 00.54. Results There were a total of 145,920 CA hospitalizations between 1999 and 2014 in the United States and 56,199 (38.5%) of them were associated with arrhythmias. The prevalence of arrhythmias remained relatively constant from 41.5% in 1999 to 40.2% in 2014. The most common arrhythmia was atrial fibrillation (25.4%). In‐patient mortality was significantly higher in CA patients with arrhythmias (10.4% vs 6.5%, P, Arrhythmias are common in patients with Cardiac amyloidosis with most common being atrial fibrillation. These are associated with worse in‐hospital outcomes, increased length of stay, and cost of hospitalization.

Background Women differ from men in their left ventricular (LV) structure, function and remodeling with age and diseases. The LV assist device (LVAD) unloads the LV and reversely remodels the heart. We sought to define the effects of sex on longitudinal reverse remodeling after LVAD implantation. Methods and Results Cardiac structure and function were assessed by serial echocardiograms. Mixed effect regression models were constructed to assess the independent contribution of sex to longitudinal changes in cardiac structure and function. A total of 355 consecutive patients with advanced heart failure received continuous flow LVADs between 2006 and 2016. The average age was 56 ± 13 years, 73% were men, and 67% were black. Early (within 3 months) after LVAD implantation, women had a greater reduction in LV dimensions and a greater increase in LV ejection fraction compared with men. These differences were independent of age, body surface area, device type, or ischemic etiology of heart failure. At long-term follow-up, LV dimensions increased slightly over time in women compared with men, but overall, earlier changes were maintained. Conclusion Women had significantly more favorable longitudinal changes in cardiac structure and function in response to LV unloading compared with men. Understanding the cause of sex difference in reverse remodeling after LVAD may help to devise novel therapeutic strategies for women with advanced heart failure.

Background Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (ACEIs-ARBs) improve outcomes in heart failure (HF). Less is known about this association in nursing home (NH) residents. Methods Of the 8024 hospitalized HF patients, 542 were NH residents, of whom 250 received ACEIs-ARBs. We assembled a propensity score-matched cohort of 157 pairs of NH residents receiving and not receiving ACEIs-ARBs balanced on 29 baseline characteristics (mean age, 83 years, 74% women, 17% African American), in which we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for outcomes associated with ACEI-ARB use. We then checked for interaction in a matched cohort of 5130 patients (378 were NH residents) assembled from the 8024 patients. Results Among 314 matched NH residents, HRs (95% CIs) for 30-day all-cause readmission, HF readmission, and all-cause mortality were 0.78 (0.47-1.28), 0.68 (0.29-1.60), and 1.26 (0.70-2.27), respectively. Respective HRs (95% CIs) at 1 year were 0.76 (0.56-1.02), 0.68 (0.42-1.09), and 1.04 (0.78-1.38). Among 5130 matched patients, ACEI-ARB use was associated with a significantly lower risk of all outcomes at both times, with no significant interactions, except for 1-year mortality, which was only significant in the non-NH subgroup (P for interaction, 0.026). Conclusions We found no evidence that the use of ACEIs or ARBs is associated with improved outcomes in patients with HF in the NH setting. However, we also found no evidence that this association is different in NH residents with HF versus non-NH patients with HF. Future larger studies are needed to demonstrate effectiveness of these drugs in the NH setting.

Objective To evaluate the outcomes of men diagnosed with prostate cancer (CaP) following implanted treatments for advanced heart failure. Given the increasingly favorable 10-year life expectancy, MedStar Washington Hospital Center screens heart transplant (HT) candidates for CaP and other malignancies prior to intervention. Methods Men aged 18-90 with available pretransplant Prostate Specific Antigen (PSA) who underwent left ventricular assist device (LVAD) and/or HT at MedStar Washington Hospital Center from 2007 to 2018 were identified. Serum PSA, CaP diagnosis, and treatment were captured and analyzed. Survival was analyzed using Kaplan-Meier curves. Results Data were available for 34 patients. Median age was 53 [IQR = 51-58]. Median follow-up was 77 months (95% CI = 40-87 months). Six men had postimplant elevated PSA (5.3; SD = 8.5) and 4 were diagnosed with CaP. Median age of CaP diagnosis was 59 [IQR = 58.5-62). As of 2018, 31 of the 34 patients were living, and none died from CaP. Five-year survival was 96% in those without CaP and 100% in those with CaP (Figure 2). Conclusion Our cohort represents the largest known cohort with heart failure treated by LVAD and/or HT and CaP. Our median age of 59 at CaP diagnosis is considerably younger than the national median of 66. 1 Of the 4 individuals diagnosed with CaP, 3 had high-grade disease. Given the favorable long-term survival of these patients post-LVAD and/or HT, age-appropriate treatment for CaP should be continued postimplantation.

Heart transplantation is the most effective long-term therapy for end-stage heart disease. There is limited data related to sudden cardiac arrest (SCA) in postheart transplant recipients. We aimed to describe the trends, and rate of SCA following heart transplantation and thereby identify clinical predictors as well as outcomes of SCA in patients post-transplant. We queried the National Inpatient Sample (NIS) with administrative codes for SCA and heart transplant. We assessed baseline differences between SCA and non-SCA admissions, with hazard ratios adjusted for age, gender, CCI, and race. Multivariable logistic regression models were generated to identify the independent predictors for SCA. There was a total of 30,020 hospitalizations of heart transplant recipients between 1999 and 2014 in the United States and among these 1,953 patients (6.5%) suffered SCA with an increasing trend of admissions for SCA. Among the patients who suffered from SCA, 18.83% died during the same hospitalization, 19.29% were discharged to a long-term facility, and 61.38% were discharged home. Multivariate analysis demonstrated that conduction system disorders (Hazard ratio [95% confidence interval]; 7.1 [4.5-11.1]), female gender (HR:1.2 [1.1-1.3]), diabetes (HR:1.4 [1.2-1.6]), and hypertension (HR:1.2 [1.1-1.4]) were the strongest predictors for SCA. SCA hospitalizations occur in 6.5% of patients post cardiac transplant and have been increasing from 1999 to 2014. Conduction block, graft rejection, female gender, hypertension, diabetes are independent predictors for SCA in heart transplant recipients.

Durable mechanical circulatory support (MCS) therapy improves survival in patients with advanced heart failure. Knowledge regarding the outcomes experienced by patients with inflammatory cardiomyopathy (CM) who receive durable MCS therapy is limited.We compared patients with inflammatory CM with patients with idiopathic dilated CM enrolled in the STS-INTERMACS registry. Among 19,012 patients, 329 (1.7%) had inflammatory CM and 5978 had idiopathic dilated CM (31.4%). The patients with inflammatory CM were younger, more likely to be White, and women. These patients experienced more preoperative arrhythmias and higher use of temporary MCS. Patients with inflammatory CM had a higher rate of early adverse events (3 months after device implant), including bleeding, arrhythmias, non-device-related infections, neurologic dysfunction, and respiratory failure. The rate of late adverse events (≥3 months) was similar in the 2 groups. Patients with inflammatory CM had a similar 1-year (80% vs 84%) and 2-year (72% vs 76%, P = .15) survival. Myocardial recovery resulting in device explant was more common among patients with inflammatory CM (5.5% vs 2.3%, P.001).Patients with inflammatory CM who received durable MCS appear to have a similar survival compared with patients with idiopathic dilated CM despite a higher early adverse event burden. Our findings support the use of durable MCS in an inflammatory CM population.

Background Multi-detector gated cardiac computed tomography (CCT) allows three-dimensional (3D) quantification of cardiac chambers and is clinically indicated to assess left ventricular assist device (LVAD) malfunction and complications. Automated volumetric analysis is, however, disrupted by inflow cannula artifact in patients with LVAD. With this study, we evaluated intra-observer variability in semi-automated 3D cardiac volumetric analysis using CCT in patients with LVADs. Methods Ten clinically indicated CCTs were studied retrospectively from 9 patients with LVADs. 3D chamber quantification included left and right ventricles end-systolic and end-diastolic volumes (ESV, EDV); and left and right atrial ESV. Derived measurements included cardiac output (CO), ejection fraction (EF), and stroke volume (SV). Automated volumetric analysis was performed, and manual corrections were added when necessary. Absolute and relative differences, Bland-Altman plots, and interclass correlation coefficients (ICCs) were used to assess intra-observer reproducibility for these measurements. Results Intra-observer reproducibility was excellent for volumetric (ICC >0.99) and derived data (ICC >0.91). Comparing right vs left heart volumetric assessments, the former had a higher relative difference (atria 2.8% vs 1.6%, ESV 3.0% vs 1.9%, EDV 2.7% vs 1.3%), which also translated to a greater relative difference in right-side derived data (CO 11.1% vs. 8.8%, EF 10.5% vs. 9.9%, SV 10.9% vs. 9.0%). The mean difference in left ventricular ejection fraction was 0.4% (limits of agreement [LOA]: −2 and 3.2) and right ventricular ejection fraction was 1.2% (LOA: −4.7 and 7.1). Conclusions Our results for semi-automated 3D volumetric analysis showed excellent reproducibility for both volumetric and derived data. Summary Electrocardiography-gated cardiac computed tomography with semi-automated volumetric analysis has excellent reproducibility in patients with left ventricular assist device making it imaging modality of choice for functional assessment in this patient population, where cardiac magnetic resonance imaging is contraindicated and transthoracic echocardiography may be limited by poor acoustic windows.

Background Amyloidosis is a group of protein-folding disorders characterised by organ deposits, derived from one of several amyloidogenic precursor proteins. The involvement of coronary arteries has been previously described in amyloidosis, however the pattern of the disease in the coronaries is still unknown. Purpose The aim of this study is to characterise the pattern and severity of coronary artery lesions in cardiac amyloidosis. Methods We retrospectively compared patients with heart failure who tested positive (i.e. biopsy or gene tests – HF/CA+) against those that tested negative (HF/CA−) for cardiac amyloidosis. Groups were compared demographically and angiographically for qualitative and quantitative variables to determine patterns of involvement in the major epicardial coronary vessels. Results In total, 110 heart failure patients were included in the study, of whom 55 were HF/CA+ patients (88 lesions) and 55 were HF/CA− patients (66 lesions). Despite the advanced age in the HF/CA+, (74.53±11.02 vs 54.11±15.08; p=0.05), severe calcification was reported in HF/CA− group (4.5% vs to 0.0%; p=0.018). The HF/CA+ group also had fewer ostial lesions (3.4% vs. 15.15%, p=0.0095), reduced TIMI flow grade (83% vs 76%; p=0.21) and a higher TIMI frame count (30±12 Vs 27±11 frames; p=0.06). In the HF/CA+ group, compared to women, men had a significant number of tandem lesions (14.55% vs 0.0%, p=0.02). Men trended to have more ulcerations in comparison to women (9.09% vs 0.0%; p=0.15). Conclusion Overall, patients with HF/CA+ were older but found to have lesser calcified lesions, ostial involvement and a reduced anterograde blood flow. This is the first report outlining the coronary lesions in patients with HF/CA+. Funding Acknowledgement Type of funding source: None

BACKGROUND: Digoxin use has been associated with a lower risk of 30‐day all‐cause admission and readmission in patients with heart failure and reduced ejection fraction (HFrEF). HYPOTHESIS: Digoxin use will be associated with improved outcomes in patients with HFrEF receiving β‐blockers. METHODS: Of the 3076 hospitalized Medicare beneficiaries with HFrEF (EF

Purpose Despite significant advances in US CV health, ethnic disparities in outcomes persist. The prognosis of HF among African-Americans (AA) is less favorable than other groups. The impact of race on durable LVAD outcomes is not well defined. We therefore sought to determine the characteristics and long term outcomes of AA LVAD recipients. Methods We performed a retrospective review of all LVAD recipients at a single center from October 1, 2006 to June 30, 2019. We compared clinical characteristics of AAs to non-AAs. Survival and rates of adverse events (AEs) for AA patients (pts) were determined. 571 pts were included in the analysis. Results 394 AA (69% of the population) underwent LVAD implantation. The mean follow up time of AA cohort was 670+617 days. The AA group was younger (54+13 vs 60+13, p Conclusion In the largest ever reported cohort of AA LVAD recipients, AA were shown to have excellent long term survival with rates of AEs comparable to those reported in published clinical trials. Further research is warranted to determine predictors of survival in AA pts.

Purpose Patients who suffer from device malfunction after axial-flow left ventricular assist device (af-LVAD) implantation often require device exchange. Although af-LVAD to af-LVAD exchange is reported as a safe procedure, rate of recurrent malfunction remains high. We hypothesized that af-LVAD to centrifugal-flow LVAD (cf-LVAD) exchange is associated with lower rate of recurrent malfunction requiring repeat exchange compared to af-LVAD to af-LVAD exchange. Methods We retrospectively reviewed all patients who underwent af-LVAD implantation between 5/2011 and 3/2019 at out institution. Of these, 31 patients underwent 43 device exchanges either to af-LVAD (AE group, N = 29) or to cf-LVAD (CE group, N = 14). Results Reasons of device exchange in the AE group were pump thrombosis in 19 (66 %), infection in 1 (3 %) and others in 9 (31 %), and those in the CE group were pump thrombosis in 8 (58 %), infection in 3 (21 %) and others in 3 (21 %). There was no difference in baseline characteristics between the groups except higher rate of more than mild aortic insufficiency in the CE group (CE; 50 % vs AE; 0 %, P Conclusion Af-LVAD to cf-LVAD exchange is a safe procedure for af-LVAD patients who require device exchange, and possibly decrease recurrent device malfunction event requiring repeat device exchange.

Background: Optimization of health care delivery in different settings with the goal of improving quality of life and reduction of heart failure (HF) morbidity continues to be an unmet need. Digital engagement between patients and providers is becoming more prevalent for care coordination and management of heart failure.Aims: To design and test a customized and interactive heart failure disease specific functionality with activated technology (Amazon's Echo Dot or an Avatar) as a tool for management of HF patients at home. To identify the effect of a voice activated technology in the reduction of heart failure hospitalizations, improvement of medication adherence, improvement in health-related quality of life and increase in comfort with voice activated technologies. Methods We compared two types of conversational agent technologies to standard of care, using speech recognition, to evaluate patient engagement in HF patients. The first technologyutilized the Amazon Echo Dot Alexa technology and only communicated with the patient through audio and the second was an application on a tablet using an Avatar, combining audio and visual. The conversational agent asks the HF patients a series of 11 questions, divided into three components: compliance (questions 1-3), mild HF symptoms (questions 4-6) and moderate/severe HF symptoms (questions 7-11). Participants completed questions regarding their use and comfort with technology. Inclusion criteria: admitted or treated for HF;18 or older; and resides with access to wifi. Exclusion criteria: heart transplant or ventricular assist device recipients. Participants were monitored for three months.Results: Thirty patients were enrolled in each intervention arm of the two studies with the Alexa or Avatar. Mean age was 54 years in the Alexa group and 56 years in the Avatar group. There were predominately males 61% and 63%, Alexa and Avatar, respectively. In the Alexa and Avatar groups race was predominately black, 64% and 63% followed by white 21% and 30%. The Alexa group was statistically more likely to complete the three compliance factors of weight checking (p=.030), salt monitoring (p=0.016) and medication adherence (p=0.005). Initial results suggest that older people and individuals using the smart phone answer the questionnaire at higher rates, and individuals taking an increased number of medications to treat HF had lower participation.Conclusion: Voice enabled, internet connected devices are poised to have profound impacts on the quality of life for in-home, independent, and assisted-living patients by vastly increasing the connectivity to healthcare providers.

e19335 Background: Left ventricular assist devices (LVAD) are increasingly utilized in advanced heart failure (HF). There is a paucity of data regarding outcomes of cancer-directed therapies (CDT) in patients with LVAD. The aim of this study was to describe outcomes in this newly identified group of patients. Methods: Institutional LVAD database review to identify patients with cancer diagnosis who had at least 6 months of follow up. Chart review to capture cancer history, CDT and high-severity complications. Results: 12 of the 588 patients who received LVAD were diagnosed with cancer and received CDT. Six patients were males, 9 African Americans and 3 Caucasians. Ischemic cardiomyopathy (CM) was the etiology of HF in 4 (33%) patients, 9 (66%) patients had non-ischemic CM (including: chemotherapy induced n = 3, idiopathic n = 3, myocarditis n = 1, sarcoidosis n = 1). Cancer diagnoses, staging and high severity complications are described in table. The median age of cancer diagnosis was 59 (41-72). The median time from LVAD placement to cancer diagnosis was 21.5 months (3-47). The median number of hospitalizations was 4 (range 1-7). Conclusions: Cancer diagnosis after LVAD placement requires a multidisciplinary approach due to high rates of adverse cardiovascular and cancer related outcomes. To the best of our knowledge this is the first report of patients with LVAD receiving chemo-immunotherapy, they did not tolerate the combination and immunotherapy was discontinued after one cycle, a larger study is required to assess safety in LVAD patients. Larger prospective studies are required to determine outcomes in this complex patient population. [Table: see text]

Purpose A thoracotomy approach for left ventricular assist device implantation is theoretically beneficial in patients who had previous sternotomy. The aim of this study is to investigate short-term outcomes of a thoracotomy approach versus a re-do sternotomy approach for left ventricular assist device implantation in patients with previous sternotomy. Methods We retrospectively reviewed 227 patients who underwent left ventricular assist device (HeartWare, HVAD) implantation between 7/2011 and 1/2019. Of these, 52 had a previous sternotomy. Twenty-eight patients were excluded because they had an extracorporeal ventricular assist device, cardiac surgery during the same hospitalization, concomitant procedures or an alternative outflow graft anastomosis at the time of the implantation. The study cohort was divided in two groups based on incision approach: a left anterior thoracotomy approach (LAT group, N=14) and a re-do sternotomy approach (RS group, N=10). Results Previous cardiac surgeries of the cohort were coronary artery bypass grafting (CABG) in 16 patients, aortic valve replacement (AVR) in 1, mitral valve (MV) replacement in 1, MV repair in 1, CABG + AVR in 1, CABG + MV repair in 1, atrial septal defect closure in 2, and heart transplant in 1. There was no difference in baseline characteristics between the groups. Median cardiopulmonary bypass time was similar, though median operative time in the LAT group was longer than that in the RS group (LAT; 267 mins vs RS; 235 mins). There was no statistical difference in postoperative short-term outcomes between the groups, except the LAT group required less postoperative red blood cell transfusion compared to the RS group (LAT; 57 % vs RS; 100 %, P = 0.024). Conclusion A thoracotomy approach was feasible alternative in patients with previous cardiac surgery and associated with less blood transfusion requirement compared with a re-do sternotomy approach.

Purpose Excellent outcomes following HM3 LVAD implantation have been reported in the setting of a large multicenter randomized controlled trial. Real world experience reports with this device are still limited. We sought to review our experience with this fully magnetically levitated LVAD. Methods The first 125 consecutive patients who received a HM3 LVAD at our institution from October 1, 2015 to August 30, 2019 were analyzed. Pump exchange procedures were excluded. We investigated clinical outcomes including survival and the development of postoperative complications. Results All devices were implanted via median sternotomy. Mean patient age was 57.5 ± 11 years, 72 % were males and 74% African-Americans. Idiopathic dilated cardiomyopathy was the most common diagnosis (73%). 67 % of the patients were INTERMACS profiles 1 or 2. 19 % of devices were implanted as bridge to transplant and 59% as destination therapy. Mean body-mass index at the time of implant was 30.5 ± 8 Kg/m2. Mean creatinine level was 1.29 ± 0.4 mg/dl and mean bilirubin was 1.45 ± 1.6 mg/dl. The mean length of stay during index admission for LVAD was 30 ± 17 days and the mean follow-up time was 411 ± 34 days. The rate of complications measured as EPPY was 0.42 for GI bleeding, 0.03 for ischemic stroke, 0.01 for hemorrhagic stroke, 0 for clinically suspected pump thrombosis or confirmed pump thrombosis, 0.22 for LVAD related infection, 0.16 for other systemic infection and 0.59 for acute heart failure. Survival was estimated at 96%, 91%, 88%, 81% and 74% at 30-day, 90-day, 1-year, 2-year, and overall 3-year follow-up, respectively (Figure). Conclusion In this single center, real world experience, HeartMate 3 implantation was associated with excellent survival comparable to those demonstrated in a recent clinical trial. The incidence of complications was also low, including no episodes of suspected or confirmed pump thrombosis.

Purpose Serial measurements of lactate levels are commonly performed after LVAD implantation, but the prognostic implications have not been well studied. The objective of this study is to evaluate the association of lactic acid levels with in-hospital mortality, after LVAD implantation. Methods We retrospectively identified all patients at our Institution who underwent implantation of a durable LVAD between 1/1/2009 and 12/1/2018 and had lactate levels recorded in the immediate 48-hour postoperative period (n=507). We excluded patients who received biventricular mechanical support (N=19). Baseline characteristics were compared using T-test/Wilcoxon rank-sum test and Chi squared test. Multivariable logistic regression was used to assess peak-lactate levels between those who were discharge alive after index LVAD implant hospitalization (S-group) vs. those who died during the index hospitalization (M-group). Results A total of 488 patients were included in the analysis. The baseline characteristics of the S-group (N=432) and the M-group (N=56) are compared in the Table. The two groups had similar preimplant lactate levels (1.1 [0.9-1.4] vs. 1.0 [0.9-1.3] mmol/L, p=0.72). However, peak lactate levels were significantly lower in the S-group compared to the M-group (2.8 [2.0-4.2] vs. 4.6 [2.8-6.9] mmol/L, p Conclusion Lactate level in the first 48-hours after LVAD implantation surgery is an independent predictor of mortality. Further research is needed to assess the mechanisms responsible for elevated postoperative lactate levels and whether targeted therapy will improve clinical outcomes. Baseline Characteristics

Purpose The HeartMate 3 (HM3) LVAD has demonstrated the lowest rates of hemocompatibility adverse events (AEs) in randomized controlled trials. Despite this success, rate of bleeding remains high. HM3 instruction for use recommends starting parenteral heparin 12-24 hours after device implantation or when chest tube drainage is 2 days post implant). The aim of the study is to evaluate the association of thrombotic and hemorrhagic events with delayed heparin initiation in HM3 recipients Methods We performed a retrospective analysis of all HM3 patients implanted at a single center from Oct 1, 2015 to Jun 30, 2019. Patients who received IV heparin ≤2 days after implant were excluded from the analysis (n=6) Results 113 patients were included in the analysis. Mean follow up time was 382±331 days. Mean age was 57±12 years. The cohort was predominantly men (72%), African-American (77%) with a NICM etiology (74%). HM3 implantation as DT represented 54% of the population (BTT 26%). 18% of patients had a history of CVA pre-implant, 2% had history of GIB. The mean time to heparin initiation was 5±2 days. Mean time to warfarin and ASA initiation was 11±9 and 2+6 days respectively. The rates of neurologic event, and hemorrhagic/ischemic CVAs were numerically similar to the rates seen in clinical trials. No confirmed pump thrombosis event was seen. The rate of GI bleeding was higher than seen in trials. Overall, the survival of this cohort was 88% and 84% at 1 and 2 years, respectively Conclusion In this single center study, a strategy of delayed heparin initiation post HM3 implantation does not appear to increase the risk of CVA or pump thrombosis. A prospective clinical study is warranted.

Purpose Outcomes of patients with small body size following HM3 LVAD implantation have not been well characterized. We sought to compare preoperative characteristics and clinical outcomes among patients stratified by body surface area. Methods Patients who received a HeartMate 3 LVAD at our institution between October 1, 2015 and June 30, 2019 were analyzed. Patients who received a HM3 LVAD as pump exchange were excluded. The cohort was divided in 4 groups: BSA ≤1.8 m2 (group 1), BSA >1.8 - ≤2.0 m2 (group 2), BSA >2.0 - ≤2.2 m2 (group 3) and BSA >2.2 (group 4). Results One hundred and nineteen patients were included in this analysis. Preoperative characteristics and postoperative results of each group are shown in Table 1. Group 1 patients were older and mostly females. A history of diabetes was less common in this group. Mean postoperative length of stay was similar between groups. Pump speed at the time of discharge was lower in group 1 patients. Mean follow-up was similar between groups. Mean days out of the hospital after discharge did not differ among the groups. One-year survival was 93% for group 1, 85% for group 2, 86% for group 3 and 84% for group 4 (p=0.69). Kaplan Meier survival curves are shown in Figure 1 (log rank: 0.692). Conclusion Outcomes following HM3 LVAD implantation were comparable between patients with small body surface area and patients with larger body size. Small body size should not be an exclusion criteria for HM3 LVAD implantation in patients with advanced heart failure who are otherwise candidates for durable mechanical support.

Purpose Outcomes in patients with small left ventricular end diastolic diameter (LVEDD) following HM3 LVAD implantation have not been well characterized. We sought to compare the clinical outcomes of patients with small LVEDD to those with dilated left ventricles. Methods Patients who received a HeartMate 3 LVAD at our institution between October 1, 2015 and June 30, 2019 were analyzed. Patients who received a HM3 LVAD as a pump exchange were excluded. The cohort was divided in 2 groups: smaller LVEDD (≤60 mm in males and ≤58 mm in females) and larger LVEDD (>60 mm in males and >58 mm in females). Results One hundred and nineteen patients underwent HeartMate 3 LVAD implantation at our institution. Patients in the smaller LVEDD group (n: 22) had a mean LVEDD of 55.7±5 mm and patients in the larger LVEDD group had a mean LVEDD of 70.6±8 mm (p= Conclusion Adult patients with smaller LVEDD who received a HeartMate 3 LVAD have comparable clinical outcomes to patients with larger LVEDD. A small left ventricle should not be a contraindication to implantation of this particular durable device in adult patients.

Purpose Cardiopulmonary exercise testing (CPET) is well validated for prognostication before advanced surgical heart failure therapies but its role in prognostication after LVAD surgery has never been studies. Methods All CPET studies from a single institution were collected between September 2007 and March 2018. Patients who ultimately underwent LVAD implantation were selectively analyzed. Peak VO2, and VE/VCO2 slope were measured for all patients. We evaluated their association with hemodynamic and clinical markers of RV dysfunction as well mortality. Results 449 patients underwent CPET testing. 120 patients were ultimately referred to the advanced heart failure program and 61 patients later received LVAD implantation (18 axial flow, 43 centrifugal flow, 70% male). CPET testing occurred 554 ± 624 days before LVAD and RHC occurred 232 ± 243 days after LVAD. Patients with a ventilatory class of III or greater (VE/VCO2 slope of ≥ 36, n = 38) had greater rates of death (21% vs. 0%, p = 0.02) than patients with VE/VCO2 slope Conclusion Elevated preoperative VE/VCO2 slope is a predictor of post-operative mortality and is associated with post-operative hemodynamic markers of impaired RV performance.

Purpose Advanced kidney disease is often considered a relative contraindication to LVAD implantation and many implanting centers view stage 4 and 5 chronic kidney disease (CKD) as an absolute contraindication. We sought to analyze the impact of CKD at the time of LVAD implant on outcomes. Methods All LVAD patients between September 2007 and September 2017 with CKD at the time of LVAD implantation from a single institution were analyzed. Patients were stratified by CKD stage (CKD 1 through 5) at the time of implant and rates of worsening renal function, need for renal replacement therapy (RRT), hospitalizations, LVAD-related complications and death were analyzed. Results Of the 405 total patients, 191 patients (59% centrifugal, 80% male, average age 59 ± 11 years) had varying degrees of renal dysfunction at the time of LVAD implantation (17% CKD 1 or 2, 35% CKD 3a, 34% CKD 3b and 15% CKD 4 or 5). Patients with CKD 4 or 5 were more likely to require RRT than lesser CKD Stages 3b, 3a, and 1 or 2 (37.9% vs. 3.1%, vs. 7.6% vs. 0%, p trend Conclusion Patients with advanced CKD at the time of LVAD implant were more likely to have persistent renal dysfunction and require RRT thereafter. However, there were no statistically significantly differences in LVAD-related morbidity and mortality across the stages of CKD.

Despite increasing recognition of the importance of right ventricular (RV) dysfunction (RVD) in the pathophysiology of left heart disease, our understanding of its epidemiology in heart failure (HF) with preserved ejection fraction (HFpEF) remains incomplete. In part, this is due to complex RV geometry and challenging and inconsistent assessment of RV function . Consequently, the prevalence of RVD in HFpEF varies widely depending on study design and population characteristics; however, on average is observed in one third of HFpEF subjects. In these patients, RVD is most commonly associated with an advanced HF state, pulmonary hypertension, atrial fibrillation, right ventricular pacing, and tricuspid valve regurgitation. Whether these associations are causal remains uncertain.Right ventricular dysfunction is recognized to confer poor outcomes in patients with HFpEF, including increased HF hospitalization and higher overall and cardiovascular mortality. Moreover, the prognostic significance of RVD in HFpEF is independent of, and additive to, the severity of pulmonary hypertension. As greater emphasis is placed on phenotyping subgroups of patients with HFpEF in order to tailor therapeutic strategies, improved characterization of the large subset of HFpEF patients with RVD, with and without antecedent pulmonary hypertension may yield critical insights, which inform novel therapeutic interventions.

A lower heart rate is associated with better outcomes in patients with heart failure (HF) with reduced ejection fraction (EF). Less is known about this association in patients with HF with preserved ejection fraction (HFpEF).The aims of this study were to examine associations of discharge heart rate with outcomes in hospitalized patients with HFpEF.Of the 8,873 hospitalized patients with HFpEF (EF ≥50%) in the Medicare-linked OPTIMIZE-HF (Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure) registry, 6,286 had a stable heart rate, defined as ≤20 beats/min variation between admission and discharge. Of these, 2,369 (38%) had a discharge heart rate of 70 beats/min. Propensity scores for discharge heart rate 70 beats/min, estimated for each of the 6,286 patients, were used to assemble a cohort of 2,031 pairs of patients with heart rate 70 versus ≥70 beats/min, balanced on 58 baseline characteristics.The 4,062 matched patients had a mean age of 79 ± 10 years, 66% were women, and 10% were African American. During 6 years (median 2.8 years) of follow-up, all-cause mortality was 65% versus 70% for matched patients with a discharge heart rate 70 versus ≥70 beats/min, respectively (hazard ratio [HR]: 0.86; 95% confidence interval [CI]: 0.80 to 0.93; p 0.001). A heart rate 70 beats/min was also associated with a lower risk for the combined endpoint of HF readmission or all-cause mortality (HR: 0.90; 95% CI: 0.84 to 0.96; p = 0.002), but not with HF readmission (HR: 0.93; 95% CI: 0.85 to 1.01) or all-cause readmission (HR: 1.01; 95% CI: 0.95 to 1.08). Similar associations were observed regardless of heart rhythm or receipt of beta-blockers.Among hospitalized patients with HFpEF, a lower discharge heart rate was independently associated with a lower risk of all-cause mortality, but not readmission.

Background— Exercise intolerance is a hallmark of heart failure, but factors associated with impaired exercise capacity in heart failure with preserved ejection fraction are unclear. We hypothesized that in heart failure with preserved ejection fraction, the severity of resting ventricular and vascular dysfunction are associated with impairment in exercise tolerance as assessed by peak oxygen consumption. Methods and Results— Subjects with heart failure with preserved ejection fraction enrolled in the PhosphodiesteRasE-5 Inhibition to Improve CLinical Status And EXercise Capacity in Diastolic Heart Failure (RELAX) clinical trial (n=216) underwent baseline Doppler echocardiography, cardiopulmonary exercise testing, and cardiac MRI. RELAX participants were elderly (median age 69 years) and 48% were women. Ejection fraction (60%) and stroke volume (77 mL) were normal, while diastolic dysfunction (medial E / e ′, 16; deceleration time, 185 ms; left atrial volume, 44 mL/m 2 ) and increased arterial load (arterial elastance, 1.51 mm Hg/mL) were evident. Peak oxygen consumption was reduced (11.7 mLkg −1 min −1 , 1141 mL/min) and age, sex, body mass index, hemoglobin, and chronotropic response collectively explained 64% of the variance in raw peak oxygen consumption (mL/min). After adjustment for these variables, left ventricular structure (diastolic dimension [1.5%, P =0.008] and left ventricular mass [1.6%, P =0.008]), resting stroke volume (2.0%, P =0.002), left ventricular diastolic dysfunction (deceleration time [0.9%, P =0.03] and E / e ′ [1.4%, P =0.009]), and arterial function (arterial elastance [2.1%, P =0.002] and systemic arterial compliance [1.5%, P =0.007]), each explained only a small additional portion of the variance in peak oxygen consumption. Conclusions— In heart failure with preserved ejection fraction, potentially modifiable factors (obesity, anemia, and chronotropic incompetence) are strongly associated with exercise capacity, whereas resting measures of ventricular and vascular structure and function are not. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00763867

Objectives This study sought to determine the frequency of left ventricular amyloid in heart failure with preserved ejection fraction (HFpEF). Background Left ventricular amyloid deposition can cause diastolic dysfunction and HFpEF. Methods Autopsy of left ventricular specimens from patients with antemortem diagnosis of HFpEF without clinically apparent amyloid (n = 109) and from control subjects (n = 131) were screened with sulfated Alcian blue and subsequent Congo red staining with microdissection for mass spectrometry–based proteomics to determine amyloid type. Fibrosis was assessed with quantitative whole-field digital microscopy. Results The presence of wild-type transthyretin (wtTTR) amyloid was associated with age at death and male sex, but the age- and sex-adjusted prevalence of wtTTR amyloid was higher in HFpEF patients than in control subjects (odds ratio: 3.8, 95% confidence interval: 1.5 to 11.3; p = 0.03). Among HFpEF patients, moderate or severe interstitial wtTTR deposition, consistent with senile systemic amyloidosis as the primary etiology of HFpEF, was present in 5 (5%) patients (80% men), with mild interstitial and/or variable severity of intramural coronary vascular deposition in 13 (12%) patients. While, wtTTR deposition was often mild, adjusting for age and presence of HFpEF, wtTTR amyloid was associated with more fibrosis (p = 0.005) and lower age, sex, and body size–adjusted heart weight (p = 0.04). Conclusions Given the age- and sex-independent association of HFpEF and wtTTR deposition and an emerging understanding of the pathophysiology of the amyloidoses, the current findings support further investigation of the role of wtTTR in the pathophysiology of HFpEF.

Background— Atrial fibrillation (AF) is common among patients with heart failure and preserved ejection fraction (HFpEF), but its clinical profile and impact on exercise capacity remain unclear. RELAX (Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in HFpEF) was a multicenter randomized trial testing the impact of sildenafil on peak V O 2 in stable outpatients with chronic HFpEF. We sought to compare clinical features and exercise capacity among patients with HFpEF who were in sinus rhythm (SR) or AF. Methods and Results— RELAX enrolled 216 patients with HFpEF, of whom 79 (37%) were in AF, 124 (57%) in SR, and 13 in other rhythms. Participants underwent baseline cardiopulmonary exercise testing, echocardiogram, biomarker assessment, and rhythm status assessment before randomization. Patients with AF were older than those in SR but had similar symptom severity, comorbidities, and renal function. β-blocker use and chronotropic indices were also similar. Despite comparable left ventricular size and mass, AF was associated with worse systolic (lower EF, stroke volume, and cardiac index) and diastolic (shorter deceleration time and larger left atria) function compared with SR. Pulmonary artery systolic pressure was higher in AF. Patients with AF had higher N-terminal pro-B-type natriuretic peptide, aldosterone, endothelin-1, troponin I, and C-telopeptide for type I collagen levels, suggesting more severe neurohumoral activation, myocyte necrosis, and fibrosis. Peak V O 2 was lower in AF, even after adjustment for age, sex, and chronotropic response, and V E /V CO 2 was higher. Conclusions— AF identifies an HFpEF cohort with more advanced disease and significantly reduced exercise capacity. These data suggest that evaluation of the impact of different rate or rhythm control strategies on exercise tolerance in patients with HFpEF and AF is warranted. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00763867.

Background There is limited published literature on acute eosinophilic myocarditis (EM), a rare form of acute myocarditis, wherein eosinophils invade the myocardium with wide-ranging clinical sequalae. We aim to describe our experience in the largest contemporary case series of histologically-proven EM. Methods Two authors independently reviewed the surgical pathology and autopsy databases for acute EM (01/2009 to 12/2017). Only patients with endomyocardial biopsy/autopsy and clinical course consistent with acute EM were included. We abstracted demographic data, comorbidities, clinical diagnostics, and clinical outcomes. Results Seven patients had acute EM (Table). The average age was 53-years and five subjects were women. The most common etiology of EM was idiopathic. Five patients had peripheral eosinophilia. Three patients had elevated pulmonary capillary wedge pressure and three patients had reduced cardiac output. Six patients were treated with steroids, four of whom received IV pulse dosed steroids. Two patients required intra-aortic balloon pump support, one of whom subsequently underwent durable left ventricular assist device implantation. Two patients died during index hospitalization, one of septic shock and one of refractory ventricular tachycardia. Conclusion The etiologies, clinical presentation, and course of acute EM varied widely. Prompt diagnosis, treatment with immunosuppression, and circulatory support may reduce cardiovascular mortality in this population.

Purpose Advanced renal dysfunction is often viewed as a relative contraindication to durable left ventricular assist device (LVAD) implantation. We investigated the impact of early renal recovery on clinical outcomes after LVAD implantation. Methods All patients with baseline renal dysfunction who were implanted with a durable LVAD between September 2007 and September 2017 from a single institution were studied. Glomerular filtration rates at time of LVAD implant, 1 week, 1 month and 6 months after implant were collected. Early renal improvement was defined as an increase in eGFR of ≥ 15% within 1 week of implant (ΔGFR≥15%). Outcomes collected included index hospitalization length of stay (LOS), LVAD-related complications, hospitalizations and death. Results 405 patients were implanted with durable LVADs, of which, 191 patients (average age 59 years, 80% male, 73% African American, 46% bridge to transplant, 59% centrifugal) had varying degrees of renal dysfunction at implantation (17% CKD 1 or 2, 35% CKD 3a, 33% CKD 3b and 15% CKD 4 or 5). 68% of patients experienced ΔGFR≥15%. African American ethnicity and obesity (BMI 31.6 ± 6.9 vs. 28.7 ± 6.9, p =0.01) was associated with less renal improvement compared with their counterparts. Patients with ΔGFR≥15% were more likely to be CKD stage 1 or 2 six months after LVAD implant (53% vs. 22%, p = 0.005) (figure top). Index hospitalization LOS (39 ± 21 vs. 50 ± 32 days, p =0.02) was lower in patients with ΔGFR≥15% with fewer percutaneous endoscopic gastrostomy tube placement (4% vs. 15%, p = 0.02) and tracheostomy (6% vs 13%, p = 0.14). Patients with ΔGFR≥15% also had fewer heart failure readmissions (12% vs. 24%, p Conclusion Early improvement in renal function is associated with sustained renal recovery, decreased length of stay, fewer complications at index hospitalization and reduced heart failure readmissions.

Cardiac sarcoidosis has a wide range of manifestations. Fluorodeoxyglucose (FDG)-positron emission tomography (PET) scan and cardiac magnetic resonance imaging (CMR) are the two major diagnostic modalities for cardiac sarcoidosis, but may not detect isolated conduction system involvement. A 55 year

Multi-detector computed tomography is clinically indicated to assess left ventricular assist devices (LVAD) dysfunction, position, and device-related complications. With this study, we tried to evaluate intra-observer variability in quantitative three-dimensional (3D) volumetric analysis of all 4

Heart failure (HF) with preserved ejection fraction (HFpEF) has traditionally been viewed as a form of hypertensive heart disease with increased left ventricular (LV) afterload ultimately leading to HFpEF. However, HFpEF patients typically have numerous other comorbidities.1 Although the severity of LV remodeling and ventricular vascular dysfunction2 and the rate of adverse outcomes3 are greater in patients with HFpEF than in patients with comorbidities alone, some argue that HFpEF is not a distinct syndrome but rather a collection of comorbidities masquerading as HF. See Article by Srivaratharajah et al More recently, based on integrative physiological studies in human HFpEF, the biology of nitric oxide–cyclic guanosine monophosphate–protein kinase G signaling, and elegant studies of human HFpEF myocardium, Paulus and Tschope synthesized an alternate HFpEF pathophysiologic paradigm.1 This paradigm postulates that multimorbidity creates a systemic proinflammatory milieu, coronary microvascular endothelial inflammation, and migration of inflammatory cells to the myocardium with production of proinflammatory cytokines, myocardial inflammation, and subsequent fibrosis. Further, they propose that microvascular endothelial inflammation promotes oxidative stress with generation of oxidative/nitrosative species, which limits myocardial nitric oxide–cyclic guanosine monophosphate–protein kinase G signaling by diminishing nitric oxide bioavailability and oxidizing downstream nitric oxide targets, thus promoting cardiomyocyte hypertrophy. Impaired protein kinase G activity and peroxynitrite-stimulated phosphatases are proposed to alter the phosphorylation status of proteins that influence myofiber relaxation and stiffness and, thus, further impair LV diastolic function. This paradigm has sparked great interest in therapies that target impaired myocardial cyclic guanosine monophosphate–protein kinase G signaling in HFpEF. However, the Paulus paradigm has an important correlate in that an established consequence of coronary microvascular endothelial inflammation is impaired coronary microvascular endothelial function and ultimately coronary microvascular remodeling and rarefaction with decreased microvascular density (MVD).4 The potential impact of diffuse microvascular endothelial inflammation on the functional and …

Background—Right ventricular (RV) dysfunction (RVD) is a poor prognostic factor in heart failure with preserved ejection fraction (HFpEF). The physiological perturbations associated with RVD or RV function indexed to load (RV–pulmonary arterial [PA] coupling) in HFpEF have not been defined. HFpEF patients with marked impairment in RV–PA coupling may be uniquely sensitive to sildenafil.Methods and Results—In a subset of HFpEF patients enrolled in the Phosphodiesteas-5 Inhibition to Improve Clinical Status And Exercise Capacity in Diastolic Heart Failure (RELAX) trial, physiological variables and therapeutic effect of sildenafil were examined relative to the severity of RVD (tricuspid annular plane systolic excursion [TAPSE]) and according to impairment in RV–PA coupling (TAPSE/pulmonary artery systolic pressure) ratio. The prevalence of atrial fibrillation and diuretic use, n-terminal probrain natriuretic peptide levels, renal dysfunction, neurohumoral activation, myocardial necrosis and fibrosis biomarkers, and the severity of diastolic dysfunction all increased with severity of RVD. Peak oxygen consumption decreased and ventilatory inefficiency (VE/VCO2slope) increased with increasing severity of RVD. Many but not all physiological derangements were more closely associated with the TAPSE/pulmonary artery systolic pressure ratio. Compared with placebo, at 24 weeks, TAPSE decreased, and peak oxygen consumption and VE/CO2slope were unchanged with sildenafil. There was no interaction between RV–PA coupling and treatment effect, and sildenafil did not improve TAPSE, peak oxygen consumption, or VE/VCO2in patients with pulmonary hypertension and RVD.Conclusions—HFpEF patients with RVD and impaired RV–PA coupling have more advanced heart failure. In RELAX patients with RVD and impaired RV–PA coupling, sildenafil did not improve RV function, exercise capacity, or ventilatory efficiency.Clinical Trial Registration—URL:http://www.clinicaltrials.gov. Unique identifier: NCT00763867.

Heart failure with preserved ejection fraction (HFpEF) or diastolic heart failure (HF) accounts for approximately half of HF cases in the community, and the portion of HF with preserved ejection fraction (EF) is increasing.1 Patients with HFpEF have limited functional capacity and poor prognosis. With ongoing shifts in the age distribution of the population, the burden of HFpEF is projected to increase. To date, there is no proven therapy for HFpEF. There is an urgent need for effective therapies for HFpEF. To date, 3 randomized control trials in HFpEF have tested the impact of renin-angiotensin-aldosterone antagonists on clinical outcomes in HFpEF. None of these trials demonstrated benefit individually (Figure 1) or in a pooled analysis (n=8021).2 An aldosterone antagonist trial in HFpEF is ongoing (clinicaltrials.gov NCT00094302). A trial of the β-blocker nebivolol in HF patients with normal or reduced EF was underpowered but suggested a benefit of β-blocker in the relatively small subset of HFpEF patients (Figure 1).3 The digitalis investigation group (DIG) trial showed no reduction in mortality with digoxin in a small ancillary study of HFpEF patients.4 Figure 1. Previous randomized clinical trials in heart failure with preserved ejection fraction (HFpEF): Summary of the hazards ratios (95% CI) for the primary outcome measure of the large randomized placebo-controlled clinical trials in HFpEF to date. CHARM-Preserved indicates Candesartan in Patients With Chronic Heart Failure and Preserved Left Ventricular Ejection Fraction; I-PRESERVE, Irbesartan in Patients With Heart Failure and Preserved Ejection Fraction; PEP-CHF, Perindopril in Elderly People With Chronic Heart Failure; SENIORS, Study of Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors With Heart Failure; DIG, Digitalis Investigation Group Trial. Although inadequate power or crossover may have contributed to negative findings in these trials, unique pathophysiology in HFpEF may mediate the differential response to neurohumoral …