Background:Solid organ transplant (SOT) recipients with COVID-19 have a higher risk of mortality than those without COVID-19. However, it is unclear how SOT patient outcomes compare to the general population without SOT who contract COVID-19. Methods:We used the National Inpatient Sample from January to December 2020 to investigate inpatient outcomes seen in SOT recipients after contracting COVID-19 compared to nontransplant patients. We identified our study sample using ICD-10 CM and excluded those <18 years of age and those with dual organ transplants. Inpatient outcomes were compared in SOT and non-SOT COVID cohorts, and we further evaluated predictors of mortality in the SOT with COVID population. Results:Out of the 1,416,445 COVID-19 admissions included in the study, 8315 (0.59%) were single SOT recipients. Our analysis that adjusted for multiple baseline characteristics and comorbidities demonstrated that COVID-19 in SOT patients was associated with higher rates of acute kidney injury (adjusted odds ratio [aOR] 2.34, 95% confidence interval [CI] 1.81-3.02, P < 0.01), lower rates of acute respiratory distress syndrome (aOR 0.68, 95% CI 0.54-0.85, P < 0.01), and similar rates of cardiac arrest, pulmonary embolism, circulatory shock, cerebrovascular events, and in-hospital mortality. Age >65 was associated with mortality in SOT patients. Conclusion:In this nationally representative sample, SOT patients presenting with COVID-19 experienced similar rates of mortality compared to those without SOT. SOT patients were more likely to develop acute kidney injury. Further research is needed to understand the complex relationship between transplant patient outcomes and COVID-19.

BACKGROUND:In patients with heart failure and reduced ejection fraction, sleep-disordered breathing, comprising obstructive sleep apnoea (OSA) and central sleep apnoea (CSA), is associated with increased morbidity, mortality, and sleep disruption. We hypothesised that treating sleep-disordered breathing with a peak-flow triggered adaptive servo-ventilation (ASV) device would improve cardiovascular outcomes in patients with heart failure and reduced ejection fraction. METHODS:We conducted a multicentre, multinational, parallel-group, open-label, phase 3 randomised controlled trial of peak-flow triggered ASV in patients aged 18 years or older with heart failure and reduced ejection fraction (left ventricular ejection fraction ≤45%) who were stabilised on optimal medical therapy with co-existing sleep-disordered breathing (apnoea-hypopnoea index [AHI] ≥15 events/h of sleep), with concealed allocation and blinded outcome assessments. The trial was carried out at 49 hospitals in nine countries. Sleep-disordered breathing was stratified into predominantly OSA with an Epworth Sleepiness Scale score of 10 or lower or predominantly CSA. Participants were randomly assigned to standard optimal treatment alone or standard optimal treatment with the addition of ASV (1:1), stratified by study site and sleep apnoea type (ie, CSA or OSA), with permuted blocks of sizes 4 and 6 in random order. Clinical evaluations were performed and Minnesota Living with Heart Failure Questionnaire, Epworth Sleepiness Scale, and New York Heart Association class were assessed at months 1, 3, and 6 following randomisation and every 6 months thereafter to a maximum of 5 years. The primary endpoint was the cumulative incidence of the composite of all-cause mortality, first admission to hospital for a cardiovascular reason, new onset atrial fibrillation or flutter, and delivery of an appropriate cardioverter-defibrillator shock. All-cause mortality was a secondary endpoint. Analysis for the primary outcome was done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT01128816) and the International Standard Randomised Controlled Trial Number Register (ISRCTN67500535), and the trial is complete. FINDINGS:The first and last enrolments were Sept 22, 2010, and March 20, 2021. Enrolments terminated prematurely due to COVID-19-related restrictions. 1127 patients were screened, of whom 731 (65%) patients were randomly assigned to receive standard care (n=375; mean AHI 42·8 events per h of sleep [SD 20·9]) or standard care plus ASV (n=356; 43·3 events per h of sleep [20·5]). Follow-up of all patients ended at the latest on June 15, 2021, when the trial was terminated prematurely due to a recall of the ASV device due to potential disintegration of the motor sound-abatement material. Over the course of the trial, 41 (6%) of participants withdrew consent and 34 (5%) were lost to follow-up. In the ASV group, the mean AHI decreased to 2·8-3·7 events per h over the course of the trial, with associated improvements in sleep quality assessed 1 month following randomisation. Over a mean follow-up period of 3·6 years (SD 1·6), ASV had no effect on the primary composite outcome (180 events in the control group vs 166 in the ASV group; hazard ratio [HR] 0·95, 95% CI 0·77-1·18; p=0·67) or the secondary endpoint of all-cause mortality (88 deaths in the control group vs. 76 in the ASV group; 0·89, 0·66-1·21; p=0·47). For patients with OSA, the HR for all-cause mortality was 1·00 (0·68-1·46; p=0·98) and for CSA was 0·74 (0·44-1·23; p=0·25). No safety issue related to ASV use was identified. INTERPRETATION:In patients with heart failure and reduced ejection fraction and sleep-disordered breathing, ASV had no effect on the primary composite outcome or mortality but eliminated sleep-disordered breathing safely. FUNDING:Canadian Institutes of Health Research and Philips RS North America.

Introduction The COVID 19 pandemic fueled a rapid shift for medical care to be provided in a virtual or telehealth platform. Medications changes can be challenging to implement over the phone due to lack of data from physical exam findings and vital signs to support medical decision making. In-person visits allow for complete vital signs and proper physical examination to inform medical decision making. We sought to determine which types of cardiac care are best positioned to succeed in a telehealth environment and which require greater emphasis on in-person care. Methods We sought to determine what cardiology visit type was associated with a higher rate of medication changes and what factors informed those changes. We compared medication changes made between heart failure (HF), electrophysiology (EP), and general cardiology (GC) visits completed in-person in the pre-pandemic era. Number of medication changes, type of medication change, and clinical data used to implement medication changes were compared between the three providers types. Results During February 2020 each provider completed a total of 48 HF visits, 23 EP visits and 35 GC in-person visits. A total of 116 medication changes were made. HF visits were associated with the highest rate of medication changes per visit (1.79 changes per visit) followed by EP (0.61 changes per visit) and GC (0.46 changes per visit), overall p<0.001 (See Table). Individual comparisons showed that medication changes were made more frequently in HF compared to both EP and GC (each p<0.001). There was no statistical difference between frequency of medication changes between EP and GC (p=0.50). Types of medication changes included initiations, discontinuations, and dose titrations, each of which were made more frequently in HF. Medication changes were made during most HF visits but during only a minority of visits for EP and GC. Medication changes during HF visits were based on both vital sign and physical exam assessment most (67.5%) of the time, but rarely for EP or GC visits (0 and 18%, respectively). Conclusions Our study demonstrated that HF visits incorporate a higher rate of medication changes compared to EP and GC, and that these decisions were based on physical exam and vital signs more often compared to other cardiology sub-specialties. Despite a shift towards increased telehealth due to the pandemic, these data suggest that HF management may require more in-person visits compared to EP and GC, which appear more amenable to telehealth care delivery.

Volume recruitment from the splanchnic compartment is an important physiological response to stressors such as physical activity and blood loss. In the setting of heart failure (HF), excess fluid redistribution from this compartment leads to increased cardiac filling pressures with limitation in exercise capacity. Recent evidence suggests that blocking neural activity of the greater splanchnic nerve (GSN) could have significant benefits in some patients with HF by reducing cardiac filling pressures and improving exercise capacity. However, to date the long-term safety of splanchnic nerve modulation (SNM) in the setting of HF is unknown. SNM is currently used in clinical practice to alleviate some forms of chronic abdominal pain. A systematic review of the series where permanent SNM was used as a treatment for chronic abdominal pain indicates that permanent SNM is well tolerated, with side-effects limited to transient diarrhoea or abdominal colic and transient hypotension. The pathophysiological role of the GSN in volume redistribution, the encouraging findings of acute and chronic pilot SNM studies and the safety profile from permanent SNM for pain provides a strong basis for continued efforts to study this therapeutic target in HF.

Patients with heart failure (HF) who we take care of over many years don't exactly become "friends," but mutual bonds do form that transcend the strict doctor/patient relationship. They become more than simply "patients." We get to know family members, likes and dislikes, anecdotes from their lives, sometimes political stances, and more. And although they generally know a lot less about us than we do about them, they still often find out about major life events like births of kids and grandkids, marriages, and more, as well as random facts we might share. So when their HF takes a turn for the worse, it is very different than when we meet a patient for the first time who may be in dire straits or even dying, when it is somehow more purely clinical, and we as clinicians are a bit more detached. In patients we have know a long time, subtle differences also become easier to detect, including when things seem to be starting to go downhill and approaching later stages of disease. We may see it coming before saying anything to them, trying to gauge how to best time it so that things like end-of-life discussions occur at just the right time: not too early, not too late, sort of like Goldilocks.

Volume recruitment from the splanchnic compartment is an important physiological response to stressors such as physical activity and blood loss. In the setting of heart failure (HF), excess fluid redistribution from this compartment leads to increased cardiac filling pressures with limitation in exercise capacity. Recent evidence suggests that blocking neural activity of the greater splanchnic nerve (GSN) could have significant benefits in some patients with HF by reducing cardiac filling pressures and improving exercise capacity. However, to date the long-term safety of splanchnic nerve modulation (SNM) in the setting of HF is unknown. SNM is currently used in clinical practice to alleviate some forms of chronic abdominal pain. A systematic review of the series where permanent SNM was used as a treatment for chronic abdominal pain indicates that permanent SNM is well tolerated, with side-effects limited to transient diarrhoea or abdominal colic and transient hypotension. The pathophysiological role of the GSN in volume redistribution, the encouraging findings of acute and chronic pilot SNM studies and the safety profile from permanent SNM for pain provides a strong basis for continued efforts to study this therapeutic target in HF.

While many of the cardiac limitations to exercise performance are now well-characterized, extracardiac limitations to exercise performance have been less well recognized but are nevertheless important. We propose that abnormalities of cardiac preload reserve represents an under-recognized but common cause of exercise limitations. We further propose that mechanistic links exist between conditions as seemingly disparate as heart failure with preserved ejection fraction, nonalcoholic fatty liver disease, and pelvic venous compression/obstruction syndromes (eg, May-Thurner). We conclude that extracardiac abnormalities of preload reserve serve as a major pathophysiologic mechanism underlying these and other disease states.

IntroductionIV furosemide is used in most patients hospitalized with HF. A buffered formulation of furosemide delivered via an on-body subcutaneous delivery system (scPharmacauticals) that potentially would allow for treatment to be shifted to the outpatient setting was evaluated in 2 pilot studies in patients hospitalized for HF with signs and symptoms of congestion.HypothesisTreatment with sc furosemide is a safe and feasible approach to treatment of patients with HF and congestion.MethodsPatients hospitalized for HF with and congestion regardless of EF were enrolled in 2 sequential pilot studies at 5 centers. Patients requiring high doses of iv loop diuretics (> 200 mg furosemide/day) or clinical instability were excluded. The Sub-Q inpatient pilot (IP) enrolled 20 patients and treated them for 48 hours with sc furosemide (80mg sc over 5 hours given QD or BID based on need) in place of iv loop diuretics while they remained hospitalized. The Sub-Q outpatient pilot (OP) enrolled 20 patients with transition (within 24 hours) to the OP setting where they continued sc furosemide (80mg sc over 5 hours given QD or BID based on need) for up to 7 days. Data were collected on feasibility, urine output, weights, symptoms, and safety.ResultsIn the IP, median age was 70, median EF was 39, and median Cr was 1.4 mg/dL. Patients received a mean of 2.9 treatments over 48 hours and urine output over the 2 days of treatment was 5.3 L (figure). There were 8 device issues observed. There were 4 AEs in the IP, 3 were injection site discomfort. In the OP, median age was 61, median EF was 35, and median cr was 1.4 mg/dL. Patients received a mean of 6.9 treatments over 7 days. Signs and symptoms of congestion improved in most patients, although weight did not change significantly from baseline to day 7. There were 21 device issues in 10 unique patients (mostly difficulty the filling the delivery system). There were 18 AE's (mostly mild and related to injection site discomfort). There was 1 SAE that was unrelated to study treatment. There were 2 rehospitalizations for HF over 14 days from randomization in the OP.ConclusionsTreatment of selected HF patients with sc furosemide provided the anticipated effects on decongestion in both the inpatient and outpatient settings, although there were issues with the drug delivery system that limited feasibility. Ongoing developments of the delivery system for sc furosemide may make this a safe and feasible approach for treatment of congestion in the outpatient setting in selected patients.

The autonomic nervous system plays an integral role in cardiovascular physiology, and autonomic dysregulation (AD) contributes to the pathophysiology of many cardiovascular disorders. AD in patients with heart failure (HF), consisting primarily of sympathetic up-regulation, parasympathetic down-regulation, and abnormal cardiovascular reflexes, is associated with poor outcomes, and has been the target of many interventional studies.1

Background: Activation of neurohormonal systems contributes to the progression of heart failure (HF). The mechanism(s) whereby these systems become activated is(are) not fully explained. We determined whether vagal cardiopulmonary baroreflex control of renal sympathetic nerve activity is abnormal in dogs with left ventricular (LV) dysfunction in the absence of clinical HF, and the relationship of abnormalities in baroreflexes to the development of the neurohumoral excitatory state. Methods: LV end-systolic and end-diastolic dimensions (echocardiography), arterial baroreflex sensitivity (slope of ARR/Asystolic BP during phenylephrine or nitroglycerin bolus), and neurohumoral profiles (plasma norepinephrine, renin activity, and arginine vasopressin) were measured serially in conscious dogs (n=24) with progressive LV dysfunction due to rapid ventricular pacing. LV dimensions were used to define groups with mild, moderate, and marked LV dilatation (LVD; increase in LV end-diastolic volume <15%, 15-30%, and >30% of control, respectively). Changes in renal nerve activity (RNA) were recorded in response to increases in pulmonary capillary wedge pressure (PCWP) induced by volume infusion in anesthetized, sinoaortic-denervated dogs. Results: Cardiopulmonary baroreflex sensitivity (slope of %ARNA/APCWP) for mild LVD (-17.8%/ mmHg) was the same as controls (-17.7%/mmHg). However, the slopes of moderate (-5.8%/mmHg) and severe LVD (-1.9%/mmHg) were decreased significantly compared with controls (P <.05). Arterial baroreflex sensitivity was preserved at all stages of LVD. Plasma norepinephrine, renin activity, and arginine vasopressin remained unchanged after 4, 7, and 11 days of pacing. Conclusions: Vagal cardiopulmonary baroreflex control of renal sympathetic nerve activity is blunted early in the development of LVD. These abnormalities precede neurohumoral excitation and abnormal arterial baroreflexes and become apparent when LV end-diastolic volume starts to increase.

Background Hyponatremia (HN) occurs commonly in patients with acute heart failure and confers a worse prognosis. Current HN treatment varies widely, with no consensus. This study recorded treatment practices currently used for patients hospitalized with acute heart failure and HN. Methods and Results Data were collected prospectively from 146 US sites on patients hospitalized with acute heart failure and HN (serum sodium concentration [Na+] ≤130 mEq/L) present at admission or developing in the hospital. Baseline variables, HN treatment, and laboratory values were recorded. Of 762 patients, median [Na+] was 126 mEq/L (interquartile range, 7) at baseline and increased to 130 mEq/L at discharge. Fluid restriction was the most commonly prescribed therapy (44%), followed by no specific HN treatment beyond therapy for congestion (23%), isotonic saline (5%), tolvaptan (4%), and hypertonic saline (2%). Median rate of change in [Na+] varied by treatment (0.5 [interquartile range, 1.0] to 2.3 [8.0] mEq/L/d) and median treatment duration ranged from 1 (interquartile range, 1) to 6 (5) days. Fluid restriction and no specific HN treatment resulted in similar changes in [Na+], and were least effective in correcting HN. Few patients (19%) had [Na+] ≥135 mEq/L at discharge. Conclusions The most commonly used treatment approaches for HN (fluid restriction and no specific treatment) in acute heart failure increased [Na+] minimally, and most patients remained hyponatremic at discharge.

Background: Cognitive impairment (CI) is one of the major contributing factors for increased morbidity and mortality in Heart failure with reduced ejection fraction (HFrEF) patients, unfortunately this is frequently unrecognized and un-addressed. Often, these patients go untested prospectively for cognitive impairment. CNSVitals Signs (CNSVS) is a computerized test with high test-retest reliability able to detect subtle to severe degrees of CI in multiple domains, though it has not been studied in HF previously. Objective: We sought to determine the prevalence of CI in HFrEF. Specifically, we tested the hypothesis that stable chronic HFrEF outpatients without clinically apparent CI have significant moderate to severe CI, compared to controls. Methods: 2680 subjects were screened. Subjects with moderate to severe CI were excluded using the Mini-Mental Status Exam (MMSE score < 20), as were subjects on medications known to cause CI and subjects with known CI. 38 HFrEF patients and 26 age matched non-HF controls were included. Cognitive function was tested using CNSVS, and t-tests were used to examine between-group differences. Results: Table 1 shows baseline demographics, and Fig. 1 shows prevalence of CI (%) in different domains. Despite similar MMSE scores in each group, compared to age-matched controls, HFrEF subjects demonstrated significantly higher prevalence of moderate-severe CI across all domains and overall neurocognitive index. Conclusion: Stable chronic HFrEF patients not previously recognized to have CI, despite normal MMSE showed higher prevalence of Moderate-severe CI. Cognitive damage involving different domains, interferes with the ability for patient to self-care and to cope with treatment regimens, hence increased morbidity, mortality and financial impact. This study suggests that routine formal testing for CI is beneficial in HFrEF, though further studies are needed to determine the reversible factors of CI and hence improve outcomes in these patients.Table 1Comparison of characteristicsFig. 1Comparisons of moderate to severe cognitive impairment.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Dr. Douglas Schocken from Duke University, Durham, NC moderated the topic Heart Failure in the Euvolemic Patient with Drs. Mark Dunlap from Case Western Reserve University, Cleveland, OH, Paul Sobotka from the University of Minnesota, Minneapolis, MN, and Irving Zucker from the University of Nebraska Medical Center, Omaha, NE. The discussion focused primarily on: (1) a case of a woman presenting with decompensated HF caused by possible weight gain and salt and volume overload; (2) causes that lead to re-hospitalization, including signs for arrhythmias, ischemia, and nonadherence to dietary or pharmacologic recommendations; (3) what governs the movement of volume into and out of storage areas; (4) the future development of diagnostic tests and treatments for acute decompensated HF; (5) prevention of acute translocation of volume into effective arterial circulation. (Med Roundtable Cardiovasc Ed. 2012;3(1):102-109) ©2012 FoxP2 Media, LLC

A growing number of countries and geographical regions are involved in major clinical trials. Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure is the largest trial in acutely decompensated heart failure (HF) with patients from 5 geographical regions: North America (NA), Latin America (LA), Western Europe (WE), Central Europe (CE), and Asia-Pacific (AP). Data from the 5 geographical, areas were compared including baseline characteristics, medications, 30-day outcomes (mortality and mortality or HF hospitalization), and 180-day mortality. Of the 7,141 study patients, 3,243 (45.4%) were from NA (average of 15.2 patients/site), 1,762 (24.7%) from AP (28.4 patients/site), 967 (13.5%) from CE (20.2 patients/site), 665 (9.3%) from LA (17.1 patients/site), and 504 (7.1%) from WE (14.4 patients/site). There were marked differences in co-morbidities, clinical profile, medication use, length of stay, 30-day event rates, and 180-day mortality by region. Compared with NA, the adjusted risk for death or HF hospitalization at 30 days was significantly lower in CE (odds ratio [OR] 0.46, 95% CI 0.33 to 0.64), WE (OR 0.52 95% CI 0.35 to 0.75), and AP (OR 0.62 95% CI 0.48 to 0:79) and numerically lower in LA (OR 0.77, 95% CI 0.57 to 1.04) with similar results for 180-day mortality. In conclusion, in patients with acutely decompensated HF, major differences in baseline characteristics, treatments, length of the hospital stay, and 30-day HF rehospitalization rates, and 180-day mortality were found in patients enrolled from different, geographical areas. (C) 2016 Elsevier Inc. All rights reserved.

Background Although various studies revealed the beneficial effects of statins in post-cardiac transplant patients, these were relatively small and low-powered studies. We performed a meta-analysis of published studies to evaluate the role of statins in post-cardiac transplant patients, specifically examining the effects on hemodynamically significant/fatal graft rejection, coronary vasculopathy, terminal cancer, and overall survival.Methods and Results We searched PubMed, Cochran CENTRAL, and Web of Science databases using the search terms cardiac transplant or heart transplant, and statin for a literature search. A random-effects model with Mantel-Haenszel method was used to pool the data. We identified 10 studies, 4 randomized controlled trials, and 6 nonrandomized studies, which compared outcomes in heart transplant recipients undergoing statin therapy to statin-naive patients. A pooled analysis of 9 studies reporting mortality revealed that the use of statins was associated with significant reduction in all-cause mortality (odds ratio, 0.26; 95% confidence interval, 0.20-0.35; P<0.0001). Statins also decreased the odds of hemodynamically significant/fatal rejection (odds ratio, 0.37; 95% confidence interval, 0.21-0.65; P=0.0005), incidence of coronary vasculopathy (odds ratio, 0.33; 95% confidence interval, 0.16-0.68; P=0.003), and terminal cancer (odds ratio, 0.30; 95% confidence interval, 0.15-0.63; P=0.002).Conclusions The evidence from a pooled analysis suggests that statins improve survival in heart transplant recipients. Statins may prevent fatal rejection episodes, decrease terminal cancer risk, and reduce the incidence of coronary vasculopathy. Additional prospective studies are needed to further investigate and explain this association.

Heart transplantation is a life-saving treatment option for carefully selected end-stage heart failure patients. Posttransplant care consists primarily of immunosuppression and treatment of hypertension. Statin therapy immediately after cardiac transplant has become an integral part of post–cardiac transplant care. The molecular mechanisms responsible for the beneficial effects of statins extend beyond cholesterol-lowering action. Pleiotropic properties of statins include promotion of apoptosis, inhibition of angiogenesis, downregulation of circulating cytokines, and reduction of circulating monocytes. These pleiotropic properties may contribute to reduction in the incidence of cardiac allograft dysfunction in heart transplant recipients. Terminal malignancy is an important cause of death late after heart transplantation. Statins, through inhibition of 3-hydroxy3-methylglutaryl-coenzyme A reductase enzyme, decrease the production of farnesyl pyrophosphate, geranylgeranyl pyrophosphate, and other molecules involved in tumor cell proliferation, angiogenesis, and cell differentiation. This molecular mechanism suggests that statins might decrease the incidence of cancer in heart transplant recipients. However, statins also enhance the production of regulatory T cells, which impairs antitumor immune response and consequently promote the development of cancer. The effect of statin therapy on the incidence of cancer is not entirely clear.