On-treatment analysis of torsemide versus furosemide for patients hospitalized for heart failure: A post-hoc analysis of TRANSFORM-HF.

AIM: The TRANSFORM-HF trial demonstrated no significant outcome differences between torsemide and furosemide following hospitalization for heart failure (HF), but may have been impacted by non-adherence to the randomized diuretic. The current study sought to determine the treatment effect of torsemide versus furosemide using an on-treatment analysis inclusive of all randomized patients except those confirmed non-adherent to study diuretic. METHODS AND RESULTS: TRANSFORM-HF was an open-label, pragmatic randomized trial of 2859 patients hospitalized for HF from June 2018 through March 2022. Patients were randomized to a loop diuretic strategy of torsemide versus furosemide with investigator-selected dosage. This post-hoc on-treatment analysis included all patients alive with either known or unknown diuretic status, and excluded patients confirmed to be non-adherent to study diuretic. This modified on-treatment definition was applied separately at time of hospital discharge and 30-day follow-up. All-cause mortality and hospitalization outcomes were assessed over 12 months. Overall, 2570 (89.9%) and 2374 (83.0%) patients were included in on-treatment analyses at discharge and 30-day follow-up, respectively. There was no significant difference in all-cause mortality between torsemide and furosemide in patients on-treatment at discharge (17.5% vs. 17.8%; hazard ratio [HR] 1.01 [95% confidence interval [CI] 0.83-1.22], p = 0.96) and at 30-day follow-up (14.5% vs. 15.0%; HR 1.02 [95% CI 0.81-1.27], p = 0.90). All-cause mortality or all-cause hospitalization was similar between torsemide and furosemide in patients who were on-treatment at discharge (58.3% vs. 61.3%; HR 0.92 [95% CI 0.82-1.03]) and 30-day follow-up (60.9% vs. 64.4%; HR 0.93 [95% CI 0.82-1.05]). In patients who were on-treatment at 30-day follow-up, there were 677 total hospitalizations in the torsemide group and 686 total hospitalizations in the furosemide group (rate ratio 0.99 [95% CI 0.86-1.14], p = 0.87). CONCLUSIONS: In TRANSFORM-HF, a post-hoc on-treatment analysis did not meaningfully differ from the original trial results. Among those deemed compliant with the assigned diuretic, there remained no significant difference in mortality or hospitalization after HF hospitalization with a strategy of torsemide versus furosemide. CLINICAL TRAIL REGISTRATION: ClinicalTrials.gov Identifier: NCT03296813.

Impact of left ventricular ejection fraction and aortic valve gradient on mortality following transcatheter aortic valve intervention.

BACKGROUND: Data regarding the impact of reduced left ventricular ejection fraction (LVEF) and/or reduced mean aortic valve gradient (AVG) on outcomes following transcatheter aortic valve intervention (TAVI) have been conflicting. We sought to assess the relationship between LVEF, AVG, and 1-year mortality in patients undergoing TAVI. METHODS: We prospectively evaluated 298 consecutive adults undergoing TAVI from 2015 to 2018 at an academic tertiary medical center. Patients were categorized according to LVEF and mean AVG. The primary outcome of interest was all-cause mortality at 1 year. RESULTS: Of 298 adults undergoing TAVI, 66 (22.1%) had baseline LVEF ≤45% while 232 (77.9%) had baseline LVEF >45%; 173 (58.1%) had baseline AVG < 40mmHg while 125 (41.9%) had baseline AVG ≥ 40mmHg. Rates of 1-year all-cause mortality were significantly higher in patients with LVEF ≤45% (28.8% vs 12.1%, p = 0.001) and those with AVG < 40mmHg (19.7% vs 10.4%, p = 0.031) compared to those with LVEF >45% and AVG ≥ 40mmHg respectively. In multivariable analysis, higher AVG (per mmHg) (OR 0.97, 95% CI 0.94-0.99, p = 0.026) was noted to be independently associated with lower rates of 1-year mortality, while LVEF was not (OR 0.98, 95% CI 0.96-1.01). CONCLUSIONS: In this prospective, contemporary registry of adults undergoing TAVI, while 1-year unadjusted mortality rates are significantly higher in patients with reduced LVEF and reduced AVG, risk-adjusted mortality at 1 year is only higher in those with reduced AVG - not in those with reduced LVEF.

Transcatheter aortic valve replacement in heart failure.

Patients with severe aortic stenosis (AS) may develop heart failure (HF), the presence of which has traditionally been deemed as a final stage in AS progression with poor outcomes. The use of transcatheter aortic valve replacement (TAVR) has become the preferred therapy for most patients with AS and concomitant HF. With its instant afterload reduction, TAVR offers patients with HF significant haemodynamic benefits, with corresponding changes in left ventricular structure and improved mortality and quality of life. The prognostic covariates and optimal timing of TAVR in patients with less than severe AS remain unclear. The purpose of this review is to describe the association between TAVR and outcomes in patients with HF, particularly in the setting of left ventricular systolic dysfunction, acute HF, and right ventricular systolic dysfunction, and to highlight areas for future research.

Biomarkers and Strain Echocardiography for the Detection of Subclinical Cardiotoxicity in Breast Cancer Patients Receiving Anthracyclines.

The optimal surveillance and management strategies for breast cancer patients receiving anthracycline therapy are limited by our incomplete understanding of the role of biomarkers heralding the onset of cardiotoxicity. The purpose of this study was to determine whether there is a temporal correlation between cardiac biomarkers and subclinical left ventricular dysfunction in breast cancer patients receiving anthracycline chemotherapy. Thirty-one females between 46 and 55 years old with breast cancer treated with anthracycline chemotherapy were prospectively enrolled. Cardiac biomarkers were correlated with echocardiography with speckle tracking at baseline, post-anthracycline therapy, and 6 months post-anthracycline chemotherapy. Subclinical cardiotoxicity was defined as ≥ 10% reduction in global longitudinal strain (GLS). There was a relative reduction in left ventricular ejection fraction (LVEF) ≥ 10% in 5/30 (17%) and 7/27 (26%) patients post-anthracycline therapy and 6 months post-anthracycline therapy, respectively. Subclinical cardiotoxicity was noted in 8/30 (27%) and 10/26 (38%) patients post-anthracycline and 6 months post-anthracycline therapy, respectively. Baseline N-terminal pro B-type natriuretic peptide (NT-proBNP) was the strongest predictor of LVEF (ρ = -0.45; p = 0.019), with post-therapy NT-proBNP values illustrating similar predictive value (ρ = -0.40; p = 0.038). Interim changes in suppression of tumorigenicity 2 (ST2) and galectin-3 correlated with a 6-month change in LVEF (ρ = -0.48; p = 0.012 and ρ = -0.45; p = 0.018, for ST2 and galectin-3, respectively). Changes in galectin-3 from baseline to mid-therapy paralleled changes in GLS. NT-proBNP, ST2, and galectin-3 correlate with reduced LVEF among breast cancer patients receiving anthracycline therapy. Additional trials focusing on a cardiac biomarker approach may provide guidance in the early diagnosis and management of anthracycline-induced cardiotoxicity.

Five-Year Cardiovascular Outcomes after Infective Endocarditis in Patients with versus without Drug Use History.

Background: Disparities in treatment and outcomes of infective endocarditis (IE) between people who use drugs (PWUD) and non-PWUD have been reported, but long-term data on cardiovascular and cerebrovascular outcomes are limited. We aim to compare 5-year rates of mortality, cardiovascular and cerebrovascular events after IE between PWUD and non-PWUD. Methods: Using data from the TriNetX Research Network, we examined 5-year cumulative incidence of mortality, myocardial infarction, heart failure, atrial fibrillation/flutter, ventricular tachyarrhythmias, ischemic stroke, and intracranial hemorrhage in 7132 PWUD and 7132 propensity score-matched non-PWUD patients after a first episode of IE. We used the Kaplan−Meier estimate for incidence and Cox proportional hazards models to estimate relative risk. Results: Matched PWUD were 41 ± 12 years old; 52.2% men; 70.4% White, 19.8% Black, and 8.0% Hispanic. PWUD had higher mortality vs. non-PWUD after 1 year (1−3 year: 9.2% vs. 7.5%, p = 0.032; and 3−5-year: 7.3% vs. 5.1%, p = 0.020), which was largely driven by higher mortality among female patients. PWUD also had higher rates of myocardial infarction (10.0% vs. 7.0%, p < 0.001), heart failure (19.3% vs. 15.2%, p = 0.002), ischemic stroke (8.3% vs. 6.3%, p = 0.001), and intracranial hemorrhage (4.1% vs. 2.8%, p = 0.009) compared to non-PWUD. Among surgically treated PWUD, interventions on the tricuspid valve were more common; however, rates of all outcomes were comparable to non-PWUD. Conclusions: PWUD had higher 5-year incidence of cardiovascular and cerebrovascular events after IE compared to non-PWUD patients. Prospective investigation into the causes of these disparities and potential harm reduction efforts are needed.

Prevalence and Predictors of Cardiovascular Disease and Risk Factors in Transgender Persons in the United States.

BACKGROUND: The cardiovascular health of transgender and gender diverse (TGD) persons, a growing population in the United States, has become a subject of heightened interest. We sought to assess the prevalence and predictors of cardiovascular disease (CVD) in transgender men, transgender women, and gender nonconforming persons in the United States. METHODS: A cohort of individuals self-identified as TGD (ie, transgender or gender nonconforming) in the United States was identified using the 2018 Centers for Disease Control's Behavioral Risk Factor Surveillance Survey. RESULTS: Among the 1019 TGD individuals studied, 378 (37.1%) identified their transition status as male-to-female, 394 (38.7%) as female-to-male, and the remaining 247 (24.2%) as gender nonconforming. A total of 138 (13.5%) had reported CVD, while 881 (86.5%) did not. The prevalence of CVD in TGD individuals identified as male-to-female, female-to-male, and gender nonconforming were noted to be similar (14.6% vs. 13.5% vs. 12.1%; P = 0.69). TGD persons with CVD were older with lower annual income. They also had higher rates of smoking, lower rates of regular exercise, and higher rates of smoking and chronic medical comorbidities. Independent predictors of CVD in TGD persons included older age, diabetes, chronic kidney disease, chronic obstructive pulmonary disease, and depressive disorder. CONCLUSIONS: In this contemporary cross-sectional nationally representative survey, CVD was prevalent in nearly 14% of TGD persons. Further studies examining interventions to reduce CV risk and enhance access to medical care in the TGD population are warranted.

Association of Serum Ferritin Levels and Methylprednisolone Treatment With Outcomes in Nonintubated Patients With Severe COVID-19 Pneumonia.

Importance: Serum ferritin, an acute phase marker of inflammation, has several physiologic functions, including limiting intracellular oxidative stress. Whether the effectiveness of corticosteroids differs according to serum ferritin level in COVID-19 has not been reported. Objective: To examine the association between admission serum ferritin level and methylprednisolone treatment outcomes in nonintubated patients with severe COVID-19. Design, Setting, and Participants: This retrospective cohort study included patients with severe COVID-19 admitted to an academic referral center in Stony Brook, New York, from March 1 to April 15, 2020, receiving high-flow oxygen therapy (fraction of inspired oxygen, ≥50%). The outcomes of treatment with methylprednisolone were estimated using inverse probability of treatment weights, based on a propensity score comprised of clinical and laboratory variables. Patients were followed up for 28 days. Data were analyzed from December 19, 2020, to July 22, 2021. Exposures: Systemic methylprednisolone administered per the discretion of the treating physician. Main Outcomes and Measures: The primary outcome was mortality, and the secondary outcome was a composite of death or mechanical ventilation at 28 days. Results: Among 380 patients with available ferritin data (median [IQR] age, 60 years [49-72] years; 130 [34.2%] women; 250 [65.8%] men; 310 White patients [81.6%]; 47 Black patients [12.4%]; 23 Asian patients [6.1%]), 142 patients (37.4%) received methylprednisolone (median [IQR] daily dose, 160 [120-240] mg). Ferritin levels were similar in patients who received methylprednisolone vs those who did not (median [IQR], 992 [509-1610] ng/mL vs 893 [474-1467] ng/mL; P = .32). In weighted analyses using tertiles of ferritin values (lower: 29-619 ng/mL; middle: 623-1316 ng/mL; upper: 1322-13 418 ng/mL), methylprednisolone was associated with lower mortality in patients with ferritin in the upper tertile (HR, 0.16; 95% CI, 0.06-0.45) and higher mortality in those with ferritin in the middle (HR, 2.46; 95% CI, 1.15-5.28) and lower (HR, 2.43; 95% CI, 1.13-5.22) tertiles (P for interaction < .001). Composite end point rates were lower with methylprednisolone in patients with ferritin in the upper tertile (HR, 0.45; 95% CI, 0.25-0.80) but not in those with ferritin in the middle (HR, 0.83; 95% CI, 0.50-1.39) and lower (HR, 0.89; 95% CI, 0.51-1.55) tertiles (P for interaction = .11). Conclusions and Relevance: In this cohort study of nonintubated patients with severe COVID-19, methylprednisolone was associated with improved clinical outcomes only among patients with admission ferritin in the upper tertile of values.

Admission NT-proBNP and outcomes in patients without history of heart failure hospitalized with COVID-19.

AIMS: We examined the value of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in patients admitted for coronavirus disease 2019 (COVID-19) without prior history of heart failure (HF) or cardiomyopathy. METHODS AND RESULTS: Retrospective cohort of consecutive adults (N = 679; median age 59 years; 38.7% women; 87.5% White; 7.1% Black; 5.4% Asian; 34.3% Hispanic) admitted with documented COVID-19 in an academic centre in Long Island, NY. Admission NT-proBNP was categorized using the European Society of Cardiology Heart Failure Association age-specific criteria for acute presentations. We examined (i) mortality and the composite of death or mechanical ventilation and (ii) out-of-hospital, intensive care unit (ICU)-free, and ventilator-free days at 28 days. Estimates were adjusted for confounders using a lasso selection process. Using age-specific criteria, 417 patients (61.4%) had low, 141 (20.8%) borderline, and 121 (17.8%) high NT-proBNP. Mortality was 5.8%, 20.6%, and 36.4% for patients with low, borderline, and high NT-proBNP, respectively. In lasso-adjusted models, high NT-proBNP was associated with higher mortality [hazard ratio (HR) 2.15; 95% confidence interval (CI) 1.06-4.39; P = 0.034] and composite endpoint rates (HR 1.66; 95%CI 1.04-2.66; P = 0.035). Patients with high NT-proBNP had 32%, 33%, and 33% fewer out-of-hospital, ICU-free, and ventilator-free days compared with low NT-proBNP counterparts. Results were consistent across age, sex, and race, and regardless of coronary artery disease or hypertension, except for stronger mortality signal with high NT-proBNP in women. CONCLUSIONS: In patients with COVID-19 and no HF history, high admission NT-proBNP is associated with higher mortality and healthcare resources utilization. Preventive strategies may be required for these patients.

Impact of Percutaneous Coronary Intervention on Outcomes in Patients With Heart Failure: JACC State-of-the-Art Review.

Coronary artery disease (CAD) is highly prevalent in patients with heart failure (HF) and accounts for nearly two-thirds of cases. The use of percutaneous coronary intervention (PCI) in HF patients with CAD has markedly increased and has been suggested to be associated with improved outcomes in numerous observational studies. Randomized data comparing the impact of PCI with that of coronary artery bypass graft (CABG) or contemporary guideline-directed medical therapy alone on clinical outcomes and myocardial recovery in patients with HF are lacking. The purpose of this review is to describe the available evidence regarding the impact of PCI in acute HF (in the presence and absence of an acute coronary syndrome), chronic HF with reduced ejection fraction, and HF with preserved ejection fraction. Adequately-powered randomized clinical trials examining the outcomes with PCI in these distinct HF populations are warranted.

High-dose methylprednisolone in nonintubated patients with severe COVID-19 pneumonia.

BACKGROUND: Recent trials with dexamethasone and hydrocortisone have demonstrated benefit in patients with coronavirus disease 2019 (COVID-19). Data on methylprednisolone are limited. METHODS: Retrospective cohort of consecutive adults with severe COVID-19 pneumonia on high-flow oxygen (FiO2  ≥ 50%) admitted to an academic centre in New York, from 1 March to 15 April 2020. We used inverse probability of treatment weights to estimate the effect of methylprednisolone on clinical outcomes and intensive care resource utilization. RESULTS: Of 447 patients, 153 (34.2%) received methylprednisolone and 294 (65.8%) received no corticosteroids. At 28 days, 102 patients (22.8%) had died and 115 (25.7%) received mechanical ventilation. In weighted analyses, risk for death or mechanical ventilation was 37% lower with methylprednisolone (hazard ratio 0.63; 95% CI 0.47-0.86; P = .003), driven by less frequent mechanical ventilation (subhazard ratio 0.56; 95% CI 0.40-0.79; P = .001); mortality did not differ between groups. The methylprednisolone group had 2.8 more ventilator-free days (95% CI 0.5-5.1; P = .017) and 2.6 more intensive care-free days (95% CI 0.2-4.9; P = .033) during the first 28 days. Complication rates were not higher with methylprednisolone. CONCLUSIONS: In nonintubated patients with severe COVID-19 pneumonia, methylprednisolone was associated with reduced need for mechanical ventilation and less-intensive care resource utilization without excess complications.

Continued In-Hospital Angiotensin-Converting Enzyme Inhibitor and Angiotensin II Receptor Blocker Use in Hypertensive COVID-19 Patients Is Associated With Positive Clinical Outcome.

BACKGROUND: This study investigated continued and discontinued use of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARB) during hospitalization of 614 hypertensive laboratory-confirmed COVID-19 patients. METHODS: Demographics, comorbidities, vital signs, laboratory data, and ACEi/ARB usage were analyzed. To account for confounders, patients were substratified by whether they developed hypotension and acute kidney injury (AKI) during the index hospitalization. RESULTS: Mortality (22% vs 17%, P > .05) and intensive care unit (ICU) admission (26% vs 12%, P > .05) rates were not significantly different between non-ACEi/ARB and ACEi/ARB groups. However, patients who continued ACEi/ARBs in the hospital had a markedly lower ICU admission rate (12% vs 26%; P = .001; odds ratio [OR] = 0.347; 95% confidence interval [CI], .187-.643) and mortality rate (6% vs 28%; P = .001; OR = 0.215; 95% CI, .101-.455) compared to patients who discontinued ACEi/ARB. The odds ratio for mortality remained significantly lower after accounting for development of hypotension or AKI. CONCLUSIONS: These findings suggest that continued ACEi/ARB use in hypertensive COVID-19 patients yields better clinical outcomes.

Predictors of Aspirin Nonadherence in Adults With Prior Myocardial Infarction.

BACKGROUND: Medication nonadherence is an alarming public health concern due to its effect on both individual treatment success and overall health care costs. This study sought to identify the predictors of aspirin nonadherence in adults with prior myocardial infarction (MI). METHODS: The 2017 Centers for Disease Control's Behavioral Risk Factor Surveillance Survey, a nationally representative, cross-sectional survey, was utilized to identify a cohort of community-dwelling adults (age ≥ 18 years) with prior MI (n = 2173). The primary outcome of interest was presence of self-reported aspirin nonadherence. RESULTS: Among 2173 participants with prior MI studied, a total of 550 participants (25.3%) reported aspirin nonadherence, whereas 1623 participants (74.7%) reported adherence to aspirin. Adults with aspirin nonadherence were younger and more likely to be female, Black, and of Hispanic ethnicity. They also had lower annual income and were less likely to have health insurance or own a home. Participants with aspirin nonadherence had less frequent medical checkups and lower rates of multiple comorbidities including diabetes mellitus, hypertension, hyperlipidemia, and obesity. In multivariable analysis, independent predictors of aspirin nonadherence included female sex [odds ratio (OR), 1.42; 95% confidence interval (CI), 1.14-1.83], Black race (OR, 1.64; 95% CI, 1.19-2.26), Hispanic ethnicity (OR, 2.27; 95% CI, 1.60-3.21), current employment (OR, 1.74; 95% CI, 1.28-2.36), and absence of homeowner status (OR, 0.71; 95% CI, 0.55-0.93). CONCLUSIONS: In this observational contemporary study of adults with prior MI, predictors of aspirin nonadherence included female sex, Black race, Hispanic ethnicity, currently employed status, and absence of homeowner status.

Sex-Related Differences in Early- and Long-Term Mortality After Transcatheter and Surgical Aortic Valve Replacement: A Systematic Review and Meta-Analysis.

BACKGROUND: Observational data suggest that early- and long-term outcomes of transcatheter aortic valve replacement (TAVR) and surgical aortic valve replacement (SAVR) differ significantly between men and women, but have demonstrated conflicting results. This study sought to examine early- and long-term mortality with TAVR and SAVR in women versus men. METHODS: Electronic search was performed until February 2018 for studies reporting sex-specific mortality following TAVR or isolated SAVR. Data were pooled using random-effects models. Outcomes included rates of early mortality (in hospital or 30 days) and long term (1 year or longer). RESULTS: With 35 studies, a total of 80,928 patients were included in our systematic review and meta-analysis, including 40,861 men and 40,067 women. Pooled analyses suggested considerable sex-related differences in longterm mortality following TAVR and SAVR. Following SAVR, women had higher long-term mortality (odds ratio [OR], 1.35; 95% confidence interval [CI], 1.16-1.56; P<.001) and a trend toward higher early mortality (OR, 1.69; 95% CI, 0.97-2.97; P=.07) compared to men. Following TAVR, women had lower long-term mortality (OR, 0.78; 95% CI, 0.71-0.86; P<.001) and no difference in early mortality (OR, 1.09; 95% CI, 0.96-1.23; P=.17) compared to men. CONCLUSIONS: In this systematic review and meta-analysis, women had higher long-term mortality and a trend toward higher early mortality compared to men following SAVR. Following TAVR, women had lower long-term mortality and no difference in early mortality compared with men.

Rationale and design of a randomized controlled trial of allogeneic mesenchymal stem cells in patients with nonischemic cardiomyopathy.

AIMS: This article describes an ongoing study investigating the safety and efficacy of ischemia-tolerant mesenchymal stem cell (MSC) therapy in patients with nonischemic heart failure and dysfunctional viable myocardium without scarring. This study will follow principles of the previously described mechanistic translational-phase concept whereby the effect of the study agent on laboratory and imaging markers of cardiac structure and function will be tested in a small homogenous cohort with the goal to enhance the understanding of the effect of interventions on cardiac remodeling and performance. STUDY DESIGN: This single-blind, placebo-controlled, crossover, multicenter, randomized study will assess the safety, tolerability, and preliminary efficacy of a single intravenous (i.v.) dose of allogeneic ischemia-tolerant MSCs in individuals with heart failure of nonischemic cause, ejection fraction 40% or less, and dysfunctional viable myocardium who have been receiving guideline-directed medical therapy. Eligible patients will have no evidence of baseline replacement scarring on delayed-enhancement cardiac magnetic resonance (CMR). Approximately 20 patients will be randomized in a 1 : 1 ratio to receive an i.v. infusion of ischemia-tolerant MSCs or placebo. At 90 days, the two groups will undergo crossover and received the alternative treatment. The primary endpoint is safety, as evaluated through at least 1-year post-MSC infusion. Additional efficacy endpoints will include measures of cardiac structure and function, as evaluated by serial cine-CMR and transthoracic echocardiography at 90 and 180 days post-initial infusion. CONCLUSION: This pilot study will explore the safety and effects on cardiac structure and function of i.v. injection of ischemia-tolerant MSCs in a small homogenous cohort of nonischemic heart failure patients with reduced ejection fraction and absent replacement scarring on CMR. This study also represents a prospective mechanistic translational-phase study using baseline and serial CMR imaging in heart failure patients and serves as a potential model for design of future heart failure trials (ClinicalTrials.gov identifier: NCT02467387).

Intravenous Allogeneic Mesenchymal Stem Cells for Nonischemic Cardiomyopathy: Safety and Efficacy Results of a Phase II-A Randomized Trial.

RATIONALE: Potential benefits of mesenchymal stem cell (MSC) therapy in heart failure may be related to paracrine properties and systemic effects, including anti-inflammatory activities. If this hypothesis is valid, intravenous administration of MSCs should improve outcomes in heart failure, an entity in which excessive chronic inflammation may play a pivotal role. OBJECTIVE: To assess the safety and preliminary efficacy of intravenously administered ischemia-tolerant MSCs (itMSCs) in patients with nonischemic cardiomyopathy. METHODS AND RESULTS: This was a single-blind, placebo-controlled, crossover, randomized phase II-a trial of nonischemic cardiomyopathy patients with left ventricular ejection fraction ≤40% and absent hyperenhancement on cardiac magnetic resonance imaging. Patients were randomized to intravenously administered itMSCs (1.5×106 cells/kg) or placebo; at 90 days, each group received the alternative treatment. Overall, 22 patients were randomized to itMSC (n=10) and placebo (n=12) at baseline. After crossover, data were available for 22 itMSC patients. No major differences in death, hospitalization, or serious adverse events were noted between the 2 treatments. Change from baseline in left ventricular ejection fraction and ventricular volumes was not significantly different between therapies. Compared with placebo, itMSC therapy increased 6-minute walk distance (+36.47 m, 95% confidence interval 5.98-66.97; P=0.02) and improved Kansas City Cardiomyopathy clinical summary (+5.22, 95% confidence interval 0.70-9.74; P=0.02) and functional status scores (+5.65, 95% confidence interval -0.11 to 11.41; P=0.06). The data demonstrated MSC-induced immunomodulatory effects, the magnitude of which correlated with improvement in left ventricular ejection fraction. CONCLUSIONS: In this pilot study of patients with nonischemic cardiomyopathy, itMSC therapy was safe, caused immunomodulatory effects, and was associated with improvements in health status and functional capacity. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02467387.

Utility of positron emission tomography for drug development for heart failure.

Only about 1 in 5,000 investigational agents in a preclinical stage acquires Food and Drug Administration approval. Among many reasons for this includes an inefficient transition from preclinical to clinical phases, which exponentially increase the cost and the delays the process of drug development. Positron emission tomography (PET) is a nuclear imaging technique that has been used for the diagnosis, risk stratification, and guidance of therapy. However, lately with the advance of radiochemistry and of molecular imaging technology, it became evident that PET could help novel drug development process. By using a PET radioligand to report on receptor occupancy during novel agent therapy, it may help assess the effectiveness, efficacy, and safety of such a new medication in an early preclinical stage and help design successful clinical trials even at a later phase. In this article, we explore the potential implications of PET in the development of new heart failure therapies and review PET's application in the respective pathophysiologic pathways such as myocardial perfusion, metabolism, innervation, inflammation, apoptosis, and cardiac remodeling.

Reversible left ventricular dysfunction and acute kidney injury in a patient with nonamyloid light chain deposition disease.

Non-amyloid light chain deposition disease (LCDD) is a rare entity that most commonly presents as proteinuria and/or renal dysfunction. We report on a patient who initially presented with acutely decompensated heart failure and subsequently developed nephrotic range proteinuria with attendant advanced renal dysfunction. The diagnosis of LCCD was made on renal biopsy.She was treated with five cycles of bortezomib and dexamethasone followed by cyclophosphamide priming for peripheral blood stem cell (PBSC) mobilization and auto logousstem cell transplant (ASCT). Four years later, she remains in very good partial response (VGPR) with a left ventricular ejection fraction (LVEF) of 58% and serum creatinine of 1.1 mg/dl. This observation supports the approach of aggressive management of patients with LCDD who have multiple organ failure.

Macrophage migration inhibitory factor within the alveolar spaces induces changes in the heart during late experimental sepsis.

Respiratory dysfunction during sepsis is common. However, although lung function can often be adequately supported, death frequently results from cardiovascular collapse. Despite intense investigation, the mechanism underlying the myocardial dysfunction of sepsis remains unclear. Macrophage migration inhibitory factor (MIF), an important cytokine released in sepsis and the acute respiratory distress syndrome, is a known cardiac depressant. We hypothesized that MIF released from the lung results in myocardial dysfunction during sepsis. In murine models of polymicrobial sepsis, we demonstrate a significant increase in the lungs of total and lavagable MIF between 20 and 30 h post induction of sepsis. At 30 h post sepsis, the lungs released MIF into the pulmonary circulation, increasing the plasma concentration by up to 51% in a single pass. Exogenous MIF, instilled into the lungs, increased alveolar keratinocyte-derived chemokine (KC), Macrophage inflammatory protein-2 (MIP2), and tumor necrosis factor alpha (TNFalpha) at 3 h, and plasma KC and MIP2 at 6 h postinstillation. This was associated with an increase in p38 mitogen-activated protein kinase and c-Jun N-terminal kinase phosphorylation. Because changes in mitogen-activated protein kinase activation can lead to myocardial depression, these data suggest that MIF released from the lungs may be responsible, at least in part, for the cardiac dysfunction seen in the late stages of sepsis.