The effects of canagliflozin compared to sitagliptin on cardiorespiratory fitness in type 2 diabetes mellitus and heart failure with reduced ejection fraction: The CANA-HF study.

BACKGROUND: Canagliflozin reduces hospitalizations for heart failure (HF) in type 2 diabetes mellitus (T2DM). Its effect on cardiorespiratory fitness and cardiac function in patients with established HF with reduced ejection fraction (HFrEF) is unknown. METHODS: We conducted a double-blind randomized controlled trial of canagliflozin 100 mg or sitagliptin 100 mg daily for 12 weeks in 88 patients, and measured peak oxygen consumption (VO2 ) and minute ventilation/carbon dioxide production (VE/VCO2 ) slope (co-primary endpoints for repeated measure ANOVA time_x_group interaction), lean peak VO2 , ventilatory anaerobic threshold (VAT), cardiac function and quality of life (ie, Minnesota Living with Heart Failure Questionnaire [MLHFQ]), at baseline and 12-week follow-up. RESULTS: The study was terminated early due to the new guidelines recommending canagliflozin over sitagliptin in HF: 17 patients were assigned to canagliflozin and 19 to sitagliptin, total of 36 patients. There were no significant changes in peak VO2 and VE/VCO2 slope between the two groups (P = .083 and P = .98, respectively). Canagliflozin improved lean peak VO2 (+2.4 mL kgLM-1 min-1 , P = .036), VAT (+1.5 mL kg-1 min-1 , P = .012) and VO2 matched for respiratory exchange ratio (+2.4 mL Kg-1 min-1 , P = .002) compared to sitagliptin. Canagliflozin also reduced MLHFQ score (-12.1, P = .018). CONCLUSIONS: In this small and short-term study of patients with T2DM and HFrEF, interrupted early after only 36 patients, canagliflozin did not improve the primary endpoints of peak VO2 or VE/VCO2 slope compared to sitagliptin, while showing favourable trends observed on several additional surrogate endpoints such as lean peak VO2 , VAT and quality of life.

Healthcare Resource Use and Cost Implications in the MOMENTUM 3 Long-Term Outcome Study.

BACKGROUND: The MOMENTUM 3 trial compares the centrifugal HeartMate 3 (HM3) with the axial HeartMate II (HMII) continuous-flow left ventricular assist system in patients with advanced heart failure, irrespective of the intended goal of therapy. The trial's 2-year clinical outcome (n=366) demonstrated superiority of the HM3 for the primary end point (survival free of a disabling stroke or reoperation to replace or remove a malfunctioning pump). This analysis evaluates health resource use and cost implications of the observed differences between the 2 devices while patients were enrolled in the trial. METHODS: We analyzed all hospitalizations and their associated costs occurring after discharge from the implant hospitalization until censoring (study withdrawal, heart transplantation, and pump exchange with a nonstudy device or death). Each adjudicated episode of hospital-based care was used to calculate costs (device-attributable and non-device-attributable event costs), estimated by using trial data and payer administrative claims databases. Cost savings stratified by subgroups (study outcome [transplant, death, or ongoing on device], intended goal of therapy, type of insurance, or sex) were also assessed. RESULTS: In 366 randomly assigned patients, 361 comprised the as-treated group (189 in the HM3 group and 172 in the HMII group), of whom 337 (177 in the HM3 group and 160 in the HMII group) were successfully discharged following implantation. The HM3 arm experienced fewer total hospitalizations per patient-year (HM3: 2.1±0.2 versus HMII: 2.7±0.2; P=0.015) and 8.3 fewer hospital days per patient-year on average (HM3: 17.1 days versus HMII: 25.5 days; P=0.003). These differences were driven by patients hospitalized for suspected pump thrombosis (HM3: 0.6% versus HMII: 12.5%; P<0.001) and stroke (HM3: 2.8% versus HMII: 11.3%; P=0.002). Controlled for time spent in the study (average cumulative cost per patient-year), postdischarge HM3 arm costs were 51% lower than with the HMII (HM3: $37 685±4251 versus HMII: $76 599±11 889, P<0.001) and similar in either bridge to transplant or destination therapy intent. CONCLUSIONS: In this 2-year outcome economic analysis of the MOMENTUM 3 trial, the HM3 demonstrated a reduction in rehospitalizations, hospital days spent during rehospitalizations, and a significant cost savings following discharge in comparison with the HMII left ventricular assist system, irrespective of the intended goal of therapy. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02224755.

Total artificial heart implantation for biventricular failure due to eosinophilic myocarditis.

Idiopathic hypereosinophilic syndrome is a condition of unknown etiology characterized by proliferation of eosinophils and their infiltration into tissues. Although cardiac involvement is rare, eosinophilic myocarditis can lead to life-threating fulminant congestive heart failure. Treatment of patients with eosinophilic myocarditis is challenging as heart failure can be caused by biventricular dysfunction. To our knowledge, this is the first case reported in the literature describing a patient with acute severe biventricular heart failure caused by eosinophilic myocarditis with mural left ventricular apical thrombus who was successfully treated with implantation of a total artificial heart as a bridge to heart transplant.

Gender Disparities Across the Spectrum of Advanced Cardiac Therapies: Real or Imagined?

Cardiovascular disease has been responsible for more deaths in women than in men each year since 1985. This review discusses federal laws that have influenced the inclusion of women in research and reporting sex-specific differences, then addresses gender differences and gender disparities in four areas of clinical cardiovascular medicine: coronary heart disease, valvular heart disease, electrophysiology, and heart failure. The prevalence of disease in women is highlighted, the clinical characteristics of women at the time of referral for advanced therapies are reviewed, and the clinical outcomes of women are discussed. With the emergence of new technology such as smaller devices and less invasive procedures, more women are being referred for advanced therapies. However, a gap in awareness and diagnosis remains, contributing to later referrals for women. Women who do undergo advanced therapies often have more comorbidities and worse outcomes than men. A call is made to increase awareness, educate healthcare providers, and report more sex-specific data to resolve these gender disparities.

Gene-expression profiling for rejection surveillance after cardiac transplantation.

BACKGROUND: Endomyocardial biopsy is the standard method of monitoring for rejection in recipients of a cardiac transplant. However, this procedure is uncomfortable, and there are risks associated with it. Gene-expression profiling of peripheral-blood specimens has been shown to correlate with the results of an endomyocardial biopsy. METHODS: We randomly assigned 602 patients who had undergone cardiac transplantation 6 months to 5 years previously to be monitored for rejection with the use of gene-expression profiling or with the use of routine endomyocardial biopsies, in addition to clinical and echocardiographic assessment of graft function. We performed a noninferiority comparison of the two approaches with respect to the composite primary outcome of rejection with hemodynamic compromise, graft dysfunction due to other causes, death, or retransplantation. RESULTS: During a median follow-up period of 19 months, patients who were monitored with gene-expression profiling and those who underwent routine biopsies had similar 2-year cumulative rates of the composite primary outcome (14.5% and 15.3%, respectively; hazard ratio with gene-expression profiling, 1.04; 95% confidence interval, 0.67 to 1.68). The 2-year rates of death from any cause were also similar in the two groups (6.3% and 5.5%, respectively; P=0.82). Patients who were monitored with the use of gene-expression profiling underwent fewer biopsies per person-year of follow-up than did patients who were monitored with the use of endomyocardial biopsies (0.5 vs. 3.0, P<0.001). CONCLUSIONS: Among selected patients who had received a cardiac transplant more than 6 months previously and who were at a low risk for rejection, a strategy of monitoring for rejection that involved gene-expression profiling, as compared with routine biopsies, was not associated with an increased risk of serious adverse outcomes and resulted in the performance of significantly fewer biopsies. (ClinicalTrials.gov number, NCT00351559.)

Young patients with nonischemic cardiomyopathy have higher likelihood of left ventricular recovery during left ventricular assist device support.

BACKGROUND: Recovery of ventricular function during left ventricular assist device (LVAD) support allowing device explantation occurs infrequently. We explored the hypothesis that certain patient profiles are more likely to exhibit LV recovery during LVAD support. METHODS AND RESULTS: A retrospective analysis of data from the HeartMate II bridge to transplant (BTT) and destination therapy (DT) trials was conducted, including 490 BTT, 600 DT, and 18 compassionate-use patients. Of the 1,108 patients, 20 (1.8%; 10 BTT, 10 DT) were explanted owing to LV recovery. The median age was 33 years, and 12 patients (60%) were <40 years of age. History of heart failure was <1 year for 11 patients (61%), and the primary etiology was nonischemic (90%). Of the patients with nonischemic etiologies and <1-year history of heart failure, 13% were explanted. Three patients required LVAD reimplantation; of the remaining 17, 16 remain alive. At follow-up (median 510 days), the mean ejection fraction was 42% (20%-67%) and the mean left ventricular end-diastolic diameter was 55 ± 8 mm. At the 2-year follow-up (n = 13), patients were New York Heart Association functional class I or II and overall survival rate was 85 ± 11%. CONCLUSIONS: The results of this study suggest that LV recovery is most likely to occur in young patients (<40 years) with nonischemic cardiomyopathy of <1 year duration. Two-year postexplant survival was excellent.

Short-term mechanical management of cardiogenic shock.

OPINION STATEMENT: Cardiogenic shock (CS), a state of cardiac dysfunction that results in systemic hypoperfusion and end-organ dysfunction, is associated with high in-hospital mortality. Various forms of mechanical circulatory support have been used to treat CS. First employed in the 1960s, the intra-aortic balloon pump (IABP) has been a mainstay in the treatment of acute CS. However, the IABP is unable to provide adequate support in many patients, and newer technologies, including extracorporeal membrane oxygenation and percutaneous ventricular assist devices, appear to be more effective in reversing CS. These devices are also useful for supporting patients during complex percutaneous coronary intervention. Perhaps most importantly, they can be used as a bridge to decision or definitive therapy in CS patients who are potential candidates for surgical ventricular assist devices or cardiac transplantation.

Devices in heart failure: potential methods for device-based monitoring of congestive heart failure.

Congestive heart failure has long been one of the most serious medical conditions in the United States; in fact, in the United States alone, heart failure accounts for 6.5 million days of hospitalization each year. One important goal of heart-failure therapy is to inhibit the progression of congestive heart failure through pharmacologic and device-based therapies. Therefore, there have been efforts to develop device-based therapies aimed at improving cardiac reserve and optimizing pump function to meet metabolic requirements. The course of congestive heart failure is often worsened by other conditions, including new-onset arrhythmias, ischemia and infarction, valvulopathy, decompensation, end-organ damage, and therapeutic refractoriness, that have an impact on outcomes. The onset of such conditions is sometimes heralded by subtle pathophysiologic changes, and the timely identification of these changes may promote the use of preventive measures. Consequently, device-based methods could in the future have an important role in the timely identification of the subtle pathophysiologic changes associated with congestive heart failure.

The effect of etanercept on cardiac transplant recipients: a study of TNFalpha antagonism and cardiac allograft hypertrophy.

Cardiac allograft hypertrophy is associated with persistent expression of cardiac tumor necrosis factor (TNF)-alpha. We investigated whether TNFalpha antagonism would impact allograft hypertrophy. EFECT (EFfect of Etanercept on Cardiac Transplantation) was a randomized, controlled, double-blind trial evaluating the effect of etanercept versus placebo treatment immediately posttransplant. The primary end-point was change in left ventricular (LV) mass after 6 months. Secondary endpoints included degree of collagen deposition at 6 months and incidence of adverse events. Forty-nine patients were randomized to either etanercept or placebo. LV mass increased significantly in both arms at 6 months, with a smaller increase in the etanercept group (19% vs. 33%, P=ns). Myocardial collagen content increased in the placebo, but not the etanercept, group (+39.8%, P<0.08 vs. -7.0%, P=NS). Allograft hypertrophy develops posttransplant with a corresponding increase in extracellular matrix. Etanercept appeared to decrease LV hypertrophy by decreasing extracellular matrix deposition.

Utility of gene expression profiling score variability to predict clinical events in heart transplant recipients.

BACKGROUND: Gene expression profiling test scores have primarily been used to identify heart transplant recipients who have a low probability of rejection at the time of surveillance testing. We hypothesized that the variability of gene expression profiling test scores within a patient may predict risk of future events of allograft dysfunction or death. METHOD: Patients from the IMAGE study with rejection surveillance gene expression profiling tests performed at 1- to 6-month intervals were selected for this cohort study. Gene expression profiling score variability was defined as the standard deviation of an individual's cumulative test scores. Gene expression profiling ordinal score (range, 0-39), threshold score (binary value=1 if ordinal score ≥ 34), and score variability were studied in multivariate Cox regression models to predict future clinical events. RESULTS: Race, age at time of transplantation, and time posttransplantation were significantly associated with future events in the univariate analysis. In the multivariate analyses, gene expression profiling score variability, but not ordinal scores or scores over threshold, was independently associated with future clinical events. The regression coefficient P values were <0.001, 0.46, and 0.773, for gene expression profiling variability, ordinal, and threshold scores, respectively. The hazard ratio for a 1 unit increase in variability was 1.76 (95% CI, 1.4-2.3). DISCUSSION: The variability of a heart recipient's gene expression profiling test scores over time may provide prognostic utility. This information is independent of the probability of acute cellular rejection at the time of testing that is rendered from a single ordinal gene-expression profiling test score.

Gender Differences in Self-Reported Symptoms of Depression among Patients with Acute Coronary Syndrome.

This study examined the prevalence of self-reported depressive symptoms and the self reported somatic depressive symptoms as measured by the Beck Depression Inventory-II (BDI-II) among patients hospitalized for acute coronary syndrome (ACS), and explored the impact of gender on both. A convenience sample of 789 adults (248 women and 541 men) was recruited for the study during hospital admission for ACS and participants were screened for self-reported depressive symptoms. BDI-II scores of ≥14 indicate a moderate level of depressive symptoms and this cut-off score was used to categorize patients into depressed and non-depressed groups. Pearson chi-square tests for independence (categorical variables) and t tests for independent samples (continuous variables) were used for gender comparisons. Results showed that depressive symptoms during ACS episodes were different between women and men. Women reported greater overall depressive symptoms (BDI-II mean = 11.89, S.D. = 9.68) than men (BDI-II mean = 9.00, S.D. = 7.93) (P < 0.000). Significantly more women (7.66%) were identified positive for somatic depressive symptoms (sleep and appetite disturbances and fatigue) than men (2.22%) (P = 0.0003). Findings support that there are gender differences in depressive symptoms experienced by patients hospitalized for ACS. Somatic symptoms of depression may be important indicators of depression especially among female ACS patients.

Remission of chronic anthracycline-induced heart failure with support from a continuous-flow left ventricular assist device.

We report the case of a patient who had chronic anthracycline-induced cardiomyopathy that was reversed after treatment with a left ventricular assist device. A 29-year-old woman had undergone anthracycline-based chemotherapy as a teenager in 1991 and 1992 and received a diagnosis of dilated cardiomyopathy 10 years later. Optimal medical therapy had initially controlled the symptoms of heart failure. However, in June 2006, the symptoms worsened to New York Heart Association functional class IV status. We implanted a continuous-flow left ventricular assist device as a bridge to cardiac transplantation; of note, a left ventricular core biopsy at that time showed no replacement fibrosis. The patient's clinical status improved thereafter, enabling left ventricular assist device ex-plantation after 17 months. To our knowledge, this is the first report of the use of left ventricular assist device support to reverse chronic anthracycline-induced heart failure.

Thrombotic occlusion of an aortic-root xenograft during left ventricular assistance.

A 45-year-old man underwent repair of a congenital bicuspid aortic valve and complex aortic-root aneurysm with an aortic-root xenograft. A CentriMag® left ventricular assist device was implanted for cardiac support and was subsequently replaced with a HeartMate II® left ventricular assist device. A day later, the patient was returned to the operating room for control of bleeding, and thrombotic occlusion of the prosthetic aortic valve was detected. The patient underwent thrombus removal, oversewing of the prosthetic valve, and bypass of the left anterior descending coronary artery. This case emphasizes the hazard of bypassing a failed left ventricle with a cardiac assist device after aortic valve replacement, even with a bioprosthesis.

Molecular genetic and functional characterization implicate muscle-restricted coiled-coil gene (MURC) as a causal gene for familial dilated cardiomyopathy.

BACKGROUND: Dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) are classic forms of systolic and diastolic heart failure, respectively. Mutations in genes encoding sarcomere and cytoskeletal proteins are major causes of HCM and DCM. MURC, encoding muscle-restricted coiled-coil, a Z-line protein, regulates cardiac function in mice. We investigated potential causal role of MURC in human cardiomyopathies. METHODS AND RESULTS: We sequenced MURC in 1199 individuals, including 383 probands with DCM, 307 with HCM, and 509 healthy control subjects. We found 6 heterozygous DCM-specific missense variants (p.N128K, p.R140W, p.L153P, p.S307T, p.P324L, and p.S364L) in 8 unrelated probands. Variants p.N128K and p.S307T segregated with inheritance of DCM in small families (χ(2)=8.5, P=0.003). Variants p.N128K, p.R140W, p.L153P, and p.S364L were considered probably or possibly damaging. Variant p.P324L recurred in 3 independent probands, including 1 proband with a TPM1 mutation (p.M245T). A deletion variant (p.L232-R238del) was present in 3 unrelated HCM probands, but it did not segregate with HCM in a family who also had a MYH7 mutation (p.L907V). The phenotype in mutation carriers was notable for progressive heart failure leading to heart transplantation in 4 patients, conduction defects, and atrial arrhythmias. Expression of mutant MURC proteins in neonatal rat cardiac myocytes transduced with recombinant adenoviruses was associated with reduced RhoA activity, lower mRNA levels of hypertrophic markers and smaller myocyte size as compared with wild-type MURC. CONCLUSIONS: MURC mutations impart loss-of-function effects on MURC functions and probably are causal variants in human DCM. The causal role of a deletion mutation in HCM is uncertain.

Comparison of outcomes in women versus men using a continuous-flow left ventricular assist device as a bridge to transplantation.

BACKGROUND: The use of large, pulsatile left ventricular assist devices (LVADs) has been limited in women because of their small body size. METHODS: We compared the survival outcomes, quality of life, and adverse events in 465 patients (104 women, 361 men) with advanced systolic heart failure in their first 18 months of support with the HeartMate II (Thoratec Corp, Pleasanton, CA) continuous-flow LVAD for bridge to transplantation. RESULTS: During the first 18 months, there were no differences in survival between women and men while on LVAD support (73% ± 3% vs 73% ± 5%, p = 0.855) but fewer women (40%) underwent heart transplantation than did men (55%; p = 0.001). More women continued on support after 18 months (p = 0.007). Median duration of support was 238 days for women and 184 days for men (p = 0.003). Mortality was 20% for women and 19% for men (p = 0.89). Adverse events were similar, with the exception of hemorrhagic stroke, which occurred more frequently in women (0.10 vs 0.04 events/patient-year, p = 0.02), and device-related infections, which occurred less frequently in women (0.23 vs 0.44, p = 0.006). Functional capacity and quality of life at 6 months improved significantly in women and men. CONCLUSIONS: Continuous-flow left ventricular assistance as a bridge to transplantation is associated with similar survival rates in women and men. Differences observed in higher stroke rates and fewer infections among women require further study.

Arteriovenous malformation and gastrointestinal bleeding in patients with the HeartMate II left ventricular assist device.

BACKGROUND: In this study we investigated gastrointestinal (GI) bleeding and its relationship to arteriovenous malformations (AVMs) in patients with the continuous-flow HeartMate II (HMII) left ventricular assist device (LVAD). METHODS: The records of 172 patients who received HMII support between November 2003 and June 2010 were reviewed. Patients were considered to have GI bleeding if they had 1 or more of the following symptoms: guaiac-positive stool; hematemesis; melena; active bleeding at the time of endoscopy or colonoscopy; and blood within the stomach at endoscopy or colonoscopy. The symptom(s) had to be accompanied by a decrease of >1 g/dl in the patient's hemoglobin level. The location of the bleeding was identified as upper GI tract, lower GI tract or both according to esophagogastroduodenoscopy, colonoscopy, small-bowel enteroscopy or mesenteric angiography. Post-LVAD implantation anti-coagulation therapy consisted of warfarin, aspirin and dipyridamole. RESULTS: Thirty-two of the 172 patients (19%) had GI bleeding after 63 ± 62 (range 8 to 241) days of HMII support. Ten patients had GI bleeding from an AVM; these included 3 patients who had 2 bleeding episodes and 2 patients who had 5 episodes each. Sixteen patients had upper GI bleeding (10 hemorrhagic gastritis, 4 gastric AVM, 2 Mallory-Weiss syndrome), 15 had lower GI bleeding (6 diverticulosis, 6 jejunal AVM, 1 drive-line erosion of the colon, 1 sigmoid polyp, 1 ischemic colitis) and 1 had upper and lower GI bleeding (1 colocutaneous and gastrocutaneous fistula). All GI bleeding episodes were successfully managed medically. CONCLUSIONS: Arteriovenous malformations can cause GI bleeding in patients with continuous-flow LVADs. In all cases in this series, GI bleeding was successfully managed without the need for surgical intervention.

Cardiac remodelling and myocardial recovery: lost in translation?

The insight that decreases in left ventricular (LV) volume and mass occur secondary to the recovery of the myocardium at the cellular and molecular level has engendered a wider appreciation of the importance of LV remodelling as a mechanism for worsening heart failure. Despite these recent insights into the recognition of the importance of LV reverse remodelling in heart failure, many clinicians do not consider simple measurements of LV structure (i.e. LV volume) in their routine clinical decision-making process, preferring instead to rely on measurements of LV function [e.g. ejection fraction (EF)] when making decisions about medical and surgical treatment options. Although there are probably multiple reasons of why the use of LV volumes has not gained wider acceptance in day-to-day clinical management of heart failure patients, the most likely reason is that clinicians remain extremely comfortable using the LVEF to assess their heart failure patients. Importantly, LV volumes predict outcome more reliably than does the EF. Moreover, knowledge regarding LV volumes is extremely useful in optimizing patient selection for surgical and device therapies. Based on the foregoing arguments, we suggest that it is time to begin developing individualized clinical strategies based upon a consideration of the important role that LV remodelling plays in the pathogenesis of heart failure, and that we begin to incorporate measurements of LV volume and mass into the clinical decision-making process.

Ventricular assist device placement in an adult with D-transposition of the great arteries with prior Mustard operation.

Adults with congenital heart defects and congestive heart failure are a challenging population because of their complex anatomy, prior surgical palliation, and hemodynamic status. We report one of the first cases of a ventricular assist device placement in a patient with decompensated heart failure and a history of D-transposition of the great vessels who had a prior atrial switch operation.

Recognition and management of complex rhythm disorders in heterotopic heart transplantation.

Managing arrhythmias is challenging in patients who have undergone heterotopic heart transplantation because of the superimposed rhythms of the native and donor hearts. We present the case of a 43-year-old man with a previously placed biventricular pacemaker who underwent heterotopic heart transplantation and later developed acute rejection of the donor heart, which led to bradycardia and pause-dependent ventricular fibrillation. The patient remained clinically stable in the short term, likely because of partial recovery of myocardial function in the native heart. He later underwent placement of a pacing lead in the donor heart, allowing linking of the two hearts via a biventricular pacemaker.