Histopathological assessment of seven year-classes of Delta Smelt.

The Delta Smelt (Hypomesus transpacificus) is an imperiled, annual fish endemic to the Sacramento-San Joaquin Delta and San Francisco Estuary. This study examined the severity and prevalence of liver and gill lesions of juvenile through adult Delta Smelt from 2011 through 2017 collected from five regions throughout its habitat (n = 1,053). The first and last years of the study were wet, but bracketed an extreme drought in CA (2012-2016), during which the Delta Smelt population reached historical lows. Overall, the three most common lesions were gill ionocyte hyperplasia, liver lipidosis, and gill aneurysm. Individuals with higher fork lengths exhibited increased gill and liver lesion score (summations of the severity scores), suggesting that Delta Smelt accumulate lesions through their lives, and that larger individuals were more tolerant of liver and gill lesions. Liver lesion score showed significant regional differences, while salinity was a better predictor of gill lesions than region, with lower gill lesion scores associated with higher salinities. Largely consistent with previously reported histopathology patterns, Delta Smelt collected from the Confluence and Suisun Marsh had the lowest liver lesion score, while Delta Smelt collected from Cache Slough and Suisun Bay had the highest lesion scores, and Suisun Marsh had the lowest glycogen depletion, suggesting heterogeneous levels of exposure to environmental stressors across regions. Gill and liver lesion score also varied significantly with year-class. The highest gill lesion score occurred in the 2015/16 year-class, and the lowest occurred in the 2017/18 year-class, a 2.8-fold difference. Controlling for size and regional effects, individuals with comparatively high liver lesion scores were prevalent in the population until the 2014/15 year-class. In the two subsequent year-classes, Delta Smelt livers were in the best condition, coinciding with peak drought conditions and record low abundances.

Durable Biventricular Support Using Right Atrial Placement of the HeartWare HVAD.

Patients with Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) levels 1-2 who either have or are at risk for right ventricular failure face significant morbidity and mortality after continuous flow left ventricular assist device (CF-LVAD) implantation. Currently, the options for biventricular support are limited the Total Artificial Heart (TAH; CardioWest, Syncardia, Tuscon, AZ) or biventricular assist device (BiVAD), which uses bulky extracorporeal or implantable displacement pumps. We describe a successful series based on an innovative approach for biventricular support in consecutive INTERMACS levels 1-2 patients utilizing a HeartWare Ventricular Assist Device (HVAD; HeartWare, Framingham, MA) in a left ventricular (LV-HVAD) and a right atrial (RA-HVAD) configuration. From June 2014 through May 2016, 11 consecutive INTERMACS levels 1-2 patients with evidence of biventricular failure underwent implantation of a CF LVAD (10 LV-HVAD and 1 HeartMate II LVAD, Thoratec, Pleasanton, CA) and RA-HVAD pumps. A total of 4,314 BiVAD support days were accumulated in our case series. Seven patients have undergone orthotopic heart transplant, whereas 3 are ambulatory and are either waiting transplant or reconsideration for transplantation. There is one mortality in this case series, which was due to an intracranial bleed from supratherapeutic anticoagulation. Two other patients experienced hemorrhagic strokes, but without neurologic sequelae, whereas no patients have experienced ischemic strokes. There were two episodes of gastrointestinal bleeding. This is the largest series to date involving this approach with outcomes superior to those previously described in patients receiving biventricular support. We conclude this novel therapy is a viable alternative to current practices in the management of biventricular failure.

Intracoronary Gene Transfer of Adenylyl Cyclase 6 in Patients With Heart Failure: A Randomized Clinical Trial.

IMPORTANCE: Gene transfer has rarely been tested in randomized clinical trials. OBJECTIVE: To evaluate the safety and efficacy of intracoronary delivery of adenovirus 5 encoding adenylyl cyclase 6 (Ad5.hAC6) in heart failure. DESIGN, SETTING, AND PARTICIPANTS: A randomized, double-blind, placebo-controlled, phase 2 clinical trial was conducted in US medical centers (randomization occurred from July 19, 2010, to October 30, 2014). Participants 18 to 80 years with symptomatic heart failure (ischemic and nonischemic) and an ejection fraction (EF) of 40% or less were screened; 86 individuals were enrolled, and 56 were randomized. Data analysis was of the intention-to-treat population. Participants underwent exercise testing and measurement of left ventricular EF (echocardiography) and then cardiac catheterization, where left ventricular pressure development (+dP/dt) and decline (-dP/dt) were recorded. Participants were randomized (3:1 ratio) to receive 1 of 5 doses of intracoronary Ad5.hAC6 or placebo. Participants underwent a second catheterization 4 weeks later for measurement of dP/dt. Exercise testing and EF were assessed 4 and 12 weeks after randomization. INTERVENTIONS: Intracoronary administration of Ad5.hAC6 (3.2 × 109 to 1012 virus particles) or placebo. MAIN OUTCOMES AND MEASURES: Primary end points included exercise duration and EF before and 4 and 12 weeks after randomization and peak rates of +dP/dt and -dP/dt before and 4 weeks after randomization. Fourteen placebo participants were compared (intention to treat) with 24 Ad5.hAC6 participants receiving the highest 2 doses (D4 + 5). RESULTS: Fifty-six individuals were randomized and monitored for up to 1 year. Forty-two participants (75%) received Ad5.hAC6 (mean [SE] age, 63 [1] years; EF, 30% [1%]), and 14 individuals (25%) received placebo (age, 62 [1] years; EF, 30% [2%]). Exercise duration showed no significant group differences (4 weeks, P = .27; 12 weeks, P = .47, respectively). The D4 + 5 participants had increased EF at 4 weeks (+6.0 [1.7] EF units; n = 21; P < .004), but not 12 weeks (+3.0 [2.4] EF units; n = 21; P = .16). Placebo participants showed no increase in EF at 4 weeks or 12 weeks. Exercise duration showed no between-group differences (4-week change from baseline: placebo, 27 [36] seconds; D4 + 5, 44 [25] seconds; P = .27; 12-week change from baseline: placebo, 44 [28] seconds; D4 + 5, 58 [29 seconds, P = .47). AC6 gene transfer increased basal left ventricular peak -dP/dt (4-week change from baseline: placebo, +93 [51] mm Hg/s; D4 + 5, -39 [33] mm Hg/s; placebo [n = 21]; P < .03); AC6 did not increase arrhythmias. The admission rate for patients with heart failure was 9.5% (4 of 42) in the AC6 group and 28.6% (4 of 14) in the placebo group (relative risk, 0.33 [95% CI, 0.08-1.36]; P = .10). CONCLUSIONS AND RELEVANCE: AC6 gene transfer safely increased LV function beyond standard heart failure therapy, attainable with one-time administration. Larger trials are warranted. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00787059.

Calcium upregulation by percutaneous administration of gene therapy in patients with cardiac disease (CUPID 2): a randomised, multinational, double-blind, placebo-controlled, phase 2b trial.

BACKGROUND: Sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase (SERCA2a) activity is deficient in the failing heart. Correction of this abnormality by gene transfer might improve cardiac function. We aimed to investigate the clinical benefits and safety of gene therapy through infusion of adeno-associated virus 1 (AAV1)/SERCA2a in patients with heart failure and reduced ejection fraction. METHODS: We did this randomised, multinational, double-blind, placebo-controlled, phase 2b trial at 67 clinical centres and hospitals in the USA, Europe, and Israel. High-risk ambulatory patients with New York Heart Association class II-IV symptoms of heart failure and a left ventricular ejection fraction of 0·35 or less due to an ischaemic or non-ischaemic cause were randomly assigned (1:1), via an interactive voice and web-response system, to receive a single intracoronary infusion of 1 × 10(13) DNase-resistant particles of AAV1/SERCA2a or placebo. Randomisation was stratified by country and by 6 min walk test distance. All patients, physicians, and outcome assessors were masked to treatment assignment. The primary efficacy endpoint was time to recurrent events, defined as hospital admission because of heart failure or ambulatory treatment for worsening heart failure. Primary efficacy endpoint analyses and safety analyses were done by modified intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01643330. FINDINGS: Between July 9, 2012, and Feb 5, 2014, we randomly assigned 250 patients to receive either AAV1/SERCA2a (n=123) or placebo (n=127); 243 (97%) patients comprised the modified intention-to-treat population. Patients were followed up for at least 12 months; median follow-up was 17·5 months (range 1·8-29·4 months). AAV1/SERCA2a did not improve time to recurrent events compared with placebo (104 vs 128 events; hazard ratio 0·93, 95% CI 0·53-1·65; p=0·81). No safety signals were noted. 20 (16%) patients died in the placebo group and 25 (21%) patients died in the AAV1/SERCA2a group; 18 and 22 deaths, respectively, were adjudicated as being due to cardiovascular causes. INTERPRETATION: CUPID 2 is the largest gene transfer study done in patients with heart failure so far. Despite promising results from previous studies, AAV1/SERCA2a at the dose tested did not improve the clinical course of patients with heart failure and reduced ejection fraction. Although we did not find evidence of improved outcomes at the dose of AAV1/SERCA2a studied, our findings should stimulate further research into the use of gene therapy to treat patients with heart failure and help inform the design of future gene therapy trials. FUNDING: Celladon Corporation.

How B-Type Natriuretic Peptide (BNP) and Body Weight Changes Vary in Heart Failure With Preserved Ejection Fraction Compared With Reduced Ejection Fraction: Secondary Results of the HABIT (HF Assessment With BNP in the Home) Trial.

BACKGROUND: Heart failure is a common cause of hospitalization and can be divided into types with preserved and reduced ejection fraction (HFpEF and HFrEF, respectively). In this subanalysis of the HABIT (Heart Failure Assessment With BNP in the Home) trial, we examined the differences between home B-type natriuretic peptide (BNP) testing and weight monitoring in patients with HFpEF and with HFrEF before decompensation. METHODS AND RESULTS: This was a retrospective review of patients with HFpEF and HFrEF from the HABIT trial. The HFpEF patients compared with HFrEF patients were older and more obese and had lower baseline BNP values. Intra-individual BNP dispersion (spread of distribution over time) was greater in HFpEF than in HFrEF owing to rapid fluctuations (within 3 days). Slowly varying changes in BNP (estimated by a moving average) were equally predictive of ADHF risk in both HFpEF and HFrEF. However, in HFpEF, a rapid rise in BNP >200 pg/mL within 3 days was associated with an increased risk of acute decompensated heart failure (ADHF; hazard ratio 4.0), whereas a similar association was not observed in HFrEF. Weight gain ≥5 lb in 3 days had a high specificity but low sensitivity for ADHF in both HFpEF and HFrEF, whereas a lower threshold of ≥2 lb weight gain over 3 days in patients with HFpEF (but not HFrEF) was a moderately sensitive cutoff associated with decompensation (60% sensitivity). CONCLUSIONS: Patients with HFpEF and HFrEF have variations in their BNP and weight before decompensation. The rapid time scale behaves differently between the groups. In those with HFpEF, a 3-day period characterized by ≥2 lb weight gain and/or >200 pg/mL BNP rise was significantly associated with decompensation. Future prospective studies investigating different weight and BNP cutoffs for home monitoring of HFpEF and HFrEF patients should be performed to fully learn the value of BNP changes before clinical deompensation.

A Case Series of Biventricular Circulatory Support Using Two Ventricular Assist Devices: A Novel Operative Approach.

Increased use of continuous-flow left ventricular assist devices (LVADs) to treat advanced heart failure has heightened concern for right ventricular failure after LVAD implantation, which is associated with increased morbidity and mortality. Biventricular support is required in up to 30% of LVAD recipients. Currently, no durable long-term right ventricular assist device (RVAD) has been approved other than the Syncardia (Tucson, AZ) total artificial heart. A recent publication reported the placement of continuous flow LVAD in the heavily trabeculated right ventricle; however, this orientation may jeopardize both assist device and right ventricle function. We describe three cases of right-sided mechanical circulatory support with durable RVAD implanted in the right atrium, allowing long-term support with fewer anatomic limitations as compared with right ventricular cannulation.

Effects of exercise training on outcomes in women with heart failure: analysis of HF-ACTION (Heart Failure-A Controlled Trial Investigating Outcomes of Exercise TraiNing) by sex.

OBJECTIVES: The authors hypothesized that the women enrolled in the HF-ACTION (Heart Failure-A Controlled Trial Investigating Outcomes of Exercise TraiNing) trial and randomly assigned to exercise training (ET) would improve functional capacity as measured by peak oxygen uptake (VO2) compared with those in the usual care group. Furthermore, they hypothesized that the improvement in peak VO2 would correlate with prognosis. They explored whether exercise had a differential effect on outcomes in women versus men. BACKGROUND: There is less evidence for the benefit of ET in women with heart failure (HF) compared with men because of the small numbers of women studied. METHODS: HF-ACTION was a randomized trial of ET versus usual care in 2,331 patients with class II-IV HF and a left ventricular ejection fraction of ≤35%. Sex differences in the effects of randomized treatment on clinical outcomes were assessed through the use of a series of Cox proportional hazards models, controlling for covariates known to affect prognosis in HF-ACTION. RESULTS: Women had lower baseline peak VO2 and 6-min walk distance than did men (median, 13.4 vs. 14.9 ml/min/kg and 353 vs. 378 m, respectively). An increase in peak VO2 at 3 months was present in women and men in the ET group (mean ± SD; median, 0.88 ± 2.2, 0.80 and 0.77 ± 2.7, 0.60, respectively, women vs. men; p = 0.42). Women randomly assigned to ET had a significant reduction in the primary endpoint, (hazard ratio: 0.74) compared with men (hazard ratio: 0.99) randomly assigned to ET, with a significant treatment-by-sex interaction (p = 0.027). CONCLUSIONS: Although there is no significant difference between men and women in the effect of ET on peak VO2 change at 3 months, ET in women with HF is associated with a larger reduction in rate of the combined endpoint of all-cause mortality and hospital stay than in men.

Anemia and associated clinical outcomes in patients with heart failure due to reduced left ventricular systolic function.

BACKGROUND: Anemia is associated with decreased functional capacity, reduced quality of life, and worsened outcomes among patients with heart failure (HF) due to reduced left ventricular ejection fraction (HFREF). We sought to evaluate the independent effect of anemia on clinical outcomes among those with HFREF. HYPOTHESIS: Anemia is associated with cardiovascular events in patients with heart failure. METHODS: The HF-ACTION trial was a prospective, randomized trial of exercise therapy vs usual care in 2331 patients with HFREF. Patients with New York Heart Association class II to IV HF and left ventricular ejection fractions of ≤ 35% were recruited. Hemoglobin (Hb) was measured up to 1 year prior to entry and was stratified by quintile. Anemia was defined as baseline Hb <13 g/dL and <12 g/dL in men and women, respectively. Hemoglobin was assessed in 2 models: a global prediction model that had been previously developed, and a modified model including variables associated with anemia and the studied outcomes. RESULTS: Hemoglobin was available at baseline in 1763 subjects (76% of total study population); their median age was 59.0 years, 73% were male, and 62% were Caucasian. The prevalence of anemia was 515/1763 (29%). Older age, female sex, African American race, diabetes, hypertension, and lower estimated glomerular filtration rates were all more frequent in lower Hb quintiles. Over a median follow-up of 30 months, the primary outcome of all-cause mortality or all-cause hospitalization occurred in 78% of those with anemia and 64% in those without (P < 0.001). The secondary outcomes of all-cause mortality alone,cardiovascular (CV) mortality or CV hospitalization, and CV mortality or HF hospitalization occurred in 23% vs 15%, 67% vs 54%, and 44 vs 29%, respectively (P < 0.001). Heart failure hospitalizations occurred in 36% vs 22%, and urgent outpatient visits for HF exacerbations occurred in 67% and 55%, respectively (P < 0.001). For the global model, there was an association observed for anemia and all-cause mortality or hospitalization (adjusted hazard ratio [HR]: 1.15, 95% confidence interval [CI]: 1.01-1.32, P = 0.04), but other outcomes were not significant at P < 0.05. In the modified model, the adjusted HR for anemia and the primary outcome of all-cause mortality or all-cause hospitalization was 1.25 (95% CI: 1.10-1.42, P < 0.001). There were independent associations between anemia and all-cause death (HR: 1.11, 95% CI: 0.87-1.42, P = 0.38), CV death or CV hospitalization (HR: 1.16, 95% CI: 1.01-1.33, P = 0.035), and CV death and HF hospitalization (HR: 1.27, 95% CI: 1.06-1.51, P = 0.008). CONCLUSIONS: Anemia modestly is associated with increased rates of death, hospitalization, and HF exacerbation in patients with chronic HFREF. After adjusting for other important covariates, anemia is independently associated with an excess hazard for all-cause mortality and all-cause hospitalization. Anemia is also associated with combinations of CV death and CV/HF hospitalizations as composite endpoints.

Primary results of the HABIT Trial (heart failure assessment with BNP in the home).

OBJECTIVES: This study was a multicenter, single-arm, double-blinded observational prospective clinical trial designed to monitor daily concentrations of B-type natriuretic peptide (BNP) and to determine how these concentrations correlate with acute clinical heart failure decompensation (ADHF) and related adverse clinical outcomes in at-risk HF patients. BACKGROUND: Although BNP at discharge is predictive of 30-day outcomes, outpatient serial testing may improve the risk of detecting early decompensation. METHODS: A total of 163 patients with HF signs and symptoms of ADHF discharged from the hospital or in an outpatient setting measured their weight and BNP levels daily for 60 days with a finger-stick test. Patients and physicians were blinded to BNP levels. The composite outcome was ADHF events: cardiovascular death, admission for decompensated HF, or clinical HF decompensation requiring either parenteral HF therapy or changes in oral HF medications. RESULTS: A total of 6,934 daily BNP values were recorded, with a median of 46 measures per patient over a monitoring period of 65 days. Forty patients had 56 events. Correlations between BNP measures weakened over time, and the dispersion between BNP measures grew. During 10,035 patient-days, there were 494 (4.9%) days of weight gain (≥5 lbs). The hazard ratio per unit increase of ln BNP was 1.84, and the hazard ratio on a day of weight gain was 3.63. These effects retained significance when controlling for symptoms. When the monitoring period for each subject was broken into intervals based on ADHF events, there were 39 (18.4%) intervals of upward trending BNP corresponding to a risk increase of 59.8% and 64 (30.2%) downward trending intervals corresponding to a risk decrease of 39.0%. There were 94 (44.3%) intervals with 1 or more days of weight gain corresponding to a risk increase of 26.1%. CONCLUSIONS: This pilot study demonstrates that home BNP testing is feasible and that trials using home monitoring for guiding therapy are justifiable in high-risk patients. Daily weight monitoring is complementary to BNP, but BNP changes correspond to larger changes in risk, both upward and downward. (Heart Failure [HF] Assessment with B-type Natriuretic Peptide [BNP] In the Home [HABIT]; NCT00946231).

ACCF/SCAI/AATS/AHA/ASE/ASNC/HFSA/HRS/SCCM/SCCT/SCMR/STS 2012 appropriate use criteria for diagnostic catheterization: American College of Cardiology Foundation Appropriate Use Criteria Task Force Society for Cardiovascular Angiography and Interventions American Association for Thoracic Surgery American Heart Association, American Society of Echocardiography American Society of Nuclear Cardiology Heart Failure Society of America Heart Rhythm Society, Society of Critical Care Medicine Society of Cardiovascular Computed Tomography Society for Cardiovascular Magnetic Resonance Society of Thoracic Surgeons.

The American College of Cardiology Foundation, in collaboration with the Society for Cardiovascular Angiography and Interventions and key specialty and subspecialty societies, conducted a review of common clinical scenarios where diagnostic catheterization is frequently considered. The indications (clinical scenarios) were derived from common applications or anticipated uses, as well as from current clinical practice guidelines and results of studies examining the implementation of noninvasive imaging appropriate use criteria. The 166 indications in this document were developed by a diverse writing group and scored by a separate independent technical panel on a scale of 1 to 9, to designate appropriate use (median 7 to 9), uncertain use (median 4 to 6), and inappropriate use (median 1 to 3). Diagnostic catheterization may include several different procedure components. The indications developed focused primarily on 2 aspects of diagnostic catheterization. Many indications focused on the performance of coronary angiography for the detection of coronary artery disease with other procedure components (e.g., hemodynamic measurements, ventriculography) at the discretion of the operator. The majority of the remaining indications focused on hemodynamic measurements to evaluate valvular heart disease, pulmonary hypertension, cardiomyopathy, and other conditions, with the use of coronary angiography at the discretion of the operator. Seventy-five indications were rated as appropriate, 49 were rated as uncertain, and 42 were rated as inappropriate. The appropriate use criteria for diagnostic catheterization have the potential to impact physician decision making, healthcare delivery, and reimbursement policy. Furthermore, recognition of uncertain clinical scenarios facilitates identification of areas that would benefit from future research. © 2012 Wiley Periodicals, Inc.

Coarctation of the thoracic aorta masquerading as bilateral aorto-iliac stenosis.

We present a case with coarctation of the aorta (CoA) with lifestyle limiting claudication and lower extremity weakness, successfully treated with surgical correction. The presented case discusses the diagnostic challenges associated with identifying CoA in patients with claudication.

Who cares for the patient with heart failure?

Heart failure is a progressive and often fatal clinical syndrome caused by cardiac dysfunction. Therapeutic advances in both acute and chronic heart failure care have resulted in the ability to partially or completely reverse cardiac dysfunction, with accompanying reductions in attributable morbidity, mortality, and cost. In order to examine who is best suited to provide care for the patient with heart failure, we must recognize that treatment options vary in relationship to the stage of the disorder. Use of a contemporary heart failure classification scheme facilitates stratification of primary and secondary prevention and tertiary care options.

Heart failure in women.

Increasingly high mortality from cardiovascular disease in women has sparked nationwide campaigns to raise awareness of this significant threat to women's health. Heart failure has the most lethal prognosis of the major cardiovascular diseases, yet women demonstrate an apparent survival advantage compared with men. Sex-linked disparities in heart failure risk factors and pathophysiology contribute to this divergent clinical outcome. Heart failure etiology and clinical manifestations unique to female sex exist. At age 40, the lifetime risk of developing heart failure is equal for men and women, whereas the lifetime risk of developing coronary heart disease is one in two for men and one in three for women. Understanding sex-inherent characteristics related to heart failure may help determine whether the optimal therapy for this prevalent syndrome should be modified according to sex. Until prospective trial data prove otherwise, heart failure treatment guidelines should be uniformly applied to both women and men.