Background: In patients with heart failure (HF), malnutrition and dietary sodium excess are common and may worsen outcomes. No prior studies have provided low-sodium, nutritionally-complete meals following HF hospitalization. Methods and Results: The Geriatric OUt-of-hospital Randomized MEal Trial in Heart Failure (GOURMET-HF) study randomized patients discharged from HF hospitalization to four weeks of home-delivered sodium-restricted Dietary Approaches to Stop Hypertension meals (DASH/SRD; 1,500 mg sodium/day) vs. usual care. The primary outcome was the between-group change in the Kansas City Cardiomyopathy Questionnaire (KCCQ) Summary Score from discharge to four weeks post-discharge. Additional outcomes included changes in the KCCQ Clinical Summary Score and cardiac biomarkers. All patients were followed 12 weeks for death/all-cause readmission and potential diet-related adverse events (symptomatic hypotension, hyperkalemia, acute kidney injury). 66 patients were randomized 1:1 at discharge to DASH/SRD vs. usual care (age 71±8 years, 30% female, ejection fraction 39±18%). The KCCQ Summary Score increased similarly between groups (DASH/SRD 46±23 to 59±20 vs. usual care 43±19 to 53±24, p=0.38) but the KCCQ Clinical Summary Score increase tended to be greater in DASH/SRD participants (47±22 to 65±19 vs. 45±20 to 55±26, p=0.053). Potentially diet-related adverse events were uncommon; 30-day HF readmissions (11% vs. 27%, p=0.06) and days rehospitalized within that timeframe (17 vs. 55, p=0.055) trended lower in DASH/SRD participants. Conclusions: Home-delivered DASH/SRD following HF hospitalization appeared safe in selected patients, and had directionally favorable effects on HF clinical status and 30-day readmissions. Larger studies are warranted to clarify the effects of post-discharge nutritional support in patients with HF. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT02148679
Background/Objectives Frailty, characterized by decreased physiologic reserves, is strongly associated with vulnerability to adverse outcomes. Features of frailty overlap with those of advanced heart failure (HF), making a distinction between these phenotypes difficult. We sought to determine if implantation of a left ventricular assist device (LVAD) would improve the frailty phenotype. Design Prospective, cohort study Setting Five academic medical centers. Participants 29 frail subjects (age 70.6±5.5 years, 72.4% male) Measurements Frailty assessed prior to LVAD and at 1, 3 and 6 months post-LVAD and was defined as ≥3 Fried Frailty phenotype criteria. Other domains assessed included quality of life using the Kansas City Cardiomyopathy Questionnaire, mood using PHQ9, and cognitive function using trail maker B test Results After 6 months, 3 subjects died and 1 underwent a heart transplant; among 19 subjects with serial frailty measures, the average number of frailty criteria decreased from 3.9±0.9 at baseline to 2.8±1.4 at 6 months, p=0.003. Improvements were not observed until 3–6 months of support. However, 10 (52.6%) continued to meet ≥3 Fried criteria and all subjects met at least one at 6 months. Changes in the frailty phenotype were associated with improvement in QOL but not with changes in mood or cognition. eGFR at baseline was independently associated with improvement in frailty phenotype. Conclusions The frailty phenotype was improved in approximately 50% of older adults with advanced HF after 6 months of LVAD support. Strategies to enhance frailty reversal in this population are worthy of additional study.
Increasing evidence supports the hypothesis that soluble misfolded protein assemblies contribute to the degeneration of post-mitotic tissue in amyloid diseases. However, there is a dearth of reliable non-antibody based probes for selectively detecting oligomeric aggregate structures circulating in plasma or deposited in tissues, making it difficult to scrutinize this hypothesis in patients. Hence, understanding the structure-proteotoxicity relationships driving amyloid diseases remains challenging, hampering the development of early diagnostic and novel treatment strategies. Here, we report peptide-based probes that selectively label misfolded transthyretin (TTR) oligomers circulating in the plasma of TTR hereditary amyloidosis patients exhibiting a predominant neuropathic phenotype. These probes revealed that there are much fewer misfolded TTR oligomers in healthy controls, in asymptomatic carriers of mutations linked to amyloid polyneuropathy, and in patients with TTR-associated cardiomyopathies. The absence of misfolded TTR oligomers in the plasma of cardiomyopathy patients suggests that the tissue tropism observed in the TTR amyloidoses is structure based. Misfolded oligomers decrease in TTR amyloid polyneuropathy patients treated with disease-modifying therapies (tafamidis or liver transplant-mediated gene therapy). In a subset of TTR amyloid polyneuropathy patients, the probes also detected a circulating TTR fragment that disappeared after tafamidis treatment. Proteomic analysis of the isolated TTR oligomers revealed a specific patient associated-signature comprised of proteins that likely associate with the circulating TTR oligomers. Quantification of plasma oligomer concentrations using peptide probes could become an early diagnostic strategy, a response-to-therapy biomarker, and a useful tool for understanding structure-proteotoxicity relationships in the TTR amyloidoses.
Cardiac amyloidosis is a cause of diastolic heart failure in which ejection fraction (EF) remains "normal" despite progression of disease. The myocardial contraction fraction (MCF) is an index of myocardial function, defined as stroke volume (SV) over myocardial volume (MV). We hypothesized that MCF would be superior to EF, the conventional measure of left ventricular function, in predicting survival among patients with cardiac amyloidosis. Sixty-six subjects (mean age = 67 ± 12 years; 20% women) with cardiac amyloidosis (34 with light-chain amyloid and 32 with transthyretin amyloid) underwent two-dimensional echocardiography to determine left ventricular structure and function. Cox proportional hazard modeling was used to determine the association of MCF and EF with survival. Over a mean follow-up of 1.86 ± 1.78 years (range 0.03-7.36 years), 37 subjects (56.1%) died. Mean EF of the study population was 51 ± 13%. There was no significant difference in EF between patients who survived the study period and those who died (54 ± 11% versus 49 ± 14%; p = 0.1196) while there was a significant difference in MCF (35 ± 19% versus 23 ± 10%, p = 0.0065). Using Cox proportional hazards modeling, MCF was associated with death (HR = 0.953, 95% CI of 0.932-0.984, p = 0.0031) while EF was not (HR = 0.991, 95% CI of 0.968-1.014, p = 0.4320). In a multivariate model, amyloid light-chain (AL) amyloid type was an independent risk predictor of death with a HR of 2.841 (95% CI of 1.214-6.648, p = 0.0161) along with a MCF < 30 with a HR of 2.567 (95% CI of 1.197-5.508, p = 0.0155), which was driven by a higher risk in AL subjects with a MCF < 30, HR of 3.39 (95% CI of 1.20-9.55, p = 0.021) than TTR subjects with a MCF < 30, HR of 1.26 (95% CI of 0.36-3.28, p = 0.87). In conclusion, MCF, a novel measure of myocardial chamber function, is superior to EF in predicting overall survival among patients with AL cardiac amyloidosis.
Transthyretin cardiac amyloidosis (ATTR-CA) causes a restrictive cardiomyopathy in older adults, often diagnosed at advanced stages when emerging therapies in late phase clinical trials may not have clinical benefit. This investigation aimed to detect clinical entities that may provide more advanced warning of ATTR-CA. Since ATTR preferentially deposits in ligaments, tendons, and articular cartilage, we hypothesized that ATTR-CA patients have a greater prevalence of total hip (THA) and knee (TKA) arthroplasties compared with the general population, and that arthroplasty occurs significantly before ATTR-CA diagnosis. Three-hundred and thirteen patients with cardiac amyloidosis (172 with ATTR-CA, 141 with light-chain) from our institutional database were analyzed and compared to published data in over 300 million patients. Overall, 23.3% of patients with ATTR-CA and 9.2% of patients with light-chain cardiac amyloidosis (AL-CA) underwent lower extremity arthroplasty. Compared to the general population, both THA and TKA were significantly more common among patients with ATTR-CA (THA: RR 5.61, 95% CI 2.25-4.64; TKA: RR 3.32, 95% CI 2.25-4.64) but not those with AL-CA (THA: RR 1.87, 95% CI 0.85-4.08; TKA: RR 1.42, 95% CI 0.73-2.84). On an average, arthroplasty occurred 7.2 years before ATTR-CA diagnosis.
Background Anemia is a common co-morbidity in older adults with heart failure and a preserved ejection fraction (HFPEF) and is associated with worse outcomes. We hypothesized that treating anemia with subcutaneous epoetin alfa (ESA) would be associated with reverse ventricular remodeling and improved exercise capacity and health status compared with placebo. Methods and Results Prospective, randomized, single blind, 24-week study with blinded endpoint assessment among anemic (average hemoglobin of 10.4±1 g/dl), older adult patients (n=56, 77±11 years, 68% female) with HFPEF (EF=63±15%, BNP of 431±366 pg/ml). Treatment with ESA resulted in significant increases in hemoglobin (p<0.0001). Changes in end diastolic volume (−6±14 vs. −4±16 ml, p=0.67) at 6 month did not differ between ESA and placebo but declines in stroke volume (−5±8 vs. 2±10 ml, p=0.09) without significant changes in LV mass were observed. Changes in six minute walk distance (16±11 vs. 5±12 meters, p=0.52) did not differ. While QOL improved by the KCCQ and MLHFQ in both cohorts, there were no significant differences between groups. Conclusions Administration of ESA to older adult patients with HFPEF compared with placebo did not change LVEDV, LV Mass nor improve submaximal exercise capacity or quality of life. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00286182.
Placebo-controlled clinical trials are useful for identifying the dose of a drug candidate that produces a meaningful clinical response in a patient population. Currently Pfizer, Inc. is enrolling a 400-person clinical trial to test the efficacy of 20 or 80 mg of tafamidis to ameliorate transthyretin (TTR)-associated cardiomyopathy using clinical endpoints. Herein, we provide guidance for how to optimize the dose of tafamidis for each WT TTR cardiomyopathy patient using its mechanism of action as the key readout, i.e., we identify the dose of tafamidis that maximally kinetically stabilizes TTR in the blood. Tetramer dissociation is rate limiting for TTR aggregation, which appears to drive the pathology in the TTR amyloidosis. Hence we measure the TTR tetramer dissociation rate (kinetic stability) in the patients’ plasma as a function of tafamidis dose to optimize the dose employed to maximize kinetic stability. Historical data tells us that a subset of patients exhibiting higher tafamidis plasma concentrations are maximally kinetically stabilized at the 20 mg tafamidis dose, whereas the patient studied herein required a 60 mg once daily dose to achieve maximum kinetic stabilization. We anticipate that establishing the dose of tafamidis that achieves maximal TTR kinetic stabilization will translate into a maximal clinical effect, but that remains to be demonstrated.
BACKGROUND With increasing diagnoses and available treatment options for transthyretin amyloidosis cardiomyopathy (ATTR-CM), risk stratification of ATTR-CM patients is imperative. OBJECTIVES We hypothesized that diuretic dose and New York Heart Association (NYHA) functional class are independent predictors of mortality in ATTR-CM and would be incrementally additive to existent risk scores. METHODS Consecutive ATTR-CM patients referred to a single center were identified. Adjusted Cox proportional hazards models determined the association between diuretic dose (furosemide equivalent in mg/kg) at time of diagnosis and the primary outcome of all-cause mortality. The incremental value of adding diuretic dose and NYHA functional class to existing ATTR-CM risk scores was assessed for discrimination and calibration. RESULTS 309 patients were identified, with mean age 73.2 ± 9.8 years, 84.1% male, and 66% wild type. Daily mean diuretic dose was 0.6 ± 1.0 mg/kg and significantly associated with all-cause mortality (unadjusted hazard ratio: 2.12 per 1-mg/kg increase, [95% confidence interval: 1.71 to 2.61] and fully adjusted hazard ratio: 1.43 [95% confidence interval: 1.06 to 1.93]). Testing previously published ATTR risk scores, adding diuretic dose as categories (0 mg/kg, >0 to 0.5 mg/kg, >0.5 to 1 mg/kg, and >1 to 2 mg/kg) improved the area under the curve of the Mayo risk score from 0.693 to 0.767 and the UK risk score from 0.711 to 0.787 while preserving calibration. Adding NYHA functional class further improved the area under the curve to 0.798 and 0.816, respectively. CONCLUSIONS Diuretic dose and NYHA functional class are independent predictors of mortality in ATTR-CM patients and provide incremental value to existing ATTR-CM risk scores.
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