Mathew S. Maurer

Rationale: The frail phenotype has gained popularity as a clinically relevant measure in adults with advanced lung disease and in critical illness survivors. Because respiratory disease and chronic illness can greatly limit physical activity, the measurement of participation in traditional leisure time activities as a frailty component may lead to substantial misclassification of frailty in pulmonary and critical care patients. Objectives: To test and validate substituting the Duke Activity Status Index (DASI), a simple 12-item questionnaire, for the Minnesota Leisure Time Physical Activity (MLTA) questionnaire, a detailed questionnaire covering 18 leisure time activities, as the measure of low activity in the Fried frailty phenotype (FFP) instrument. Methods: In separate multicenter prospective cohort studies of adults with advanced lung disease who were candidates for lung transplant and older survivors of acute respiratory failure, we assessed the FFP using either the MLTA or the DASI. For both the DASI and MLTA, we evaluated content validity by testing floor effects and construct validity through comparisons with conceptually related factors. We tested the predictive validity of substituting the DASI for the MLTA in the FFP assessment using Cox models to estimate associations between the FFP and delisting/death before transplant in those with advanced lung disease and 6-month mortality in older intensive care unit (ICU) survivors. Results: Among 618 adults with advanced lung disease and 130 older ICU survivors, the MLTA had a substantially greater floor effect than the DASI (42% vs. 1%, and 49% vs. 12%, respectively). The DASI correlated more strongly with strength and function measures than did the MLTA in both cohorts. In models adjusting for age, sex, comorbidities, and illness severity, substitution of the DASI for the MLTA led to stronger associations of the FFP with delisting/death in lung transplant candidates (FFP-MLTA hazard ratio [HR], 1.42; 95% confidence interval [CI], 0.55–3.65; FFP-DASI HR, 2.99; 95% CI, 1.03–8.65) and with mortality in older ICU survivors (FFP-MLTA HR, 2.68; 95% CI, 0.62–11.6; FFP-DASI HR, 5.71; 95% CI, 1.34–24.3). Conclusions: The DASI improves the construct and predictive validity of frailty assessment in adults with advanced lung disease or recent critical illness. This simple questionnaire should replace the more complex MLTA in assessing the frailty phenotype in these populations.

In older adults with aortic stenosis, we evaluated whether accelerometer-measured physical activity provides distinct clinical information apart from self-reported surveys or performance-based function tests. We employed wrist-mounted accelerometry in 52 subjects with severe aortic stenosis prior to transcatheter aortic valve replacement (TAVR). Daily daytime activity was estimated using the maximum 10 h of daily accelerometer-measured activity (M10) reported in activity counts. Subjects completed baseline surveys (New York Heart Association (NYHA), Short Form 12 (SF12), Kansas City Cardiomyopathy Questionnaire (KCCQ), EuroQol-5D (EQ-5D), Revised Life Orientation Test (LOT-R), Life Space, Detailed Activity Form) and performance-based function tests (Short Physical Performance Battery, 6-min walk test distance, grip strength) to estimate functional status. Simple and multiple linear regression models were used to evaluate the relationship between accelerometer-measured activity and survey data and performance-based function tests. Among all baseline surveys and performance-based function tests, the only statistically significant univariable relationships identified were weak, negative associations between M10 and SF-12 Mental Composite Score (R ² = 0.1970, P = 0.04) and between M10 and grip strength (R ² = 0.1568, P = 0.004). Neither multiple linear regression of overall survey data (R ² = 0.6159, P = 0.23) nor performance-based function tests (R ² = 0.1743, P = 0.10) correlated with M10. Self-reported surveys and performance-based function tests are not meaningfully correlated with daytime accelerometer-measured activity. The results of our study suggest that accelerometer-measured physical activity provides distinct clinical information apart from self-reported surveys or performance-based function tests.

This editorial refers to ‘Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fraction’^†, by E. González-López et al., on page 2585.

Background—Transthyretin (TTR) amyloidosis is a progressive systemic disorder caused by misfolded TTR monomers that cumulatively deposit in the heart and systemically as amyloid. Methods and Results—This phase 2 open-label trial evaluated the stabilization of TTR tetramers using 20 mg of tafamidis daily at week 6 (primary end point), month 6, and month 12, as well as safety of tafamidis treatment and efficacy with respect to progression of TTR amyloid cardiomyopathy. Thirty-one wild-type patients (median age, 76.7 years; 93.5% men) with a median disease duration of 55.6 months and mild to moderate heart failure (96.8%; New York Heart Association, classes I–II) were enrolled. Thirty of 31 patients (96.8%) achieved TTR stabilization after 6 weeks and 25 of 28 patients (89.3%) after 12 months. After 12 months of treatment, 3 patients discontinued prematurely, 2 patients died, 7 patients were hospitalized because of cardiovascular events, 20 of 28 patients demonstrated preserved New York Heart Association classification status, but 15 of 31 (48.4%) patients had clinical progression (eg, admission for cardiac failure, atrial fibrillation, and syncope). N-terminal prohormone brain natriuretic peptide levels did not increase significantly over time, troponin I and troponin T increased moderately, and no consistent clinically relevant changes were seen in echocardiographic cardiac assessments. Tafamidis treatment was generally well tolerated although 7 of 31 patients had bouts of diarrhea. Conclusions—Tafamidis treatment effectively achieved and maintained TTR stabilization and was well tolerated. The absence of significant changes in most biochemical and echocardiographic parameters suggests that further evaluation of tafamidis in TTR amyloid cardiomyopathy is warranted. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00694161.

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.

Acute heart failure (AHF) remains a major cause of morbidity and mortality, with an increasing prevalence anticipated over the next few decades as the population ages, heightening already significant health and economic burdens to society. New therapies for AHF have stalled over the past decade for a multitude of reasons, principal among them the heterogeneous population of patients affected with potentially multiple operative pathophysiologic mechanisms making a single targeted therapy a challenge. Serelaxin, a recombinant form of human relaxin-2, mediates adaptive cardiovascular effects during pregnancy that could be beneficial in the AHF population, primarily through nitric oxide-mediated vasodilation. Serelaxin is a novel therapeutic agent that has shown promise in the treatment of AHF in predefined subpopulations, though studies powered for “hard” outcomes are still pending. In this review, we examine the clinical investigations to date involving serelaxin in patients with heart failure and its possible emerging role in the future therapy of AHF.

Aims: In the USA, transthyretin cardiac amyloidosis usually results from ‘wild-type’ transthyretin (senile cardiac amyloidosis [SCA]) or the V122I variant. Patients & methods: We compared presentations and outcomes among SCA and V122I patients referred to the Center for Advanced Cardiac Care at Columbia University Medical Center (NY, USA) between 2001 and 2012. Results: V122I patients were younger (mean: 71 years, standard deviation [SD]: 7) than SCA patients (mean: 77, SD: 6; p = 0.0002) and 96% were black compared with 3% of SCA patients (p < 0.0001). Average ejection fraction was lower among V122I patients (mean: 25% [SD: 12] vs mean: 47% [SD: 15]; p = 0.0001), as was mean cardiac index. Median time to death or orthotopic heart transplant was 36.4 months for V122I patients and 66.5 for SCA patients (p = 0.09). Conclusion: In this study of patients with transthyretin cardiac amyloidosis, V122I patients presented to a tertiary academic medical center at a younger age than SCA patients but had higher leve...