Comparative Outcomes of a Transthyretin Amyloid Cardiomyopathy Cohort Versus Patients With Heart Failure With Preserved Ejection Fraction Enrolled in the TOPCAT Trial.

Background Transthyretin cardiac amyloidosis (ATTR-CM), found in 6% to 15% of cohorts with heart failure with preserved ejection fraction, has long been considered a rare disease with poor prognosis. New treatments have made it one of the few directly treatable causes of heart failure. This study sought to determine whether patients with ATTR-CM, particularly those treated with tafamidis, have comparable survival to an unselected cohort with heart failure with preserved ejection fraction. Methods and Results We compared the clinical characteristics and outcomes between a single-center cohort of patients with ATTR-CM (n=114) and patients with heart failure with preserved ejection fraction enrolled in the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial (n=1761, excluding Russia and Georgia). The primary outcome was a composite of all-cause death, heart failure hospitalization, myocardial infarction, and stroke. Subgroup analysis of patients with ATTR-CM treated with tafamidis was also performed. Patients with ATTR-CM had higher rates of the primary composite outcome compared with patients enrolled in the TOPCAT trial (hazard ratio [HR], 1.44 [95% CI, 1.09-1.91]; P=0.01), with similar rates of all-cause death (HR, 1.43 [95% CI, 0.99-2.06]; P=0.06) but higher rates of heart failure hospitalizations (HR, 1.62 [95% CI, 1.15-2.28]; P<0.01). Compared with patients enrolled in TOPCAT, patients with ATTR-CM treated with tafamidis had similar rates of the primary composite outcome (HR, 1.30 [95% CI, 0.86-1.96]; P=0.21) and all-cause death (HR, 1.10 [95% CI, 0.57-2.14]; P=0.78) but higher rates of heart failure hospitalizations (HR, 1.96 [95% CI, 1.27-3.02]; P<0.01). Conclusions Patients with ATTR-CM treated with tafamidis have similar rates of all-cause death compared with patients with heart failure with preserved ejection fraction, with higher rates of heart failure hospitalizations.

Biventricular Assist Devices as a Bridge to Heart Transplantation Under the New Donor Heart Allocation System in the United States.

Biventricular assist devices (BiVADs) for pre-heart transplant care is rare. The outcomes of pretransplant BiVAD support after the 2018 heart transplant allocation policy change are entirely unknown at this time. The United Network of Organ Sharing database was retrospectively queried from October 2018 to June 2022 to identify patients supported to transplant with BiVADs. They were compared to patients listed as Status 2 for heart transplantation with an isolated VAD (uni-VAD). The primary outcome of interest was 1 year survival. Secondary outcomes included length of stay, posttransplant stroke, dialysis, and pacemaker implantation. The frequency of BiVAD use for heart transplantation has remained unchanged after the 2018 allocation policy change, making up approximately 2% of transplant recipients annually. Patients supported with BiVADs appeared to be similar to patients supported with uni-VADs. One year survival was similar between the groups (88.57% vs. 87.90%). Length of stay was longer and there was a trend toward higher frequencies of posttransplant dialysis use. Patients supported to transplant with BiVADs appear to have posttransplant outcomes comparable to patients commonly listed as Status 2 with an isolated VAD. Compared to past analyses, there is a suggestion of improved survival with the 2018 allocation policy change.

Evolving epidemiology of transthyretin amyloid cardiomyopathy due to increased recognition in women.

BACKGROUND: Transthyretin amyloid cardiomyopathy (ATTR-CM), particularly wild type (wtATTR-CM), is thought to mainly affect men. Non-invasive diagnosis and approved therapeutics have been associated with increased disease recognition. We investigated the trajectory of ATTR-CM diagnosis in women. METHODS: This observational study utilized data collected on 140 consecutive ATTR-CM patients diagnosed between 2005 and 2022 who are followed at the Oregon Health and Science University Amyloidosis Clinic. Subgroup analysis was performed on patients with wtATTR-CM which included 113 subjects (80.1%). The proportion of women among patients diagnosed with ATTR-CM prior to 2019 was compared with that of those diagnosed 2019-2022 (2019 was the year of tafamidis approval by the FDA). The clinical characteristics of male and female ATTR-CM patients were compared as well. RESULTS: Of the 140 ATTR-CM patients, 16 (11.4%) were women (age 77 ± 9 years) and 124 (88.6%) were men (age 76 ± 9 years). There was an increase in the rate of women diagnosed with ATTR-CM from pre 2019 to 2019-2022 in the overall cohort (4/68 [5.9%] vs 12/72 [16.7%]) and wild type subgroup (0/51 [0%] vs 7/62 [11.3%]). There were several differences in baseline clinical characteristics between women and men in this cohort, yet all women had a clear clinical phenotype of ATTR-CM. CONCLUSIONS: There has been a significant increase in the rate of wtATTR-CM diagnoses in women, who presented with clear phenotypes of ATTR-CM. Further studies are needed to understand the effect of increased recognition of ATTR-CM in women on disease epidemiology, natural history, and outcomes.

Reaching movements are automatically redirected to nearby options during target split.

Motor behavior often occurs in environments with multiple goal options that can vary during the ongoing action. We explored this situation by requiring subjects to select between different target options during an ongoing reach. During split trials the original target was replaced with a left and a right flanking target, and participants had to select between them. This contrasted with the standard jump trials, where the original target would be replaced with a single flanking target, left or right. When participants were instructed to follow their natural tendency, they all tended to select the split target nearest the original. The near-target preference was more prominent with increased spatial disparity between the options and when participants could preview the potential options. Moreover, explicit instruction to obtain the "far" target during split trials resulted many errors compared with a "near" instruction, ~50% vs. ~15%. Online reaction times to target change were delayed in split trials compared with jump trials, ~200 ms vs. ~150 ms, but also highly automatic. Trials in which the instructed far target was correctly obtained were delayed by a further ~50 ms, unlike those in which the near target was incorrectly obtained. We also observed nonspecific responses from arm muscles at the jump trial latency during split trials. Taken together, our results indicate that online selection of reach targets is automatically linked to the spatial distribution of the options, though at greater delays than redirecting to a single target.NEW & NOTEWORTHY This work demonstrates that target selection during an ongoing reach is automatically linked to the option nearest a voided target. Online reaction times for two options are longer than redirection to a single option. Attempts to override the near-target tendency result in a high number of errors at the normal delay and further delays when the attempt is successful.

Radioprotection of the brain white matter by Mn(III) n-Butoxyethylpyridylporphyrin-based superoxide dismutase mimic MnTnBuOE-2-PyP5+.

Cranial irradiation is a standard therapy for primary and metastatic brain tumors. A major drawback of radiotherapy (RT), however, is long-term cognitive loss that affects quality of life. Radiation-induced oxidative stress in normal brain tissue is thought to contribute to cognitive decline. We evaluated the effectiveness of a novel mimic of superoxide dismutase enzyme (SOD), MnTnBuOE-2-PyP(5+)(Mn(III) meso-tetrakis(N-n-butoxyethylpyridinium-2-yl)porphyrin), to provide long-term neuroprotection following 8 Gy of whole brain irradiation. Long-term RT damage can only be assessed by brain imaging and neurocognitive studies. C57BL/6J mice were treated with MnTnBuOE-2-PyP(5+) before and after RT and evaluated three months later. At this time point, drug concentration in the brain was 25 nmol/L. Mice treated with MnTnBuOE-2-PyP(5+)/RT exhibited MRI evidence for myelin preservation in the corpus callosum compared with saline/RT treatment. Corpus callosum histology demonstrated a significant loss of axons in the saline/RT group that was rescued in the MnTnBuOE-2-PyP(5+)/RT group. In addition, the saline/RT groups exhibited deficits in motor proficiency as assessed by the rotorod test and running wheel tests. These deficits were ameliorated in groups treated with MnTnBuOE-2-PyP(5+)/RT. Our data demonstrate that MnTnBuOE-2-PyP(5+) is neuroprotective for oxidative stress damage caused by radiation exposure. In addition, glioblastoma cells were not protected by MnTnBuOE-2-PyP(5+) combination with radiation in vitro. Likewise, the combination of MnTnBuOE-2-PyP(5+) with radiation inhibited tumor growth more than RT alone in flank tumors. In summary, MnTnBuOE-2-PyP(5+) has dual activity as a neuroprotector and a tumor radiosensitizer. Thus, it is an attractive candidate for adjuvant therapy with RT in future studies with patients with brain cancer.