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What is this plain language summary about? This plain language summary describes the results of a study looking at the effects of a medicine called ARRY-371797 (also known as PF-07265803) in people with dilated cardiomyopathy (DCM for short) caused by a faulty LMNA gene. This condition is called LMNA-related DCM. DCM happens when the heart becomes bigger and weaker than normal, impacting functional capacity and leading to symptoms of heart failure. This means the heart is not able to pump blood around the body as easily, and people are unable to do as much in their daily lives (like getting dressed and going shopping). People may inherit a faulty LMNA gene from one of their parents, or a faulty LMNA gene may develop when mistakes happen during cell growth and replication. ARRY-371797 targets a specific mechanism in the body that can lead to heart problems in people with a faulty LMNA gene. As ARRY-371797 is not currently approved for use outside of clinical trials, it doesn't currently have an easily recognizable trade name. What were the results? 12 American people (average age 50 years) with LMNA-related DCM took part in the study and received 400 mg or 100 mg of ARRY-371797 twice daily for 48 weeks. People knew which dose of ARRY-371797 they were taking. People were checked after 4, 12, 24, 36 and 48 weeks of taking ARRY-371797 to see how far they could walk in the 6-minute walk test (6MWT for short). The level of NT-proBNP in their blood was also measured. NT-proBNP is a biomarker used to measure the severity of heart failure. A biomarker is something found in the body that can be measured to indicate the extent of a disease. - After taking ARRY-371797 for 12 weeks, people were able to walk further in the 6MWT and had lower levels of NT-proBNP in their blood. This suggests improvement in functional capacity (exercise tolerance) and heart function. Researchers also asked people about their quality of life using the Kansas City Cardiomyopathy Questionnaire (KCCQ for short), and looked for any side effects. - Researchers saw some improvement in KCCQ scores. - Researchers saw no major side effects that they considered to be related to ARRY-371797 treatment. A side effect is something that people feel was caused by a medicine or treatment. Overall, this study showed that people with LMNA-related DCM who took ARRY-371797 had improved functional capacity (exercise tolerance), improved heart function, and improved quality of life. Phase 2 study ( NCT02057341 ) Phase 2 long-term extension study ( NCT02351856 ) Phase 3 REALM-DCM study ( NCT03439514 )

The cardiac phenotype of hereditary transthyretin amyloidosis (hTTR) usually presents as a restrictive or hypertrophic cardiomyopathy, and, although rarely observed as dilated cardiomyopathy (DCM), TTR is routinely included in DCM genetic testing panels. However, the prevalence and phenotypes of TTR variants in patients with DCM have not been reported.Exome sequences of 729 probands with idiopathic DCM were analyzed for TTR and 35 DCM genes.Rare TTR variants were identified in 2 (0.5%; 95% CI = 0.1%-1.8%) of 404 non-Hispanic White DCM probands; neither of them had features of hTTR. In 1 proband, a TTR His110Asn variant and a variant of uncertain significance in DSP were identified, and in the other proband, a TTR Val50Met variant known to cause hTTR and a likely pathogenic variant in FLNC were identified. The TTR Val142Ile variant was identified in 8 (3.0%) non-Hispanic Black probands, comparable with African/African American Genome Aggregation Database controls (OR = 1.01; 95% CI = 0.46-1.99).Among the 729 DCM probands, 2 had rare TTR variants identified without the features of hTTR, and both had other plausible genetic causes of DCM. Moreover, the frequency of TTR Val142Ile was comparable to a control sample. These findings suggest that hTTR variants may have a limited role in patients with DCM without TTR-specific findings.

What is this plain language summary about? This plain language summary describes some results of a study called ATTR-ACT. This was the first large study to include people with wild-type and hereditary transthyretin amyloid cardiomyopathy (ATTR-CM for short). ATTR-CM is a type of heart disease that happens when abnormal clumps of protein build up in the heart. This build-up prevents the heart from working properly, causing a condition called heart failure. Wild-type ATTR-CM happens for unknown reasons in some people as they get older. Hereditary ATTR-CM can happen because of changes in people's genes (known as gene variants or mutations). Important information about ATTR-ACT In this study, 441 people with ATTR-CM took either a medicine called tafamidis or a placebo (a capsule that looked like tafamidis but didn't contain any active medicine) by mouth for 30 months, once a day. The researchers' main aim was to find out how tafamidis treatment affected the risk of people dying or being admitted to the hospital for heart problems. They found that tafamidis lowered these risks by about one-third compared with placebo. What else did researchers find out in ATTR-ACT? As described in this summary, after ATTR-ACT was completed, researchers looked back at the results from people who took placebo to learn how ATTR-CM progressed without treatment. The researchers found that about 4 in 10 people with wild-type ATTR-CM who took placebo died and 6 in 10 were admitted to the hospital because of heart problems over 30 months. People who took placebo also could not walk as far at the end of the study as they did at the start because their heart function worsened over time. Why are these results important? By showing how ATTR-CM affects people's health when they do not take treatment, these results highlight the benefits of early diagnosis and treatment of ATTR-CM. ClinicalTrials.gov NCT number: NCT01994889

In 2021, the Medical University of South Carolina (MUSC) launched In Our DNA SC. This large-scale initiative will screen 100,000 individuals in South Carolina for three preventable hereditary conditions that impact approximately two million people in the USA but often go undetected. In anticipation of inevitable changes to the delivery of this complex initiative, we developed an approach to track and assess the impact of evaluate adaptations made during the pilot phase of program implementation. We used a modified version of the Framework for Reporting Adaptations and Modification-Enhanced (FRAME) and Adaptations to code adaptations made during the 3-month pilot phase of In Our DNA SC. Adaptations were documented in real-time using a REDCap database. We used segmented linear regression models to independently test three hypotheses about the impact of adaptations on program reach (rate of enrollment in the program, rate of messages viewed) and implementation (rate of samples collected) 7 days pre- and post-adaptation. Effectiveness was assessed using qualitative observations. Ten adaptations occurred during the pilot phase of program implementation. Most adaptations (60%) were designed to increase the number and type of patient contacted (reach). Adaptations were primarily made based on knowledge and experience (40%) or from quality improvement data (30%). Of the three adaptations designed to increase reach, shortening the recruitment message potential patients received significantly increased the average rate of invitations viewed by 7.3% (p = 0.0106). There was no effect of adaptations on implementation (number of DNA samples collected). Qualitative findings support improvement in effectiveness of the intervention after shortening the consent form and short-term positive impact on uptake of the intervention as measured by team member’s participation. Our approach to tracking adaptations of In Our DNA SC allowed our team to quantify the utility of modifications, make decisions about pursuing the adaptation, and understand consequences of the change. Streamlining tools for tracking and responding to adaptations can help monitor the incremental impact of interventions to support continued learning and problem solving for complex interventions being delivered in health systems based on real-time data.

BackgroundAs availability of genomic testing grows, variant interpretation will increasingly be performed by genomic generalists, rather than domain-specific experts. Demand is rising for laboratories to accurately classify variants in inherited cardiac condition (ICC) genes, including as secondary findings.MethodsWe analyse evidence for inheritance patterns, allelic requirement, disease mechanism and disease-relevant variant classes for 65 ClinGen-curated ICC gene-disease pairs. We present this information for the first time in a structured dataset, CardiacG2P, and assess application in genomic variant filtering.ResultsFor 36/65 gene-disease pairs, loss-of-function is not an established disease mechanism, and protein truncating variants are not known to be pathogenic. Using CardiacG2P as an initial variant filter allows for efficient variant prioritisation whilst maintaining a high sensitivity for retaining pathogenic variants compared with two other variant filtering approaches.ConclusionsAccess to evidence-based structured data representing disease mechanism and allelic requirement aids variant filtering and analysis and is pre-requisite for scalable genomic testing.

What is this plain language summary about? This summary explains the results of a long-term extension study on the effects of a specific medicine. A long-term extension study allows people who have already completed a research study to continue taking treatment. Researchers can then look at how a treatment works over a long period of time. This extension study looked at the effects of a medicine called ARRY-371797 (also known as PF-07265803) in people with dilated cardiomyopathy (DCM for short) caused by a faulty lamin A/C gene (also known as the LMNA gene). This condition is called LMNA-related DCM. In people with LMNA-related DCM, the heart muscle becomes thinner and weaker than normal. This can lead to heart failure, where the heart is unable to pump enough blood around the body. The extension study allowed people who had completed an earlier 48-week study to continue taking ARRY-371797 for another 96 weeks (around 22 months). What were the results of the extension study? 8 people joined the extension study and continued with the dose of ARRY-371797 that they had taken in the first study. This means that people could have taken ARRY-371797 continuously for up to 144 weeks (around 2 years and 9 months). Using the 6-minute walk test (6MWT for short), researchers regularly checked people taking ARRY-371797 to see how far they could walk. Throughout the extension study, people were able to walk further than they could before they started taking ARRY-371797. This suggests that people could maintain the improvements in their ability to do daily activities with long-term ARRY-371797 treatment. Researchers also looked at how severe people's heart failure was by using a test that measures levels of a biomarker called NT-proBNP. A biomarker is something found in the body that can be measured to indicate the extent of a disease. Throughout this study, the levels of NT-proBNP in people's blood was lower than before they started taking ARRY-371797. This suggests that they maintained stable heart function. Using the Kansas City Cardiomyopathy Questionnaire (KCCQ for short), researchers asked people about their quality of life, and if they experienced any side effects. A side effect is something that people feel while taking a treatment. Researchers evaluate if a side effect is related to the treatment or not. Some improvement in KCCQ response during the study was seen, although results were varied. There were no serious side effects that were considered related to treatment with ARRY-371797. What do the results of the extension study mean? Researchers found that the improvements in functional capacity and heart function seen with ARRY-371797 treatment in the original study were maintained with long-term treatment. Larger studies are needed to determine if ARRY-371797 could be an effective treatment for people with LMNA-related DCM. One such study (called REALM-DCM) was started in 2018 but ended early, as it was unlikely to show a clear treatment benefit of ARRY-371797. Phase 2 long-term extension study ( NCT02351856 ) Phase 2 study ( NCT02057341 ) Phase 3 REALM-DCM study ( NCT03439514 )

Transthyretin amyloid cardiomyopathy (ATTR-CM) is an underdiagnosed disease and an underestimated cause of both heart failure and conduction abnormalities. It is characterized by pathologic accumulation of extracellular protein arising from unstable transthyretin (TTR) tetramers, which dissociate into monomers that misfold, aggregate, and form insoluble fibrils that are resistant to proteolysis. Cardiac amyloidosis appears in two distinct forms: hereditary and wild-type. There is considerable heterogeneity in the clinical presentation of ATTR, ranging from primarily cardiac, primarily neuropathic, or mixed cardiac and neuropathic disease. Pathogenic variants in the

Background: Lamin A/C gene ( LMNA )-related dilated cardiomyopathy is a serious and life-threatening condition with a high unmet medical need. This phase 2 study assessed the effects of the oral selective p38 mitogen-activated protein kinase inhibitor ARRY-371797 on functional capacity and cardiac function in patients with LMNA -related dilated cardiomyopathy. Methods: Patients with LMNA -related dilated cardiomyopathy in New York Heart Association class II–IIIA, on background heart failure treatment, received ARRY-371797 100 or 400 mg twice daily for 48 weeks. The primary end point was change from baseline in the 6-minute walk test distance at 12 weeks. Secondary end points included changes over time in 6-minute walk test distance, NT-proBNP (N-terminal pro-B-type natriuretic peptide) concentration, left ventricular ejection fraction, and quality-of-life scores on the Kansas City Cardiomyopathy Questionnaire. Data from the 2 dose groups were combined. Results: Twelve patients were enrolled; median (minimum, maximum) 6-minute walk test distance at baseline was 314 (246, 412) m. At week 12, the mean (80% CI) increase from baseline in 6-minute walk test distance was 69 (39, 100) m (median, 47 m). Median NT-proBNP concentration declined from 1409 pg/mL at baseline to 848 pg/mL at week 12. Mean left ventricular ejection fraction was stable at week 12. There was a trend toward improvement in Kansas City Cardiomyopathy Questionnaire Overall and Clinical Summary scores at week 12. No clinically significant drug-related safety concerns were identified. Conclusions: ARRY-371797 was well tolerated and resulted in potential increases in functional capacity and lower concentrations of cardiac biomarker NT-proBNP in patients with LMNA -related dilated cardiomyopathy. Registration: URL: https://clinicaltrials.gov ; Unique identifier: NCT02057341.

Lamin A/C gene (Patients withTwelve patients were enrolled; median (minimum, maximum) 6-minute walk test distance at baseline was 314 (246, 412) m. At week 12, the mean (80% CI) increase from baseline in 6-minute walk test distance was 69 (39, 100) m (median, 47 m). Median NT-proBNP concentration declined from 1409 pg/mL at baseline to 848 pg/mL at week 12. Mean left ventricular ejection fraction was stable at week 12. There was a trend toward improvement in Kansas City Cardiomyopathy Questionnaire Overall and Clinical Summary scores at week 12. No clinically significant drug-related safety concerns were identified.ARRY-371797 was well tolerated and resulted in increases in functional capacity and lower concentrations of cardiac biomarker NT-proBNP in patients withURL: https://clinicaltrials.gov; Unique identifier: NCT02057341.

This plain language summary describes some results of a study called ATTR-ACT. This was the first large study to include people with wild-type and hereditary transthyretin amyloid cardiomyopathy (ATTR-CM for short). ATTR-CM is a type of heart disease that happens when abnormal clumps of protein build up in the heart. This build-up prevents the heart from working properly, causing a condition called heart failure. Wild-type ATTR-CM happens for unknown reasons in some people as they get older. Hereditary ATTR-CM can happen because of changes in people's genes (known as gene variants or mutations).In this study, 441 people with ATTR-CM took either a medicine called tafamidis or a placebo (a capsule that looked like tafamidis but didn't contain any active medicine) by mouth for 30 months, once a day. The researchers' main aim was to find out how tafamidis treatment affected the risk of people dying or being admitted to the hospital for heart problems. They found that tafamidis lowered these risks by about one-third compared with placebo.As described in this summary, after ATTR-ACT was completed, researchers looked back at the results from people who took placebo to learn how ATTR-CM progressed without treatment. The researchers found that about 4 in 10 people with wild-type ATTR-CM who took placebo died and 6 in 10 were admitted to the hospital because of heart problems over 30 months. People who took placebo also could not walk as far at the end of the study as they did at the start because their heart function worsened over time.By showing how ATTR-CM affects people's health when they do not take treatment, these results highlight the benefits of early diagnosis and treatment of ATTR-CM. ClinicalTrials.gov NCT number: NCT01994889.

Supplemental Digital Content is available in the text., Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited disease characterized by ventricular arrhythmias and progressive ventricular dysfunction. Genetic testing is recommended, and a pathogenic variant in an ARVC-associated gene is a major criterion for diagnosis according to the 2010 Task Force Criteria. As incorrect attribution of a gene to ARVC can contribute to misdiagnosis, we assembled an international multidisciplinary ARVC Clinical Genome Resource Gene Curation Expert Panel to reappraise all reported ARVC genes. Methods: Following a comprehensive literature search, six 2-member teams conducted blinded independent curation of reported ARVC genes using the semiquantitative Clinical Genome Resource framework. Results: Of 26 reported ARVC genes, only 6 (PKP2, DSP, DSG2, DSC2, JUP, and TMEM43) had strong evidence and were classified as definitive for ARVC causation. There was moderate evidence for 2 genes, DES and PLN. The remaining 18 genes had limited or no evidence. RYR2 was refuted as an ARVC gene since clinical data and model systems exhibited a catecholaminergic polymorphic ventricular tachycardia phenotype. In ClinVar, only 5 pathogenic/likely pathogenic variants (1.1%) in limited evidence genes had been reported in ARVC cases in contrast to 450 desmosome gene variants (97.4%). Conclusions: Using the Clinical Genome Resource approach to gene-disease curation, only 8 genes (PKP2, DSP, DSG2, DSC2, JUP, TMEM43, PLN, and DES) had definitive or moderate evidence for ARVC, and these genes accounted for nearly all pathogenic/likely pathogenic ARVC variants in ClinVar. Therefore, only pathogenic/likely pathogenic variants in these 8 genes should yield a major criterion for ARVC diagnosis. Pathogenic/likely pathogenic variants identified in other genes in a patient should prompt further phenotyping as variants in many of these genes are associated with other cardiovascular conditions.

Transthyretin (TTR), a plasma transport protein produced in the liver, is prone to misfolding, leading to the deposition of amyloid fibrils and progressive dysfunction of cardiac and nervous system tissues, a condition known as amyloid TTR (ATTR) amyloidosis. More than 140 different pathogenic variants in TTR have been documented, most of which cause hereditary forms of ATTR amyloidosis. The most common mutations, traditionally known as Val30Met, Val122Ile, and Thr60Ala, lead to predominantly sensory, motor, and autonomic neuropathies, cardiomyopathy, and mixed presentations, respectively, although each mutation may cause symptoms across the neurologic and cardiac spectrum. Val30Met is endemic to Brazil, Japan, Portugal, and Sweden. The Val122Ile variant is present in 3.4% of people with West African ancestry, whereas Thr60Ala originated in northwestern Ireland and spread to the rest of the United Kingdom, the United States, and elsewhere. Val30Met and Thr60Ala tend to have more aggressive clinical presentations at younger ages, whereas Val122Ile predominantly affects older Black men. Due to similarities with hypertrophic cardiomyopathy, heart failure with preserved ejection fraction, and other overlapping conditions, ATTR cardiomyopathy is often under recognized and underdiagnosed, especially in Val122Ile carriers. Understanding these carrier populations and differences in ATTR amyloidosis characteristics associated with each variant is essential for appropriate diagnosis and genetic counseling of affected patients and their relatives.

Background and Objectives: Genomic information is increasingly relevant for disease prevention and risk management at the individual and population levels. Screening healthy adults for Tier 1 conditions of hereditary breast and ovarian cancer, Lynch syndrome, and familial hypercholesterolemia using a population-based approach can help identify the 1–2% of the US population at increased risk of developing diseases associated with these conditions and tailor prevention strategies. Our objective is to report findings from an implementation science study that evaluates multi-level facilitators and barriers to implementation of the In Our DNA SC population-wide genomic screening initiative. Methods: We established an IMPACTeam (IMPlementAtion sCience for In Our DNA SC Team) to evaluate the pilot phase using principles of implementation science. We used a parallel convergent mixed methods approach to assess the Reach, Implementation, and Effectiveness outcomes from the RE-AIM implementation science framework during the pilot phase of In Our DNA SC. Quantitative assessment included the examination of frequencies and response rates across demographic categories using chi-square tests. Qualitative data were audio-recorded and transcribed, with codes developed by the study team based on the semi-structured interview guide. Results: The pilot phase (8 November 2021, to 7 March 2022) included recruitment from ten clinics throughout South Carolina. Reach indicators included enrollment rate and representativeness. A total of 23,269 potential participants were contacted via Epic’s MyChart patient portal with 1976 (8.49%) enrolled. Black individuals were the least likely to view the program invitation (28.9%) and take study-related action. As a result, there were significantly higher enrollment rates among White (10.5%) participants than Asian (8.71%) and Black (3.46%) individuals (p < 0.0001). Common concerns limiting reach and participation included privacy and security of results and the impact participation would have on health or life insurance. Facilitators included family or personal history of a Tier 1 condition, prior involvement in genetic testing, self-interest, and altruism. Assessment of implementation (i.e., adherence to protocols/fidelity to protocols) included sample collection rate (n = 1104, 55.9%) and proportion of samples needing recollection (n = 19, 1.7%). There were no significant differences in sample collection based on demographic characteristics. Implementation facilitators included efficient collection processes and enthusiastic clinical staff. Finally, we assessed the effectiveness of the program, finding low dropout rates (n = 7, 0.35%), the identification of eight individuals with Tier 1 conditions (0.72% positive), and high rates of follow-up genetic counseling (87.5% completion). Conclusion: Overall, Asian and Black individuals were less engaged, with few taking any study-related actions. Strategies to identify barriers and promoters for the engagement of diverse populations are needed to support participation. Once enrolled, individuals had high rates of completing the study and follow-up engagement with genetic counselors. Findings from the pilot phase of In Our DNA SC offer opportunities for improvement as we expand the program and can provide guidance to organizations seeking to begin efforts to integrate population-wide genomic screening.

Rare diseases are increasingly recognized as a global public health priority. Governments worldwide currently provide important incentives to stimulate the discovery and development of orphan drugs for the treatment of these conditions, but substantial scientific, clinical, and regulatory challenges remain. Tafamidis is a first-in-class, disease-modifying transthyretin (TTR) kinetic stabilizer that represents a major breakthrough in the treatment of transthyretin amyloidosis (ATTR amyloidosis). ATTR amyloidosis is a rare, progressive, and fatal systemic disorder caused by aggregation of misfolded TTR and extracellular deposition of amyloid fibrils in various tissues and organs, including the heart and nervous systems. In this review, we present the successful development of tafamidis spanning 3 decades, marked by meticulous laboratory research into disease mechanisms and natural history, and innovative clinical study design and implementation. These efforts established the safety and efficacy profile of tafamidis, leading to its regulatory approval, and enabled post-approval initiatives that further support patients with ATTR amyloidosis.

Background Recurrent congestion in cardiac amyloidosis (CA) remains a management challenge, often requiring high dose diuretics and frequent hospitalizations. Innovative outpatient strategies are needed to effectively manage heart failure (HF) in patients with CA. Ambulatory diuresis has not been well studied in restrictive cardiomyopathy. Therefore, we aimed to examine the outcomes of an ambulatory diuresis clinic in the management of congestion related to CA. Methods and Results We retrospectively studied patients with CA seen in an outpatient HF disease management clinic for (1) safety outcomes of ambulatory intravenous (IV) diuresis and (2) health care utilization. Forty-four patients with CA were seen in the clinic a total of 203 times over 6 months. Oral diuretics were titrated at 96 (47%) visits. IV diuretics were administered at 56 (28%) visits to 17 patients. There were no episodes of severe acute kidney injury or symptomatic hypotension. There was a significant decrease in emergency department and inpatient visits and associated charges after index visit to the clinic. The proportion of days hospitalized per 1000 patient days of follow-up decreased as early as 30 days (147.3 vs 18.1/1000 patient days of follow-up, P Conclusions We demonstrate the feasibility of ambulatory IV diuresis in patients with CA. Our findings also suggest that use of a HF disease management clinic may reduce acute care utilization in patients with CA. Leveraging multidisciplinary outpatient HF clinics may be an effective alternative to hospitalization in patients with HF due to CA, a population who otherwise carries a poor prognosis and contributes to high health care burden.

© 2020 Elsevier Ltd. All rights reserved., Background: Hereditary transthyretin-mediated amyloidosis is a rare, inherited, progressive disease caused by mutations in the transthyretin (TTR) gene. We assessed the safety and efficacy of long-term treatment with patisiran, an RNA interference therapeutic that inhibits TTR production, in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy. Methods: This multicentre, open-label extension (OLE) trial enrolled patients at 43 hospitals or clinical centres in 19 countries as of Sept 24, 2018. Patients were eligible if they had completed the phase 3 APOLLO or phase 2 OLE parent studies and tolerated the study drug. Eligible patients from APOLLO (patisiran and placebo groups) and the phase 2 OLE (patisiran group) studies enrolled in this global OLE trial and received patisiran 0·3 mg/kg by intravenous infusion every 3 weeks with plans to continue to do so for up to 5 years. Efficacy assessments included measures of polyneuropathy (modified Neuropathy Impairment Score +7 [mNIS+7]), quality of life, autonomic symptoms, nutritional status, disability, ambulation status, motor function, and cardiac stress, with analysis by study groups (APOLLO-placebo, APOLLO-patisiran, phase 2 OLE patisiran) based on allocation in the parent trial. The global OLE is ongoing with no new enrolment, and current findings are based on the interim analysis of the patients who had completed 12-month efficacy assessments as of the data cutoff. Safety analyses included all patients who received one or more dose of patisiran up to the data cutoff. This study is registered with ClinicalTrials.gov, NCT02510261. Findings: Between July 13, 2015, and Aug 21, 2017, of 212 eligible patients, 211 were enrolled: 137 patients from the APOLLO-patisiran group, 49 from the APOLLO-placebo group, and 25 from the phase 2 OLE patisiran group. At the data cutoff on Sept 24, 2018, 126 (92%) of 137 patients from the APOLLO-patisiran group, 38 (78%) of 49 from the APOLLO-placebo group, and 25 (100%) of 25 from the phase 2 OLE patisiran group had completed 12-month assessments. At 12 months, improvements in mNIS+7 with patisiran were sustained from parent study baseline with treatment in the global OLE (APOLLO-patisiran mean change -4·0, 95 % CI -7·7 to -0·3; phase 2 OLE patisiran -4·7, -11·9 to 2·4). Mean mNIS+7 score improved from global OLE enrolment in the APOLLO-placebo group (mean change from global OLE enrolment -1·4, 95% CI -6·2 to 3·5). Overall, 204 (97%) of 211 patients reported adverse events, 82 (39%) reported serious adverse events, and there were 23 (11%) deaths. Serious adverse events were more frequent in the APOLLO-placebo group (28 [57%] of 49) than in the APOLLO-patisiran (48 [35%] of 137) or phase 2 OLE patisiran (six [24%] of 25) groups. The most common treatment-related adverse event was mild or moderate infusion-related reactions. The frequency of deaths in the global OLE was higher in the APOLLO-placebo group (13 [27%] of 49), who had a higher disease burden than the APOLLO-patisiran (ten [7%] of 137) and phase 2 OLE patisiran (0 of 25) groups. Interpretation: In this interim 12-month analysis of the ongoing global OLE study, patisiran appeared to maintain efficacy with an acceptable safety profile in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy. Continued long-term follow-up will be important for the overall assessment of safety and efficacy with patisiran.

Background: Coronary angiography to identify coronary artery disease has been foundational to distinguish the cause of dilated cardiomyopathy (DCM), including the assignment of idiopathic or ischemic cardiomyopathy. Late gadolinium enhancement (LGE) with cardiovascular magnetic resonance (CMR) has emerged as an approach to identify myocardial scar and identify etiology. Methods: The DCM Precision Medicine Study included patients with left ventricular dilation and dysfunction attributed to idiopathic DCM, after expert clinical review excluded ischemic or other cardiomyopathies. Ischemic cardiomyopathy was defined as coronary artery disease with >50% narrowing at angiography of ≥1 epicardial coronary artery. CMR was not required for study inclusion, but in a post hoc analysis of available CMR reports, patterns of LGE were classified as (1) no LGE, (2) ischemic-pattern LGE: subendocardial/transmural, (3) nonischemic LGE: midmyocardial/epicardial. Results: Of 1204 idiopathic DCM patients evaluated, 396 (32.9%) had a prior CMR study; of these, 327 (82.6% of 396) had LGE imaging (mean age 46 years; 53.2% male; 55.4% White); 178 of the 327 (54.4%) exhibited LGE, and 156 of the 178 had LGE consistent with idiopathic DCM. The remaining 22 had transmural or subendocardial LGE. Of these 22, coronary angiography was normal (13), showed luminal irregularities (3), a distant thrombus (1), coronary artery disease with Conclusions: Of 327 probands enrolled in the DCM Precision Medicine Study cohort who had LGE-CMR data available, an ischemic-pattern of LGE was identified in 22 (6.7%), all of whom had idiopathic DCM as adjudicated by expert clinical review. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03037632.

TNNI3K expression worsens disease progression in several mouse heart pathology models. TNNI3K expression also reduces the number of diploid cardiomyocytes, which may be detrimental to adult heart regeneration. However, the gene is evolutionarily conserved, suggesting a beneficial function that has remained obscure. Here, we show that C57BL/6J-inbred Tnni3k mutant mice develop concentric remodeling, characterized by ventricular wall thickening and substantial reduction of cardiomyocyte aspect ratio. This pathology occurs in mice carrying a Tnni3k null allele, a K489R point mutation rendering the protein kinase-dead, or an allele corresponding to human I686T, the most common human non-synonymous TNNI3K variant, which is hypomorphic for kinase activity. Mutant mice develop these conditions in the absence of fibrosis or hypertension, implying a primary cardiomyocyte etiology. In culture, mutant cardiomyocytes were impaired in contractility and calcium dynamics and in protein kinase A signaling in response to isoproterenol, indicating diminished contractile reserve. These results demonstrate a beneficial function of TNNI3K in the adult heart that might explain its evolutionary conservation and imply that human TNNI3K variants, in particular the widespread I686T allele, may convey elevated risk for altered heart geometry and hypertrophy.

In the absence of contemporary, population-based epidemiological studies, estimates of the incidence and prevalence of the inherited cardiomyopathies have been derived from screening studies, most often of young adult populations, to assess cardiovascular risk or to detect the presence of disease in athletes or military recruits. The global estimates for hypertrophic cardiomyopathy (1/500 individuals), dilated cardiomyopathy (1/250) and arrhythmogenic right ventricular cardiomyopathy (1/5,000) are probably conservative given that only individuals who fulfil diagnostic criteria would have been included. This caveat is highly relevant because a substantial minority or even a majority of individuals who carry disease-causing genetic variants and are at risk of disease complications have incomplete and/or late-onset disease expression. The genetic literature on cardiomyopathy, which is often focused on the identification of genetic variants, has been biased in favour of pedigrees with higher penetrance. In clinical practice, an abnormal electrocardiogram with normal or non-diagnostic imaging results is a common finding for the sarcomere variants that cause hypertrophic cardiomyopathy, the titin and sarcomere variants that cause dilated cardiomyopathy and the desmosomal variants that cause either arrhythmogenic right ventricular cardiomyopathy or dilated cardiomyopathy. Therefore, defining the genetic epidemiology is also challenging given the overlapping phenotypes, incomplete and age-related expression, and highly variable penetrance even within individual families carrying the same genetic variant.

Objectives This study prospectively evaluated endomyocardial biopsies in patients with heart failure with preserved ejection fraction (HFpEF) to identify histopathologic phenotypes and their association with clinical characteristics. Background Myocardial tissue analysis from a prospectively defined HFpEF cohort reflecting contemporary comorbidities is lacking. Methods Patients with HFpEF (EF ≥50%) referred to the Johns Hopkins HFpEF Clinic between August 2014 and September 2018 were enrolled for right heart catheterization and endomyocardial biopsy. Clinical features, echocardiography, hemodynamics, and tissue histology were determined and compared with controls (unused donor hearts) and HF with reduced EF (HFrEF). Results Of the 108 patients enrolled, median age was 66 years (25th to 75th percentile: 57 to 74 years), 61% were women, 57% were African American, 62% had a previous HF hospitalization, median systolic blood pressure was 141 mm Hg (25th to 75th percentile: 125 to 162 mm Hg), body mass index (BMI) was 37 kg/m2 (25th to 75th percentile: 32 to 45 kg/m2), and 97% were on a loop diuretic. Myocardial fibrosis and myocyte hypertrophy were often present (93% and 88%, respectively); however, mild in 71% with fibrosis and in 52% with hypertrophy. Monocyte infiltration (CD68+ cells/mm2) was greater in patients with HFpEF versus controls (60.4 cells/mm2 [25th to 75th percentile: 36.8 to 97.8] vs. 32.1 cells/mm2 [25th to 75th percentile: 22.3 to 59.2]; p = 0.02) and correlated with age and renal disease. Cardiac amyloidosis (CA) was diagnosed in 15 (14%) patients (HFpEF-CA: 7 patients with wild-type transthyretin amyloidosis [ATTR], 4 patients with hereditary ATTR, 3 patients with light-chain amyloidosis, and 1 patient with AA (secondary) amyloidosis), of which 7 cases were unsuspected. Patients with HFpEF-CA were older, with lower BMI, higher left ventricular mass index, and higher N-terminal pro−B-type natriuretic peptide and troponin I levels. Conclusions In this large, prospective myocardial tissue analysis of HFpEF, myocardial fibrosis and hypertrophy were common, CD68+ inflammation was increased, and CA prevalence was 14%. Tissue analysis in HFpEF might improve precision therapies by identifying relevant myocardial mechanisms.

Background Gastrointestinal bleeding (GIB) is common in left ventricular assist device (LVAD) patients. Serotonin release from platelets promotes platelet aggregation, and selective serotonin reuptake inhibitor/serotonin-norepinephrine reuptake inhibitor (SSRI/SNRI) therapy inhibits the transporter responsible for re-uptake. Methods We reviewed the records of LVAD (HeartMateII™, Abbott Medical, Lake Bluff, IL, USA and Heartware™, Medtronic, Minneapolis, MN, USA) patients at the Medical University of South Carolina and Johns Hopkins Hospital between January 2009 and January 2016. After exclusions, 248 patients were included for analysis. After univariate analysis, logistic regression multivariate analysis was performed to adjust for any demographic, cardiovascular, and laboratory data variables found to be associated with GI bleeding post-LVAD. Results Gastrointestinal bleeding occurred in 85 patients (35%) with 55% of GIBs due to arteriovenous malformations (AVMs). Of the total cohort, 105 patients received an SSRI or SNRI during LVAD support. Forty-four (44) SSRI/SNRI (41.9%) and 41 non-SSRI/SNRI (28.7%) patients had a GIB (RR 1.46, p = 0.03). Twenty-six (26) (24.8%) of the SSRI/SNRI patients had a GIB due to AVMs versus 21 (14.7%) of the non-SSRI/SNRI patients (RR 1.69, p = 0.05). In fully-adjusted multivariate regression analysis, SSRI/SNRI therapy was independently associated with GIB (OR 1.78, p = 0.045). For GIB, the number needed to harm (NNH) was 7.6. Conclusion In conclusion, SSRI/SNRI therapy is independently associated with an increased risk of GIB in LVAD patients.

Purpose The Phase 3 ENDEAVOUR study evaluated revusiran, an investigational RNA interference therapeutic targeting hepatic transthyretin (TTR) production, for treating cardiomyopathy caused by hereditary transthyretin-mediated (hATTR) amyloidosis. Methods Patients with hATTR amyloidosis with cardiomyopathy were randomized 2:1 to receive subcutaneous daily revusiran 500 mg (n = 140) or placebo (n = 66) for 5 days over a week followed by weekly doses. Co-primary endpoints were 6-min walk test distance and serum TTR reduction. Results Revusiran treatment was stopped after a median of 6.71 months; the study Sponsor prematurely discontinued dosing due to an observed mortality imbalance between treatment arms. Eighteen (12.9%) patients on revusiran and 2 (3.0%) on placebo died during the on-treatment period. Most deaths in both treatment arms were adjudicated as cardiovascular due to heart failure (HF), consistent with the natural history of the disease. A post hoc safety investigation of patients treated with revusiran found that, at baseline, a greater proportion of those who died were ≥ 75 years and showed clinical evidence of more advanced HF compared with those who were alive throughout treatment. Revusiran pharmacokinetic exposures and TTR lowering did not show meaningful differences between patients who died and who were alive. Revusiran did not deleteriously affect echocardiographic parameters, cardiac biomarkers, or frequency of cardiovascular and HF hospitalization events. Conclusions Causes for the observed mortality imbalance associated with revusiran were thoroughly investigated and no clear causative mechanism could be identified. Although the results suggest similar progression of cardiac parameters in both treatment arms, a role for revusiran cannot be excluded. Clinical Trial Registration NCT02319005.

Idiopathic dilated cardiomyopathy (DCM) aggregates in families, and early detection in at-risk family members can provide opportunity to initiate treatment prior to late-phase disease. Most studies have included only White patients, yet Black patients with DCM have higher risk of heart failure-related hospitalization and death.To estimate the prevalence of familial DCM among DCM probands and the age-specific cumulative risk of DCM in first-degree relatives across race and ethnicity groups.A family-based, cross-sectional study conducted by a multisite consortium of 25 US heart failure programs. Participants included patients with DCM (probands), defined as left ventricular systolic dysfunction and left ventricular enlargement after excluding usual clinical causes, and their first-degree relatives. Enrollment commenced June 7, 2016; proband and family member enrollment concluded March 15, 2020, and April 1, 2021, respectively.The presence of DCM in a proband.Familial DCM defined by DCM in at least 1 first-degree relative; expanded familial DCM defined by the presence of DCM or either left ventricular enlargement or left ventricular systolic dysfunction without known cause in at least 1 first-degree relative.The study enrolled 1220 probands (median age, 52.8 years [IQR, 42.4-61.8]; 43.8% female; 43.1% Black and 8.3% Hispanic) and screened 1693 first-degree relatives for DCM. A median of 28% (IQR, 0%-60%) of living first-degree relatives were screened per family. The crude prevalence of familial DCM among probands was 11.6% overall. The model-based estimate of the prevalence of familial DCM among probands at a typical US advanced heart failure program if all living first-degree relatives were screened was 29.7% (95% CI, 23.5% to 36.0%) overall. The estimated prevalence of familial DCM was higher in Black probands than in White probands (difference, 11.3% [95% CI, 1.9% to 20.8%]) but did not differ significantly between Hispanic probands and non-Hispanic probands (difference, -1.4% [95% CI, -15.9% to 13.1%]). The estimated prevalence of expanded familial DCM was 56.9% (95% CI, 50.8% to 63.0%) overall. Based on age-specific disease status at enrollment, estimated cumulative risks in first-degree relatives at a typical US advanced heart failure program reached 19% (95% CI, 13% to 24%) by age 80 years for DCM and 33% (95% CI, 27% to 40%) for expanded DCM inclusive of partial phenotypes. The DCM hazard was higher in first-degree relatives of non-Hispanic Black probands than non-Hispanic White probands (hazard ratio, 1.89 [95% CI, 1.26 to 2.83]).In a US cross-sectional study, there was substantial estimated prevalence of familial DCM among probands and modeled cumulative risk of DCM among their first-degree relatives.ClinicalTrials.gov Identifier: NCT03037632.

ImportanceCardiovascular disease contributes outsized mortality in patients from underrepresented racial and ethnic groups. Understanding levels of trust in medical researchers and knowledge of genome sequencing may help identify barriers to research participation and develop strategies to educate patients about the role of genetics in cardiovascular disease.ObjectiveTo assess racial and ethnic differences in trust in medical researchers and genome-sequencing knowledge among patients with idiopathic dilated cardiomyopathy and determine the association between trust in medical researchers and genome-sequencing knowledge.Design, Setting, and ParticipantsThis cross-sectional study conducted by a consortium of 25 US heart failure programs included patients with idiopathic dilated cardiomyopathy defined as left ventricular systolic dysfunction and left ventricular enlargement after excluding usual clinical causes. Enrollment occurred from June 7, 2016, to March 15, 2020.Main Outcomes and MeasuresPercent distributions, means, and associations of genome-sequencing knowledge scores and research trust scores for Hispanic, non-Hispanic Black (hereafter referred to as Black), and non-Hispanic White participants (hereafter referred to as White).ResultsAmong 1121 participants, mean (SD) age was 51.6 (13.6) years with 41.4% Black, 8.5% Hispanic, and 43.4% female. After accounting for site effects, the level of genome-sequencing knowledge was lower in Hispanic and Black participants compared with White participants (mean score difference, −2.6; 95% CI, −3.9 to −1.2 and mean score difference, −2.9; 95% CI, −3.6 to −2.2, respectively). The level of trust in researchers was lowest in Black participants (mean score, 27.7), followed by Hispanic participants (mean score, 29.4) and White participants (mean score, 33.9). Racial and ethnic differences remained after adjusting for education, age at enrollment, duration of dilated cardiomyopathy, and health status. A higher level of trust was associated with a higher level of genome-sequencing knowledge within different racial and ethnic groups.Conclusions and RelevanceIn this cross-sectional study, large racial and ethnic differences in levels of genome-sequencing knowledge and trust in medical researchers were observed among patients with dilated cardiomyopathy. Findings from this study can inform future studies that aim to enhance the uptake of genomic knowledge and level of trust in medical researchers.

Introduction: Dilated cardiomyopathy due to LMNA gene mutations ( LMNA -DCM) accounts for ~6% of DCM cases and is a life-threatening condition with a high unmet need. No disease-specific treatment targeting the underlying mechanism of disease is currently available. ARRY-371797 (PF-0765803), a potent, selective, oral, small-molecule inhibitor of the p38α MAPK pathway, improved exercise capacity (6MWT) in symptomatic LMNA -DCM patients (n=12) in a 48-week, open-label, Phase 2 study. Methods: This was an open-label rollover study of the long-term safety and efficacy of ARRY-371797 in symptomatic LMNA -DCM patients previously participating in the Phase 2 parent study, with eligible patients continuing on the same dose. Safety and efficacy assessments (6MWT, NT-proBNP, and KCCQ) were performed at Weeks 48, 72, 96, 120, and 144 from treatment initiation in the parent study. Results: Eight patients were enrolled (mean [SD] age, 51 [10] years; 4 males). There was a >30 m mean improvement and >10% mean increase in 6MWT distance from parent study baseline up to Week 120 ( Table ), with 3 patients (37.5%) having ≥10% improvement from baseline to Week 144. The decrease in mean NT-proBNP concentration in the parent study was maintained ( Table ). KCCQ Physical Limitation score increased at all visits except Week 48. Changes in KCCQ Clinical Summary and Overall Summary scores were variable. Treatment was generally well tolerated: 3 patients discontinued due to causes not considered treatment-related (UTI and nausea, CRT-D, and LVAD implantation); 2 experienced Grade 1 adverse events considered treatment-related. There were no deaths. Conclusions: ARRY-371797 was generally well tolerated, with evidence suggesting preserved exercise capacity over >2 years’ follow-up. Efficacy and safety of ARRY-371797 is being investigated in the REALM-DCM trial, an ongoing, pivotal, Phase 3, randomized, placebo-controlled study in LMNA -DCM.