•A majority (67%) of patients with cardiogenic shock (CS) admitted to North American cardiac intensive care units have heart failure-related CS (HF-CS) unrelated to acute myocardial ...infarction.•Approximately 1 in 4 patients with HF-CS present with de novo HF-CS, defined as no known prior history of heart failure.•Compared to patients with acute-on-chronic HF-CS, those with de novo HF-CS have more severe shock, greater end-organ injury and higher in-hospital mortality.
Heart failure-related cardiogenic shock (HF-CS) accounts for an increasing proportion of cases of CS in contemporary cardiac intensive care units. Whether the chronicity of HF identifies distinct clinical profiles of HF-CS is unknown.
We evaluated admissions to cardiac intensive care units for HF-CS in 28 centers using data from the Critical Care Cardiology Trials Network registry (2017–2020). HF-CS was defined as CS due to ventricular failure in the absence of acute myocardial infarction and was classified as de novo vs acute-on-chronic based on the absence or presence of a prior diagnosis of HF, respectively. Clinical features, resource use, and outcomes were compared among groups. Of 1405 admissions with HF-CS, 370 had de novo HF-CS (26.3%), and 1035 had acute-on-chronic HF-CS (73.7%). Patients with de novo HF-CS had a lower prevalence of hypertension, diabetes, coronary artery disease, atrial fibrillation, and chronic kidney disease (all P < 0.01). Median Sequential Organ Failure Assessment (SOFA) scores were higher in those with de novo HF-CS (8; 25th–75th: 5–11) vs acute-on-chronic HF-CS (6; 25th–75th: 4–9, P < 0.01), as was the proportion of Society of Cardiovascular Angiography and Intervention (SCAI) shock stage E (46.1% vs 26.1%, P < 0.01). After adjustment for clinical covariates and preceding cardiac arrest, the risk of in-hospital mortality was higher in patients with de novo HF-CS than in those with acute-on-chronic HF-CS (adjusted hazard ratio 1.36, 95% confidence interval 1.05–1.75, P = 0.02).
Despite having fewer comorbidities, patients with de novo HF-CS had more severe shock presentations and worse in-hospital outcomes. Whether HF disease chronicity is associated with time-dependent compensatory adaptations, unique pathobiological features and responses to treatment in patients presenting with HF-CS warrants further investigation.
Gastrointestinal bleeding (GIB) is a leading cause of morbidity during continuous-flow left ventricular assist device (CF-LVAD) support. GIB risk assessment could have important implications for ...candidate selection, informed consent, and postimplant therapeutic strategies. The aim of the study is to derive and validate a predictive model of GIB in CF-LVAD patients.
CF-LVAD recipients at the Utah Transplantation Affiliated Hospitals program between 2004 and 2017 were included. GIB associated with a decrease in hemoglobin ≥2 g/dL was the primary end point. A weighted score comprising preimplant variables independently associated with GIB was derived and internally validated. A total of 351 patients (median age, 59 years; 82% male) were included. After a median of 196 days, GIB occurred in 120 (34%) patients. Independent predictors of GIB included age >54 years, history of previous bleeding, coronary artery disease, chronic kidney disease, severe right ventricular dysfunction, mean pulmonary artery pressure <18 mm Hg, and fasting glucose >107 mg/dL. A weighted score termed Utah bleeding risk score, effectively stratified patients based on their probability of GIB: low (0-1 points) 4.8%, intermediate (2-4) 39.8%, and high risk (5-9) 83.8%. Discrimination was good in the development sample (c-index: 0.83) and after internal bootstrap validation (c-index: 0.74).
The novel Utah bleeding risk score is a simple tool that can provide personalized GIB risk estimates in CF-LVAD patients. This scoring system may assist clinicians and investigators in designing tailored risk-based strategies aimed at reducing the burden posed by GIB in the individual CF-LVAD patient and healthcare systems.
Transthyretin amyloidosis (ATTR amyloidosis) is a rare, life-threatening disease caused by the accumulation of variant or wild-type (ATTRwt amyloidosis) transthyretin amyloid fibrils in the heart, ...peripheral nerves, and other tissues and organs. Established in 2007, the Transthyretin Amyloidosis Outcomes Survey (THAOS) is the largest ongoing, global, longitudinal observational study of patients with ATTR amyloidosis, including both inherited and wild-type disease, and asymptomatic carriers of pathogenic TTR mutations. This descriptive analysis examines baseline characteristics of symptomatic patients and asymptomatic gene carriers enrolled in THAOS since its inception in 2007 (data cutoff: August 1, 2021). This analysis included 3779 symptomatic patients and 1830 asymptomatic gene carriers. Symptomatic patients were predominantly male (71.4%) and had a mean (standard deviation SD) age of symptom onset of 56.3 (17.8) years. Val30Met was the most common genotype in symptomatic patients in South America (80.9%), Europe (55.4%), and Asia (50.5%), and more patients had early- versus late-onset disease in these regions. The majority of symptomatic patients in North America (58.8%) had ATTRwt amyloidosis. The overall distribution of phenotypes in symptomatic patients was predominantly cardiac (40.7%), predominantly neurologic (40.1%), mixed (16.6%), and no phenotype (2.5%). In asymptomatic gene carriers, mean (SD) age at enrollment was 42.4 (15.7) years, 42.4% were male, and 73.2% carried the Val30Met mutation. This 14-year global overview of THAOS in over 5000 patients represents the largest analysis of ATTR amyloidosis to date and highlights the genotypic and phenotypic heterogeneity of the disease.
Hereditary transthyretin amyloidosis (hATTR or ATTRv variant) is a progressive and fatal disease often associated with infiltrative cardiac involvement, with cardiac symptoms sometimes occurring ...years before diagnosis. Because there are available treatments for hATTR, prompt recognition and early diagnosis is imperative. Nurses who work closely with patients with heart failure are positioned to recognize the symptoms and early signs that should raise clinical suspicion and uncover an underlying diagnosis of hATTR.
To determine whether patients with hATTR demonstrate significant cardiovascular symptom manifestations and health care utilization before diagnosis.
Patients with newly diagnosed hATTR were identified in IBM® MarketScan® Commercial and Medicare Supplemental data (United States) using a claims-based algorithm. Diagnosis required ≥1 claim with relevant amyloidosis diagnosis code (ICD-10-CM: E85.0-.4, E85.89, E85.9) during the identification (ID) period (January 2016-December 2017), and the occurrence of ≥1 qualifying criterion during 2011-2017: ≥15 days diflunisal use, liver transplant, or claim with code E85.1 (neuropathic heredofamilial amyloidosis) or E85.2 (heredofamilial amyloidosis unspecified). Index date was defined as date of first claim with amyloidosis code in the ID period, and preindex period was defined as the 5 years before index date. Patients with a preexisting ICD-9/10 amyloidosis code during this period were excluded to focus on patients who were newly diagnosed. Control subjects without hATTR were identified and matched (age, sex, region) to patients with hATTR (ratio 3:1); these subjects were assigned same index and met same continuous enrollment requirement during preindex period. Frequency of selected cardiovascular conditions and health care use were measured in the preindex period; demographics and Charlson comorbidity index (CCI) were measured 1 year preindex.
Among 141 patients with hATTR and 423 matched controls, mean (SD) age was 62.5 (14.2) years and 53.9% were female. Mean CCI for patients with hATTR was 2.7 (3.0) versus 1.1 (1.9) for controls. In the preindex period, cardiovascular conditions/symptoms were more common among patients with hATTR relative to controls: chest pain (51.8 vs 28.1%; P < 0.001), dyspnea (49.6 vs 25.8%; P < 0.001), edema (27.0 vs 12.8%; P < 0.001), heart failure (23.4 vs 5.9%; P < 0.001), ventricular hypertrophy (19.9 vs 5.7%; P < 0.001), hypotension (18.4 vs 6.1%; P < 0.001), atrial fibrillation/flutter (18.0 vs 8.9%; P < 0.001), stroke (12.8 vs 6.1%; P = 0.011), and aortic stenosis (10.6 vs 4.5%; P = 0.008); these conditions were more prevalent for patients with hATTR compared with controls for each preindex year. Hospitalizations (47.5 vs 24.3%; P < 0.001), emergency department visits (60.3 vs 47.0%; P = 0.006) and cardiac imaging (56.7 vs 27.0%; P < 0.001) were also more frequent among patients with hATTR. Median time (months) from initial symptom manifestation to hATTR diagnosis was longest for chest pain (43.0), dyspnea (41.1), aortic stenosis (39.2), and atrial fibrillation/flutter (34.3).
Patients with hATTR have considerable cardiovascular disease burden in the 5 years preceding diagnosis. Increased awareness of characteristic cardiovascular manifestations among nurses may increase clinical suspicion, leading to early diagnosis and prompt intervention.
Abstract Objectives This study hypothesized that elevated galectin-3 (Gal-3) levels would identify patients with more advanced heart failure (HF) with preserved ejection fraction (HFpEF) as assessed ...by key pathophysiological domains. Background Gal-3 is implicated in the pathogenesis of cardiac fibrosis but is also increased with normal aging and renal dysfunction. Cardiac fibrosis may contribute to cardiac dysfunction, exercise intolerance, and congestion in HFpEF. Methods Two hundred eight patients from the RELAX (Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure) trial of sildenafil in HFpEF had Gal-3 measured at enrollment. Pathophysiological domains assessed included biomarkers of neurohumoral activation, fibrosis, inflammation and myocardial necrosis, congestion severity and quality of life, cardiac structure and function, and exercise performance. Analysis adjusted for age, sex, and/or cystatin-C levels. Potential interaction between baseline Gal-3 and treatment (sildenafil) effect on the RELAX study primary endpoint (change in peak oxygen consumption) was tested. Results Gal-3 levels were associated with age and severity of renal dysfunction. Adjusting for age, sex, and/or cystatin-C, Gal-3 was not associated with biomarkers of neurohumoral activation, fibrosis, inflammation or myocardial necrosis, congestion or quality-of-life impairment, cardiac remodeling or dysfunction, or exercise intolerance. Gal-3 did not identify patients who responded to phosphodiesterase type 5 (PDE-5) inhibitors (interaction p = 0.53). Conclusions In overt HFpEF, Gal-3 was related to severity of renal dysfunction and accounting for this, was not independently associated with severity of pathophysiological derangements or response PDE-5 inhibition. These findings underscore the need to adjust for renal function when interpreting Gal-3 levels, and call into question the value of Gal-3 to quantify disease severity in overt HFpEF.
Amyloidosis cardiomyopathy is a systemic disease with high risk of disability and death. Patient-reported outcomes (PROs) are validated tools that measure health-related quality of life (HRQoL) and ...provide prognostic information in patients with heart failure. However, data on HRQoL profile and prognostic value of PROs in patients with cardiac amyloidosis are limited.
This is an observational study of patients with transthyretin amyloidosis (ATTR) and light chain amyloidosis (AL) who completed Kansas City Cardiomyopathy Questionnaire (KCCQ-12) at the time of clinic visit. We examined KCCQ-12 scores and their relationship to HF hospitalization or death in both amyloidosis groups.
A total of 81 patients were included in the study, 48 with ATTR and 33 with AL with a mean age of 78±7 years and 65±10 years, respectively. KCCQ-12 results were similar in both groups and showed significant HRQoL limitation - median summary score of 38 (IQR 24-60) for ATTR and 51 (IQR 31-73) for AL, p = 0.128. Compared to AL, patients with ATTR had more impairment in the physical limitation domain (Table). Over a median follow-up of 343 days, HF hospitalization or death occurred in 23 (48%) patients with ATTR and 17 (51%) patients with AL. KCCQ score was associated with the risk of HF hospitalization or death with a correlation ratio of 0.9 for ATTR (p=0.025) and 1.0 for AL (p=0.03). ROC AUC for KCCQ-12 ability to predict HF hospitalization or death was 0.7 (95% CI, 0.54-0.84, p = 0.026) for ATTR and 0.8 (95% CI, 0.62-0.95, p = 0.006) for AL. In ATTR, the rate of HF hospitalization or death increased proportionally with decreasing KCCQ-12 scores while in patients with AL high events rates were seen for KCCQ-12 scores 60 or lower. (Figure).
Patients with ATTR and AL amyloidosis cardiomyopathy suffer from poor HRQoL and high burden of events. Our study shows that KCCQ provides important prognostic information in these patients. Routine KCCQ assessments could be used to identify high-risk patients in need of close monitoring.
Hereditary transthyretin amyloidosis (ATTRv) is often associated with progressive infiltrative cardiac involvement, with cardiac symptoms occurring sometimes years prior to diagnosis.
ATTRv patients ...demonstrate significant cardiovascular symptom manifestations and healthcare utilization prior to diagnosis.
Newly diagnosed ATTRv patients in IBM® MarketScan® Commercial and Medicare Supplemental data (US) were identified using a claims-based algorithm. Diagnosis required ≥1 claim with relevant amyloidosis diagnosis code (ICD-10-CM: E85.0-.4, E85.89, E85.9) during identification (ID) period (1/2016-12/2017), and the occurrence of ≥1 qualifying criteria during 2011-2017: ≥15 days diflunisal use, liver transplant, or claim with code E85.1 (neuropathic heredofamilial amyloidosis) or E85.2 (heredofamilial amyloidosis unspecified). Index date was defined as date of first claim with amyloidosis code in ID period, and the pre-index period as the 5 years prior to index date. Patients with an ICD-9/10 amyloidosis code during this period were excluded to focus on the newly diagnosed. Control subjects without ATTRv were identified and matched (age, gender, region) to ATTRv patients (ratio 3:1); meeting the same index and enrollment requirements. Frequency of selected cardiovascular (CV) conditions and healthcare use were measured in the pre-index period; demographics and Charlson comorbidity index (CCI) were measured 1 year pre-index.
Among 141 patients with ATTRv and 423 matched controls, mean (SD) age was 62.5 (14.2) years and 53.9% were female. Mean CCI for ATTRv patients was 2.7 (3.0) vs 1.1 (1.9) for controls. In the pre-index period, CV conditions were more common among ATTRv patients relative to controls: chest pain (51.8 vs. 28.1%), dyspnea (49.6 vs 25.8%), bleeding (41.8 vs 21.3%), edema (27.0 vs 12.8%), heart failure (23.4 vs 5.9%), ventricular hypertrophy (19.9 vs 5.7%), hypotension (18.4 vs 6.1%), atrial fibrillation/flutter (18.0 vs 8.9%), stroke (12.8 vs 6.1%), and aortic stenosis (10.6 vs 4.5%); conditions were relatively higher in each pre-index year. Hospitalization (47.5 vs. 24.3%), emergency department visits (60.3 vs. 47.0%) and cardiac testing (81.6 vs. 65.7%) were also more frequent among ATTRv patients. Median time (months) to ATTRv diagnosis from initial symptom manifestation were largest for chest pain (43.0), dyspnea (41.1), aortic stenosis (39.2), and atrial fibrillation/flutter (34.3).
ATTRv patients have considerable CV disease burden in the 5 years preceding diagnosis. Increased awareness of characteristic CV manifestations may increase clinical suspicion, leading to early diagnosis and prompt intervention.
Abstract
Transthyretin‐mediated amyloidosis (ATTR) is a rare, under‐recognized, progressively debilitating, fatal disease caused by the aggregation and extracellular deposition of amyloid ...transthyretin (TTR) fibrils in multiple organs and tissues throughout the body. TTR is predominantly synthesized by the liver and normally circulates as a homotetramer, while misfolded monomers aggregate to form amyloid fibrils. One strategy to treat ATTR amyloidosis is to reduce the amount of TTR produced by the liver using drugs that directly target the
TTR
mRNA or gene. This narrative review focuses on how TTR gene silencing tools act to reduce TTR production, describing strategies for improved targeted delivery of these agents to hepatocytes where TTR is preferentially expressed. Antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs), termed RNA silencers, cause selective degradation of
TTR
mRNA, while a
TTR
gene editing tool reduces TTR expression by introducing nonsense mutations into the
TTR
gene. Two strategies to facilitate tissue‐specific delivery of these nucleic acid‐based drugs employ endogenous receptors expressed by hepatocytes. Lipid nanoparticles (LNPs) that recruit apolipoprotein E support low‐density lipoprotein receptor‐mediated uptake of unconjugated siRNA and are now used for CRISPR gene editing tools. Additionally, conjugating N‐acetylgalactosamine (GalNAc) moieties to ASOs or siRNAs facilitates receptor‐mediated uptake by the asialoglycoprotein receptor. In summary, ATTR is a progressive disease with various clinical manifestations due to TTR aggregation, deposition, and amyloid formation. Receptor‐targeted ligands (eg, GalNAc) and nanoparticle encapsulation (eg, LNPs) are technologies to deliver ASOs, siRNAs, and gene editing tools to hepatocytes, the primary location of TTR synthesis.
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