Factor V haemostatic diathesis impairing thrombin activation, membrane binding and circulating antigen level due to a novel compound heterozygous mutation, Leu1821Ser and Gly2192Cys.

INTRODUCTION: Congenital factor V (FV) deficiency is a rare clotting disorder affecting ∼1 in 1,000,000, with bleeding severity that ranges broadly for poorly understood reasons. AIM: To help understand the molecular basis of the observed phenotype in FV deficient patients, the genetics and biochemistry causing a patient's FV deficiency were evaluated. METHODS AND RESULTS: A 71-year-old female, who had serious life-long bleeding upon provocation and profound menorrhagia that lead to hysterectomy, was found to have 3% of normal plasma FV antigen with normal electrophoretic mobility. Platelet FV was similarly low, although the banding pattern was less fragmented than normal. Plasma clotting activity was <1% of normal. Familial inheritance and DNA sequence analysis from peripheral blood leukocytes were consistent with novel compound heterozygosity with missense mutations in exon XVII, Leu1821 to Ser (L1821S) and exon XXV, Gly2192 to Cys (G2192C). The respective single-mutation variants were expressed and purified. Explaining why the antigen level and activity were inequivalent, thrombin activation of recombinant (r) FV/L1821S was impaired, and rFV/G2192C was unable to bind to a procoagulant phospholipid membrane. CONCLUSION: These findings are consistent with the observed phenotype, highlighting the importance of understanding FV biochemical function to rationalize clinical bleeding severity when the circulating antigen level is discordant.

Enhancing hypertension detection and control through a hypertension certification program for pharmacists: A cluster randomized trial (The RxPATH Study).

Importance: We designed an online educational program for primary care health care providers, the Hypertension Canada Professional Certification Program (HC-PCP), based upon its 2020 guidelines. Objective: The objective was to determine the effect of the HC-PCP, taken by pharmacists, on systolic blood pressure (BP) in patients with poorly controlled hypertension. Design: Stepped wedge cluster randomized trial (unit of randomization was the pharmacy). Participants: Patients with poorly controlled hypertension (BP >140/90 mmHg or >130/80 mmHg [diabetes]) in community pharmacies in Alberta, Canada, were recruited by their pharmacist. Intervention: Pharmacists completed the HC-PCP program, then provided care to their patients with poorly controlled hypertension according to what they learned in the course. Control: Pharmacists were given a copy of the Hypertension Canada guidelines and provided their usual care to their patients prior to undertaking the HC-PCP later. Main outcome and measure: The primary outcome was a difference in change in systolic BP at 3 months between groups, while the secondary outcome was patient satisfaction with using the Consultation Satisfaction Questionnaire. Results: We enrolled 890 patients from 59 pharmacies (including 104 pharmacists). Using a linear mixed-effect model with BP reduction as the dependent variable and independent variables of treatment allocation, baseline BP, site effect and patient effect, the intervention was associated with a 4.76 mmHg (95% confidence interval, 2.02-7.50, p < 0.0001) systolic BP reduction at 3 months. Patient satisfaction with using the Consultation Satisfaction Questionnaire was high at 75.9 (/90). Conclusion and relevance: Most educational programs are not evaluated at the patient care level. The HC-PCP taken by pharmacists resulted in a 4.76 mmHg systolic BP reduction in their patients over 3 months. This would have major implications for public health, reducing heart disease, stroke and kidney failure.

Pro-Inflammatory Effects of Inhaled Great Salt Lake Dust Particles.

Background: Climatological shifts and human activities have decimated lakes worldwide. Water in the Great Salt Lake, Utah, USA is at near record lows which has increased risks for exposure to windblown dust from dried lakebed sediments. Formal studies evaluating the health effects of inhaled Great Salt Lake dust (GSLD) have not been performed despite the belief that the dust is harmful. The objectives of this study were to illustrate windblown dust events, assess the impact of inhaled dust on the lungs, and to identify mechanisms that could contribute to the effects of GSLD in the lungs. Results: An animation, hourly particle and meteorological data, and images illustrate the impact of dust events on the Salt Lake Valley/Wasatch front airshed. Great Salt Lake sediment and PM 2.5 contained metals, lipopolysaccharides, natural and anthropogenic chemicals, and bacteria. Inhalation and oropharyngeal delivery of PM 2.5 triggered neutrophilia and the expression of mRNA for Il6, Cxcl1 , Cxcl2, and Muc5ac in mouse lungs, was more potent than coal fly ash (CFA) PM 2.5 , and more cytotoxic to human airway epithelial cells (HBEC3-KT) in vitro . Induction of IL6 and IL8 was replicated in vitro using HBEC3-KT and THP-1 cells. For HBEC3-KT cells, IL6 induction was variably attenuated by EGTA/ruthenium red, the TLR4 inhibitor TAK-242, and deferoxamine, while IL8 was attenuated by EGTA/ruthenium red. Inhibition of mRNA induction by EGTA/ruthenium red suggested roles for transition metals, calcium, and calcium channels as mediators of the responses. Like CFA, GSLD and a similar dust from the Salton Sea in California, activated human TRPA1, M8, and V1. However, only inhibition of TRPV1, TRPV3, and a combination of both channels impacted cytokine mRNA induction in HBEC3-KT cells. Responses of THP1 cells were partially mediated by TLR4 as opposed to TRP channels and mice expressing a "humanized" form of TRPV1 exhibited greater neutrophilia when exposed to GSLD via inhalation. Conclusions: This study suggests that windblown dust from Great Salt Lake and similar lake sediments could pose a risk to humans via mechanisms including the activation of TRPV1/V3, TLR4, and possibly oxidative stress.

Stroke Risk Reduction in Atrial Fibrillation Through Pharmacist Prescribing: A Randomized Clinical Trial.

Importance: Major gaps in the delivery of appropriate oral anticoagulation therapy (OAC) exist, leaving a large proportion of persons with atrial fibrillation (AF) unnecessarily at risk for stroke and its sequalae. Objective: To investigate whether pharmacist-led OAC prescription can increase the delivery of stroke risk reduction therapy in individuals with AF. Design, Setting, and Participants: This prospective, open-label, patient-level randomized clinical trial of early vs delayed pharmacist intervention from January 1, 2019, to December 31, 2022, was performed in 27 community pharmacies in Alberta, Canada. Pharmacists identified patients 65 years or older with 1 additional stroke risk factor and known, untreated AF (OAC nonprescription or OAC suboptimal dosing) or performed screening using a 30-second single-lead electrocardiogram to detect previously unrecognized AF. Patients with undertreated or newly diagnosed AF eligible for OAC therapy were considered to have actionable AF. Data were analyzed from April 3 to November 30, 2023. Interventions: In the early intervention group, pharmacists prescribed OAC using guideline-based algorithms with follow-up visits at 1 and 3 months. In the delayed intervention group, which served as the usual care control, the primary care physician (PCP) was sent a notification of actionable AF along with a medication list (both enhancement over usual care). After 3 months, patients without OAC optimization in the control group underwent delayed pharmacist intervention. Main Outcomes and Measures: The primary outcome was the difference in the rate of guideline-concordant OAC use in the 2 groups at 3-month follow-up ascertained by a research pharmacist blinded to treatment allocation. Results: Eighty patients were enrolled with actionable AF (9 [11.3%] newly diagnosed in 235 individuals screened). The mean (SD) age was 79.7 (7.4) years, and 45 patients (56.3%) were female. The median CHADS2 (congestive heart failure, hypertension, age, diabetes, and stroke or transient ischemic attack) score was 2 (IQR, 2-3). Seventy patients completed follow-up. Guideline-concordant OAC use at 3 months occurred in 36 of 39 patients (92.3%) in the early intervention group vs 23 of 41 (56.1%) in the control group (P < .001), with an absolute increase of 34% and number needed to treat of 3. Of the 23 patients who received appropriate OAC prescription in the control group, the PCP called the pharmacist for prescribing advice in 6 patients. Conclusions and Relevance: This randomized clinical trial found that pharmacist OAC prescription is a potentially high-yield opportunity to effectively close gaps in the delivery of stroke risk reduction therapy for AF. Scalability and sustainability of pharmacist OAC prescription will require larger trials demonstrating effectiveness and safety. Trial Registration: ClinicalTrials.gov Identifier: NCT03126214.

Mice integrate conspecific and contextual information in forming social episodic-like memories under spontaneous recognition task conditions.

The ability to remember unique past events (episodic memory) may be an evolutionarily conserved function, with accumulating evidence of episodic-(like) memory processing in rodents. In humans, it likely contributes to successful complex social networking. Rodents, arguably the most used laboratory models, are also rather social animals. However, many behavioural paradigms are devoid of sociality, and commonly-used social spontaneous recognition tasks (SRTs) are open to non-episodic strategies based upon familiarity. We address this gap by developing new SRT variants. Here, in object-in-context SRTs, we asked if context could be specified by the presence/absence of either a conspecific (experiment 1) or an additional local object (experiment 2). We show that mice readily used the conspecific as contextual information to distinguish unique episodes in memory. In contrast, no coherent behavioural response emerged when an additional object was used as a potential context specifier. Further, in a new social conspecific-in-context SRT (experiment 3) where environment-based change was the context specifier, mice preferably explored a more recently-seen familiar conspecific associated with contextual mismatch, over a less recently-seen familiar conspecific presented in the same context. The results argue that, in incidental SRT conditions, mice readily incorporate conspecific cue information into episodic-like memory. Thus, the tasks offer different ways to assess and further understand the mechanisms at work in social episodic-like memory processing.

Synthesis of LaCN3, TbCN3, CeCN5, and TbCN5 Polycarbonitrides at Megabar Pressures.

Inorganic ternary metal-C-N compounds with covalently bonded C-N anions encompass important classes of solids such as cyanides and carbodiimides, well known at ambient conditions and composed of [CN]- and [CN2]2- anions, as well as the high-pressure formed guanidinates featuring [CN3]5- anion. At still higher pressures, carbon is expected to be 4-fold coordinated by nitrogen atoms, but hitherto, such CN4-built anions are missing. In this study, four polycarbonitride compounds (LaCN3, TbCN3, CeCN5, and TbCN5) are synthesized in laser-heated diamond anvil cells at pressures between 90 and 111 GPa. Synchrotron single-crystal X-ray diffraction (SCXRD) reveals that their crystal structures are built of a previously unobserved anionic single-bonded carbon-nitrogen three-dimensional (3D) framework consisting of CN4 tetrahedra connected via di- or oligo-nitrogen linkers. A crystal-chemical analysis demonstrates that these polycarbonitride compounds have similarities to lanthanide silicon phosphides. Decompression experiments reveal the existence of LaCN3 and CeCN5 compounds over a very large pressure range. Density functional theory (DFT) supports these discoveries and provides further insight into the stability and physical properties of the synthesized compounds.

Community Pharmacy-Based Blood Pressure Screening in Newfoundland and Labrador, Canada for World Hypertension Day 2022: A Cross-Sectional Study.

Background: High blood pressure (BP) is a leading cause of cardiovascular and stroke-related events. Office-based BP measurement has declined in recent years due to the COVID-19 pandemic, which may have resulted in higher rates of undetected and uncontrolled hypertension. To gain a better idea of adult BP levels in Newfoundland and Labrador, we engaged community pharmacists in BP screening on World Hypertension Day. Methods: Data collection and BP screening occurred on May 17, 2022. Pharmacists and pharmacy students collected 3 seated BP readings from participants, using an automated device. The average of readings 2 and 3 was used to estimate BP, with elevated BP defined as ≥ 140/90 mm Hg, or ≥ 130/80 mm Hg for individuals with diabetes. Data on participant demographics, access to primary care, medical history, and antihypertensive use were also collected. Data analysis included descriptive statistics and logistic regression techniques. Results: A total of 460 participants were included in the analysis. The mean age was 56.3 years (standard deviation: 16.95); 63.3% (n = 291) were female; and 43.7% (n = 201) reported having hypertension. Elevated BP was identified in 27% (n = 123). Of those with elevated BP, 41.5% (n = 51) had no history of diagnosed hypertension. Age, sex, and diabetes were statistically significant predictors of elevated BP in the multivariable model. Conclusions: A large proportion of participants in our study had elevated BP. Targeted measures are needed to improve the detection, treatment, and control of high BP in Newfoundland and Labrador. Community pharmacists can support BP care.

Contexte: L'hypertension artérielle est une cause majeure d'événements cardiovasculaires et d'AVC. Or, la mesure de la pression artérielle (PA) en clinique a connu un déclin ces dernières années en raison de la pandémie de COVID-19, de sorte que les taux d'hypertension artérielle non détectée et non maîtrisée pourraient avoir augmenté. Afin de nous faire une idée plus précise de l'état de la PA des adultes de Terre-Neuve-et-Labrador, nous avons organisé une campagne de mesure de la PA dans les pharmacies de détail à l'occasion de la Journée mondiale de l'hypertension artérielle. Méthodologie: La collecte des données et les mesures ont eu lieu le 17 mai 2022. Les pharmaciens aidés par des étudiants en pharmacie ont pris 3 relevés en position assise par participant à l'aide d'un dispositif de mesure automatisé. La moyenne des 2 derniers relevés a été utilisée pour obtenir la PA estimative. La PA était considérée comme élevée si les valeurs étaient égales ou supérieures à 140/90 mmHg, ou à 130/80 mmHg chez les personnes diabétiques. D'autres renseignements ont été recueillis, notamment les caractéristiques démographiques des participants, leur accès aux soins primaires, leurs antécédents médicaux et leur prise d'antihypertenseurs. Les données ont ensuite été analysées à l'aide de statistiques descriptives et de techniques de régression logistique. Résultats: Au total, 460 participants ont été inclus dans l'analyse. L'âge moyen était de 56,3 ans (écart-type : 16,95); 63,3 % (n = 291) étaient de sexe féminin et 43,7 % (n = 201) ont indiqué être atteints d'hypertension. Une PA élevée a été observée chez 27 % des participants (n = 123), dont 41,5 % (n = 51) qui n'avaient jamais reçu un diagnostic d'hypertension artérielle. L'âge, le sexe et le diabète se sont avérés des facteurs de prédiction de PA élevée statistiquement significatifs dans un modèle multivarié. Conclusions: Un pourcentage important des participants à notre étude présentait une PA élevée. Des mesures ciblées s'imposent pour mieux dépister, traiter et maîtriser l'hypertension artérielle à Terre-Neuve-et-Labrador. Les pharmaciens de proximité pourraient également jouer un rôle dans la surveillance de la PA.

Empagliflozin to prevent progressive adverse remodelling after myocardial infarction (EMPRESS-MI): rationale and design.

AIMS: Patients with a reduced left ventricular ejection fraction (LVEF) following an acute myocardial infarction (MI) are at risk of progressive adverse cardiac remodelling that can lead to the development of heart failure and death. The early addition of a sodium-glucose cotransporter 2 (SGLT2) inhibitor to standard treatment may delay or prevent progressive adverse remodelling in these patients. METHODS AND RESULTS: EMpagliflozin to PREvent worSening of left ventricular volumes and Systolic function after Myocardial Infarction (EMPRESS-MI) is a randomized, double-blind, placebo-controlled, multi-centre trial designed to assess the effect of empagliflozin on cardiac remodelling evaluated using cardiovascular magnetic resonance (CMR) in 100 patients with left ventricular systolic dysfunction following MI. Eligible patients were those ≥12 h and ≤14 days following acute MI, with an LVEF <45% by CMR. Patients were randomized to empagliflozin 10 mg once a day or matching placebo. The primary outcome will be change in left ventricular end-systolic volume indexed to body surface area over 24 weeks from randomization. Secondary endpoints include measures of left ventricular and atrial volumes, left ventricular mass, LVEF, and circulating cardiac biomarkers. CONCLUSIONS: EMPRESS-MI will assess the effect of the SGLT2 inhibitor empagliflozin on cardiac remodelling in patients with left ventricular systolic dysfunction after an acute MI.

Case-finding for HPV vaccination eligibility within a dental office with concurrent development of a dialogue tool.

Background: Human papillomavirus (HPV) immunization can prevent cancers, but uptake has been incomplete (and worse with the COVID-19 pandemic). Dental clinicians already screen for oral cancers, many of which are caused by HPV, and could identify vaccination candidates, but this requires a case-finding strategy. Objective: The purpose of this study was (1) to develop and test a case-finding approach to identify patients who were candidates for HPV vaccinations, (2) to test an HPV vaccination intervention by dental professionals on vaccination uptake. Methods: Design: Prospective, non-randomized feasibility case finding study with a 4-week enrollment period and a 6 week follow up period in general dental offices.Setting: Two general and non-commercial dentistry offices in Edmonton, Alberta Canada.Subjects: Consecutive scheduled (non-emergent) patients who met the Health Canada criteria for HPV vaccination: immunocompetent males and females aged 9-45 years and those who are immunocompromised. Consent for the discussion was obtained from each subject or parent.Intervention: Scheduled dental patients meeting the inclusion criteria were flagged by a research assistant who reviewed the appointment schedule each week for 4 weeks. For these subjects, dental clinicians (dentists and dental hygienists) used our Dental Dialogue Tool to discuss HPV vaccination and answer questions. Participating patients who consented to receive the HPV vaccine were given a prescription by the attending dentist and were directed to follow-up with a local pharmacy to have the vaccine administered. Each participant that was provided with an HPV prescription was contacted after 6 weeks to identify if they received the first dose of vaccine.Outcomes: Yield of our case-finding strategy and receipt of a patient's first HPV vaccine dose during 6 weeks post vaccine prescription. Results: Our case-finding strategy assessed 656 scheduled patients over 4 weeks. From this screening,179 (a case-finding yield of 20.4 %), were candidates for HPV vaccine discussion. Forty-three of these 179 patients (24 %) were already vaccinated.. Two patients (1.1 %) did not consent to be spoken with and 134 (74.8 %) consented to the HPV vaccine discussion.. Forty-eight of 134 patients (35.8 %) of patients accepted a prescription from the dentist after speaking with the dental clinician. Ultimately, 8/48 (16 %) (patients received their first dose of the HPV vaccine by the 6 week of follow-up call. However, this is only 4.5 % (8/177) of those patients who did consent for the discussion of HPV cancers and vaccination from their dentist. Conclusion: We demonstrated that case-finding for HPV vaccine candidates in general dental offices was feasible, with a reasonable yield. While the dental dialogue tool was described as a great resource to explain the facts and answer questions, very few patients were vaccinated after 6 weeks of follow-up. Further work is necessary to sharpen the intervention, perhaps including follow-up discussions with the dental clinicians.

Liver and pancreatic-targeted interleukin-22 as a therapeutic for metabolic dysfunction-associated steatohepatitis.

Metabolic dysfunction-associated steatohepatitis (MASH) is the most prevalent cause of liver disease worldwide, with a single approved therapeutic. Previous research has shown that interleukin-22 (IL-22) can suppress ß-cell stress, reduce local islet inflammation, restore appropriate insulin production, reverse hyperglycemia, and ameliorate insulin resistance in preclinical models of diabetes. In clinical trials long-acting forms of IL-22 have led to increased proliferation in the skin and intestine, where the IL-22RA1 receptor is highly expressed. To maximise beneficial effects whilst reducing the risk of epithelial proliferation and cancer, we designed short-acting IL-22-bispecific biologic drugs that successfully targeted the liver and pancreas. Here we show 10-fold lower doses of these bispecific biologics exceed the beneficial effects of native IL-22 in multiple preclinical models of MASH, without off-target effects. Treatment restores glycemic control, markedly reduces hepatic steatosis, inflammation, and fibrogenesis. These short-acting IL-22-bispecific targeted biologics are a promising new therapeutic approach for MASH.

Predictors of heart failure readmission and all-cause mortality in patients with acute heart failure.

BACKGROUND: Predischarge risk stratification of patients with acute heart failure (AHF) could facilitate tailored treatment and follow-up, however, simple scores to predict short-term risk for HF readmission or death are lacking. METHODS: We sought to develop a congestion-focused risk score using data from a prospective, two-center observational study in adults hospitalized for AHF. Laboratory data were collected on admission. Patients underwent physical examination, 4-zone, and in a subset 8-zone, lung ultrasound (LUS), and echocardiography at baseline. A second LUS was performed before discharge in a subset of patients. The primary endpoint was the composite of HF hospitalization or all-cause death. RESULTS: Among 350 patients (median age 75 years, 43% women), 88 participants (25%) were hospitalized or died within 90 days after discharge. A stepwise Cox regression model selected four significant independent predictors of the composite outcome, and each was assigned points proportional to its regression coefficient: NT-proBNP ≥2000 pg/mL (admission) (3 points), systolic blood pressure < 120 mmHg (baseline) (2 points), left atrial volume index ≥60 mL/m2 (baseline) (1 point) and ≥ 9 B-lines on predischarge 4-zone LUS (3 points). This risk score provided adequate risk discrimination for the composite outcome (HR 1.48 per 1 point increase, 95% confidence interval: 1.32-1.67, p < 0.001, C-statistic: 0.70). In a subset of patients with 8-zone LUS data (n = 176), results were similar (C-statistic: 0.72). CONCLUSIONS: A four-variable risk score integrating clinical, laboratory and ultrasound data may provide a simple approach for risk discrimination for 90-day adverse outcomes in patients with AHF if validated in future investigations.

Circulating soluble fibroblast activation protein (FAP) levels are independent of cardiac and extra-cardiac FAP expression determined by targeted molecular imaging in patients with myocardial FAP activation.

INTRODUCTION: Tissue Fibroblast Activation Protein alpha (FAP) is overexpressed in various types of acute and chronic cardiovascular disease. A soluble form of FAP has been detected in human plasma, and low circulating FAP concentrations are associated with increased risk of death in patients with acute coronary syndrome. However, little is known about the regulation and release of FAP from fibroblasts, and whether circulating FAP concentration is associated with tissue FAP expression. This study characterizes the release of FAP in human cardiac fibroblasts (CF) and analyzes the association of circulating FAP concentrations with in vivo tissue FAP expression in patients with acute (ST-segment elevation myocardial infarction, STEMI) and chronic (severe aortic stenosis, AS) myocardial FAP expression. METHODS AND RESULTS: FAP was released from CF in a time- and concentration-dependent manner. FAP concentration was higher in supernatant of TGFß-stimulated CF, and correlated with cellular FAP concentration. Inhibition of metallo- and serine-proteases diminished FAP release in vitro. Median FAP concentrations of patients with acute (77 ng/mL) and chronic (75 ng/mL, p = 0.50 vs. STEMI) myocardial FAP expression did not correlate with myocardial nor extra-myocardial nor total FAP volume (P ≥ 0.61 in all cases) measured by whole-body FAP-targeted positron emission tomography. CONCLUSION: We describe a time- and concentration dependent, protease-mediated release of FAP from cardiac fibroblasts. Circulating FAP concentrations were not associated with increased in vivo tissue FAP expression determined by molecular imaging in patients with both chronic and acute myocardial FAP expression. These data suggest that circulating FAP and tissue FAP expression provide complementary, non-interchangeable information.

Dapagliflozin and Days of Full Health Lost in the DAPA-HF Trial.

BACKGROUND: Conventional time-to-first-event analyses cannot incorporate recurrent hospitalizations and patient well-being in a single outcome. OBJECTIVES: To overcome this limitation, we tested an integrated measure that includes days lost from death and hospitalization, and additional days of full health lost through diminished well-being. METHODS: The effect of dapagliflozin on this integrated measure was assessed in the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) trial, which examined the efficacy of dapagliflozin, compared with placebo, in patients with NYHA functional class II to IV heart failure and a left ventricular ejection fraction ≤40%. RESULTS: Over 360 days, patients in the dapagliflozin group (n = 2,127) lost 10.6 ± 1.0 (2.9%) of potential follow-up days through cardiovascular death and heart failure hospitalization, compared with 14.4 ± 1.0 days (4.0%) in the placebo group (n = 2,108), and this component of all measures of days lost accounted for the greatest between-treatment difference (-3.8 days [95% CI: -6.6 to -1.0 days]). Patients receiving dapagliflozin also had fewer days lost to death and hospitalization from all causes vs placebo (15.5 ± 1.1 days [4.3%] vs 20.3 ± 1.1 days [5.6%]). When additional days of full health lost (ie, adjusted for Kansas City Cardiomyopathy Questionnaire-overall summary score) were added, total days lost were 110.6 ± 1.6 days (30.7%) with dapagliflozin vs 116.9 ± 1.6 days (32.5%) with placebo. The difference in all measures between the 2 groups increased over time (ie, days lost by death and hospitalization -0.9 days [-0.7%] at 120 days, -2.3 days [-1.0%] at 240 days, and -4.8 days [-1.3%] at 360 days). CONCLUSIONS: Dapagliflozin reduced the total days of potential full health lost due to death, hospitalizations, and impaired well-being, and this benefit increased over time during the first year. (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure; NCT03036124).

Prognostic Models for Mortality and Morbidity in Heart Failure With Preserved Ejection Fraction.

Importance: Accurate risk prediction of morbidity and mortality in patients with heart failure with preserved ejection fraction (HFpEF) may help clinicians risk stratify and inform care decisions. Objective: To develop and validate a novel prediction model for clinical outcomes in patients with HFpEF using routinely collected variables and to compare it with a biomarker-driven approach. Design, Setting, and Participants: Data were used from the Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure (DELIVER) trial to derive the prediction model, and data from the Angiotensin Receptor Neprilysin Inhibition in Heart Failure With Preserved Ejection Fraction (PARAGON-HF) and the Irbesartan in Heart Failure With Preserved Ejection Fraction Study (I-PRESERVE) trials were used to validate it. The outcomes were the composite of HF hospitalization (HFH) or cardiovascular death, cardiovascular death, and all-cause death. A total of 30 baseline candidate variables were selected in a stepwise fashion using multivariable analyses to create the models. Data were analyzed from January 2023 to June 2023. Exposures: Models to estimate the 1-year and 2-year risk of cardiovascular death or hospitalization for heart failure, cardiovascular death, and all-cause death. Results: Data from 6263 individuals in the DELIVER trial were used to derive the prediction model and data from 4796 individuals in the PARAGON-HF trial and 4128 individuals in the I-PRESERVE trial were used to validate it. The final prediction model for the composite outcome included 11 variables: N-terminal pro-brain natriuretic peptide (NT-proBNP) level, HFH within the past 6 months, creatinine level, diabetes, geographic region, HF duration, treatment with a sodium-glucose cotransporter 2 inhibitor, chronic obstructive pulmonary disease, transient ischemic attack/stroke, any previous HFH, and heart rate. This model showed good discrimination (C statistic at 1 year, 0.73; 95% CI, 0.71-0.75) in both validation cohorts (C statistic at 1 year, 0.71; 95% CI, 0.69-0.74 in PARAGON-HF and 0.75; 95% CI, 0.73-0.78 in I-PRESERVE) and calibration. The model showed similar discrimination to a biomarker-driven model including high-sensitivity cardiac troponin T and significantly better discrimination than the Meta-Analysis Global Group in Chronic (MAGGIC) risk score (C statistic at 1 year, 0.60; 95% CI, 0.58-0.63; delta C statistic, 0.13; 95% CI, 0.10-0.15; P < .001) and NT-proBNP level alone (C statistic at 1 year, 0.66; 95% CI, 0.64-0.68; delta C statistic, 0.07; 95% CI, 0.05-0.08; P < .001). Models derived for the prediction of all-cause and cardiovascular death also performed well. An online calculator was created to allow calculation of an individual's risk. Conclusions and Relevance: In this prognostic study, a robust prediction model for clinical outcomes in HFpEF was developed and validated using routinely collected variables. The model performed better than NT-proBNP level alone. The model may help clinicians to identify high-risk patients and guide treatment decisions in HFpEF.