Prognostic association of circulating relaxin-2 in acute heart failure.

BACKGROUND: Despite the increasing interest in the study of the endogenous relaxin system in heart failure (HF), its role as a prognostic marker in acute HF remains unclear. We aimed to evaluate the association of relaxin-2 circulating levels with 6 months' mortality in acute HF. METHODS: We evaluated relaxin-2 serum levels at admission in a cohort of patients with acute HF (n = 202) using an enzyme immunoassay. The ability of relaxin-2 to predict all-cause death (primary outcome) and HF-specific death (secondary outcome) at 6 months was assessed using Cox-regression analysis. RESULTS: The median age was 79 (70-85) years old, 44% of the patients were male, and 43% had preserved ejection fraction (≥50%). Median serum relaxin-2 level was 25 pg/mL. Patients with higher relaxin-2 levels had more peripheral oedemas, higher sodium retention score, higher pulmonary artery pressures, higher prevalence of right ventricle dysfunction and lower inferior vena cava collapse at inspiration. Conversely, there was no association with left chambers parameters or with B-type natriuretic peptide (BNP). Higher relaxin-2 concentrations were associated with a higher risk of all-cause death [HR 1.15; 95%CI 1.01,1.30; P = 0.030] and HF-specific death [HR 1.21; 95% CI 1.03-1.42; P = 0.018], after adjustment for classical prognostic factors such as age, sex and BNP. CONCLUSIONS: In our acute HF population, relaxin-2 circulating levels were associated with clinical and echocardiographic markers of systemic congestion and with 6-months' mortality, independently of BNP. These results lay the groundwork for future investigations on the potential of relaxin-2 as an auxiliary biomarker in HF.

Office- versus home-based evaluation of quality of life in heart failure with reduced ejection fraction: A randomized study.

BACKGROUND: Heart failure (HF) patients often experience poor health-related quality-of-life (HR-QoL). The Kansas City Cardiomyopathy Questionnaire (KCCQ) is frequently used for assessing HR-QoL in HF. Whether KCCQ scores vary in a clinical meaningful manner according to the setting (home vs office) where patients respond to the questionnaire is currently unknown. AIMS: Assess the differences in the responses to KCCQ-23 questionnaire when completed at home or office. METHODS: Randomized parallel-group study, including patients with HF with reduced ejection fraction (HFrEF). Primary outcome was home vs office comparison of overall summary score (KCCQ-OSS). Main secondary outcomes were clinical summary score (KCCQ-CSS) and total symptom score (KCCQ-TSS). RESULTS: A total of 100 patients were included in the study: 50 home vs 50 office. Mean age was 71 yrs. Most baseline characteristics were well balanced between groups, except male sex, MRA use, and prior HF hospitalizations which were more frequent in the home group. No statistically-significant between-group differences were found regarding KCCQ-OSS (median [percentile25-75]) scores: home 69.1 (42.0-86.5) vs office 63.1 (44.3-82.3) points, P-value = 0.59, or main secondary outcomes: KCCQ-CSS home 62.2 (46.5-79.9) vs office 68.1 (51.9-79.2) points, P-value = 0.69, and KCCQ-TSS home 84.7 (59.7-97.2) vs office 76.4 (66.7-94.4) points, P-value = 0.85. Results remained similar after adjustment for differences in baseline characteristics and using non-parametric regressions. CONCLUSIONS: No major differences were found in KCCQ-23 scores regardless of whether the questionnaire was completed at home or office. These findings can be useful to make HR-QoL more accessible, allowing patients to respond at home using email or cell-phone applications.

Metabolomics and Cardiovascular Risk in Patients with Heart Failure: A Systematic Review and Meta-Analysis.

The associations of plasma metabolites with adverse cardiovascular (CV) outcomes are still underexplored and may be useful in CV risk stratification. We performed a systematic review and meta-analysis to establish correlations between blood metabolites and adverse CV outcomes in patients with heart failure (HF). Four cohorts were included, involving 83 metabolites and 37 metabolite ratios, measured in 1158 HF patients. Hazard ratios (HR) of 42 metabolites and 3 metabolite ratios, present in at least two studies, were combined through meta-analysis. Higher levels of histidine (HR 0.74, 95% CI [0.64; 0.86]) and tryptophan (HR 0.82 [0.71; 0.96]) seemed protective, whereas higher levels of symmetric dimethylarginine (SDMA) (HR 1.58 [1.30; 1.93]), N-methyl-1-histidine (HR 1.56 [1.27; 1.90]), SDMA/arginine (HR 1.38 [1.14; 1.68]), putrescine (HR 1.31 [1.06; 1.61]), methionine sulfoxide (HR 1.26 [1.03; 1.52]), and 5-hydroxylysine (HR 1.25 [1.05; 1.48]) were associated with a higher risk of CV events. Our findings corroborate important associations between metabolic imbalances and a higher risk of CV events in HF patients. However, the lack of standardization and data reporting hampered the comparison of a higher number of studies. In a future clinical scenario, metabolomics will greatly benefit from harmonizing sample handling, data analysis, reporting, and sharing.

The extent of postpartum cardiac reverse remodeling is reflected in urine proteome.

The association of postpartum cardiac reverse remodeling (RR) with urinary proteome, particularly in pregnant women with cardiovascular (CV) risk factors who show long-term increased risk of cardiovascular disease and mortality is unknown. We aim to profile the urinary proteome in pregnant women with/without CV risk factors to identify proteins associated with postpartum RR. Our study included a prospective cohort of 32 healthy and 27 obese and/or hypertensive and/or diabetic pregnant women who underwent transthoracic echocardiography, pulse-wave-velocity, and urine collection at the 3rd trimester and 6 months postpartum. Shotgun HPLC-MS/MS profiled proteins. Generalized linear mixed-effects models were used to identify associations between urinary proteins and left ventricle mass (LVM), a surrogate of RR. An increase in arterial stiffness was documented from 3rd trimester to 6 months after delivery, being significantly elevated in women with CV risk factors. In addition, the presence of at least one CV risk factor was associated with worse LVM RR. We identified 6 and 11 proteins associated with high and low LVM regression, respectively. These proteins were functionally linked with insulin-like growth factor (IGF) transport and uptake regulation by IGF binding-proteins, platelet activation, signaling and aggregation and the immune system's activity. The concentration of IGF-1 in urine samples was associated with low LVM regression after delivery. Urinary proteome showed a predicting potential for identifying pregnant women with incomplete postpartum RR.

Unravelling the Gut Microbiome Role in Cardiovascular Disease: A Systematic Review and a Meta-Analysis.

A notable shift in understanding the human microbiome's influence on cardiovascular disease (CVD) is underway, although the causal association remains elusive. A systematic review and meta-analysis were conducted to synthesise current knowledge on microbial taxonomy and metabolite variations between healthy controls (HCs) and those with CVD. An extensive search encompassing three databases identified 67 relevant studies (2012-2023) covering CVD pathologies from 4707 reports. Metagenomic and metabolomic data, both qualitative and quantitative, were obtained. Analysis revealed substantial variability in microbial alpha and beta diversities. Moreover, specific changes in bacterial populations were shown, including increased Streptococcus and Proteobacteria and decreased Faecalibacterium in patients with CVD compared with HC. Additionally, elevated trimethylamine N-oxide levels were reported in CVD cases. Biochemical parameter analysis indicated increased fasting glucose and triglycerides and decreased total cholesterol and low- and high-density lipoprotein cholesterol levels in diseased individuals. This study revealed a significant relationship between certain bacterial species and CVD. Additionally, it has become clear that there are substantial inconsistencies in the methodologies employed and the reporting standards adhered to in various studies. Undoubtedly, standardising research methodologies and developing extensive guidelines for microbiome studies are crucial for advancing the field.

Corticotropin-releasing hormone and obesity: From fetal life to adulthood.

Obesity is among the most common chronic disorders, worldwide. It is a complex disease that reflects the interactions between environmental influences, multiple genetic allelic variants, and behavioral factors. Recent developments have also shown that biological conditions in utero play an important role in the programming of energy homeostasis systems and might have an impact on obesity and metabolic disease risk. The corticotropin-releasing hormone (CRH) family of neuropeptides, as a central element of energy homeostasis, has been evaluated for its role in the pathophysiology of obesity. This review aims to summarize the relevance and effects of the CRH family of peptides in the pathophysiology of obesity spanning from fetal life to adulthood.

Mitochondrial remodeling underlying age-induced skeletal muscle wasting: let's talk about sex.

Sarcopenia is associated with reduced quality of life and premature mortality. The sex disparities in the processes underlying sarcopenia pathogenesis, which include mitochondrial dysfunction, are ill-understood and can be decisive for the optimization of sarcopenia-related interventions. To improve the knowledge regarding the sex differences in skeletal muscle aging, the gastrocnemius muscle of young and old female and male rats was analyzed with a focus on mitochondrial remodeling through the proteome profiling of mitochondria-enriched fractions. To the best of our knowledge, this is the first study analyzing sex differences in skeletal muscle mitochondrial proteome remodeling. Data demonstrated that age induced skeletal muscle atrophy and fibrosis in both sexes. In females, however, this adverse skeletal muscle remodeling was more accentuated than in males and might be attributed to an age-related reduction of 17beta-estradiol signaling through its estrogen receptor alpha located in mitochondria. The females-specific mitochondrial remodeling encompassed increased abundance of proteins involved in fatty acid oxidation, decreased abundance of the complexes subunits, and enhanced proneness to oxidative posttranslational modifications. This conceivable accretion of damaged mitochondria in old females might be ascribed to low levels of Parkin, a key mediator of mitophagy. Despite skeletal muscle atrophy and fibrosis, males maintained their testosterone levels throughout aging, as well as their androgen receptor content, and the age-induced mitochondrial remodeling was limited to increased abundance of pyruvate dehydrogenase E1 component subunit beta and electron transfer flavoprotein subunit beta. Herein, for the first time, it was demonstrated that age affects more severely the skeletal muscle mitochondrial proteome of females, reinforcing the necessity of sex-personalized approaches towards sarcopenia management, and the inevitability of the assessment of mitochondrion-related therapeutics.

Preoperative smoking status and long-term survival after coronary artery bypass grafting: a competing risk analysis.

OBJECTIVES: Patients with severe coronary artery disease who undergo coronary artery bypass grafting consistently demonstrate that continued smoking after surgery increases late mortality rates. Smoking may exert its harmful effects through the ongoing chronic process of atherosclerotic progression both in the grafts and the native system. However, it is not clear whether cardiac mortality is primary and solely responsible for the inferior late survival of current smokers. METHODS: In this retrospective analysis, we included all consecutive patients undergoing primary isolated coronary artery bypass surgery from 1 January 2000 to 30 September 2015 in an Academic Hospital in Northern Portugal. The predictive or independent variable was the patients' smoking history status, a categorical variable with 3 levels: non-smoker (the comparator), ex-smoker for >1 year (exposure 1) and current smoker (exposure 2). The primary end point was long-term all-cause mortality. Secondary outcomes were long-term cause-specific mortality (cardiovascular and noncardiovascular). We fitted overall and Fine and Gray subdistribution hazard models. RESULTS: We identified 5242 eligible patients. Follow-up was 99.7% complete (with 17 patients lost to follow-up). The median follow-up time was 12.79 years (interquartile range, 9.51-16.60). Throughout the study, there were 2049 deaths (39.1%): 877 from cardiovascular causes (16.7%), 727 from noncardiovascular causes (13.9%) and 445 from unknown causes (8.5%). Ex-smokers had an identical long-term survival than non-smokers [hazard ratio (HR) 0.99; 95% confidence interval (CI) 0.88, 1.12; P = 0.899]. Conversely, current smokers had a 24% increase in late mortality risk (HR 1.24; 95% CI 1.07, 1.44; P = 0.004) as compared to non-smokers. While the current smoker status increased the relative incidence of noncardiac death by 61% (HR 1.61; 95% CI 1.27, 2.05, P < 0.001), it did confer a 25% reduction in the relative incidence of cardiac death (HR 0.75; 95% CI 0.59, 0.97; P = 0.025). CONCLUSIONS: Whereas ex-smokers have an identical long-term survival to non-smokers, current smokers exhibit an increase in late all-cause mortality risk at the expense of an increased relative incidence of noncardiac death. By subtracting the inciting risk factor, smoking cessation reduces the relative incidence of cardiac death.

Large animal models of pressure overload-induced cardiac left ventricular hypertrophy to study remodelling of the human heart with aortic stenosis.

Pathologic cardiac hypertrophy is a common consequence of many cardiovascular diseases, including aortic stenosis (AS). AS is known to increase the pressure load of the left ventricle, causing a compensative response of the cardiac muscle, which progressively will lead to dilation and heart failure. At a cellular level, this corresponds to a considerable increase in the size of cardiomyocytes, known as cardiomyocyte hypertrophy, while their proliferation capacity is attenuated upon the first developmental stages. Cardiomyocytes, in order to cope with the increased workload (overload), suffer alterations in their morphology, nuclear content, energy metabolism, intracellular homeostatic mechanisms, contractile activity, and cell death mechanisms. Moreover, modifications in the cardiomyocyte niche, involving inflammation, immune infiltration, fibrosis, and angiogenesis, contribute to the subsequent events of a pathologic hypertrophic response. Considering the emerging need for a better understanding of the condition and treatment improvement, as the only available treatment option of AS consists of surgical interventions at a late stage of the disease, when the cardiac muscle state is irreversible, large animal models have been developed to mimic the human condition, to the greatest extend. Smaller animal models lack physiological, cellular and molecular mechanisms that sufficiently resemblance humans and in vitro techniques yet fail to provide adequate complexity. Animals, such as the ferret (Mustello purtorius furo), lapine (rabbit, Oryctolagus cunigulus), feline (cat, Felis catus), canine (dog, Canis lupus familiaris), ovine (sheep, Ovis aries), and porcine (pig, Sus scrofa), have contributed to research by elucidating implicated cellular and molecular mechanisms of the condition. Essential discoveries of each model are reported and discussed briefly in this review. Results of large animal experimentation could further be interpreted aiming at prevention of the disease progress or, alternatively, at regression of the implicated pathologic mechanisms to a physiologic state. This review summarizes the important aspects of the pathophysiology of LV hypertrophy and the applied surgical large animal models that currently better mimic the condition.

Comparison of interleukin-6 and high-sensitivity C-reactive protein for cardiovascular risk assessment: Findings from the MESA study.

BACKGROUND AND AIMS: Inflammation is a risk factor for major adverse cardiovascular events (MACE). Elevated levels of both high-sensitivity C-reactive protein (hsCRP) and interleukin-6 (IL6) have been associated with MACE. However, few studies have compared IL6 to hsCRP for cardiovascular risk assessment. Using the MESA (Multi-Ethnic Study of Atherosclerosis) study cohort, we aim to compare IL6 to hsCRP. METHODS: We divided IL6 and hsCRP by their median values and created 4 groups i.e., low-low, high-low, low-high and high-high. The median follow-up was 14 years. RESULTS: 6614 (97 %) participants had complete baseline IL6 and hsCRP data. The correlation between hsCRP and IL6 was modest (Rho = 0.53). IL6 ≥1.2 pg/mL (median) was present in 3309 participants, and hsCRP ≥1.9 mg/L (median) was present in 3339 participants. Compared to participants with low IL6 and low hsCRP, those with high IL6 and high hsCRP were older (64 vs. 60 years), more frequently women (63 % vs. 45 %), and with more cardiovascular co-morbidities. hsCRP outcome associations lost statistical significance when adjusting for IL6: MACE HR (95 %CI) 1.06 (0.93-1.20), p =0.39, whereas IL6 associations remained significant after adjusting for hsCRP: HR (95 %CI) 1.44 (1.25-1.64), p <0.001. The C-index of Framingham score for did not improve with hsCRP but improved with IL6. Compared to participants with low IL6 and low hsCRP, those with high IL6, regardless of hsCRP, experienced an increased risk of MACE, heart failure and mortality. CONCLUSIONS: In a diverse and asymptomatic population, IL6 showed a stronger association with atherosclerotic, heart failure and fatal outcomes than hsCRP.

Stretch-induced compliance mechanism in pregnancy-induced cardiac hypertrophy and the impact of cardiovascular risk factors.

Pressure overload-induced hypertrophy compromises cardiac stretch-induced compliance (SIC) after acute volume overload (AVO). We hypothesized that SIC could be enhanced by physiological hypertrophy induced by pregnancy's chronic volume overload. This study evaluated SIC-cardiac adaptation in pregnant women with or without cardiovascular risk (CVR) factors. Thirty-seven women (1st trimester, 1stT) and a separate group of 31 (3rd trimester, 3rdT) women [healthy or with CVR factors (obesity and/or hypertension and/or with gestational diabetes)] underwent echocardiography determination of left ventricular end-diastolic volume (LVEDV) and E/e' before (T0), immediately after (T1), and 15 min after (T2; SIC) AVO induced by passive leg elevation. Blood samples for NT-proBNP quantification were collected before and after the AVO. Acute leg elevation significantly increased inferior vena cava diameter and stroke volume from T0 to T1 in both 1stT and 3rdT, confirming AVO. LVEDV and E/e' also increased immediately after AVO (T1) in both 1stT and 3rdT. SIC adaptation (T2, 15 min after AVO) significantly decreased E/e' in both trimesters, with additional expansion of LVEDV only in the 1stT. NT-pro-BNP increased slightly after AVO but only in the 1stT. CVR factors, but not parity or age, significantly impacted SIC cardiac adaptation. A distinct functional response to SIC was observed between 1stT and 3rdT, which was influenced by CVR factors. The LV of 3rdT pregnant women was hypertrophied, showing a structural limitation to dilate with AVO, whereas the lower LV filling pressure values suggest increased diastolic compliance.NEW & NOTEWORTHY The sudden increase of volume overload triggers an acute myocardial stretch characterized by an immediate rise in contractility by the Frank-Starling mechanism, followed by a progressive increase known as the slow force response. The present study is the first to characterize echocardiographically the stretch-induced compliance (SIC) mechanism in the context of physiological hypertrophy induced by pregnancy. A distinct functional adaptation to SIC was observed between first and third trimesters, which was influenced by cardiovascular risk factors.

Acute and chronic effects of levosimendan in the ZSF1 obese rat model of heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) is a syndrome characterized by impaired cardiovascular reserve in which therapeutic options are scarce. Our aim was to evaluate the inodilator levosimendan in the ZSF1 obese rat model of HFpEF. Twenty-week-old male Wistar-Kyoto (WKY), ZSF1 lean (ZSF1 Ln) and ZSF1 obese rats chronically treated for 6-weeks with either levosimendan (1 mg/kg/day, ZSF1 Ob + Levo) or vehicle (ZSF1 Ob + Veh) underwent peak-effort testing, pressure-volume (PV) haemodynamic evaluation and echocardiography (n = 7 each). Samples were collected for histology and western blotting. In obese rats, skinned and intact left ventricular (LV) cardiomyocytes underwent in vitro functional evaluation. Seven additional ZSF1 obese rats underwent PV evaluation to assess acute levosimendan effects (10 µg/kg + 0.1 µg/kg/min). ZSF1 Ob + Veh presented all hallmarks of HFpEF, namely effort intolerance, elevated end-diastolic pressures and reduced diastolic compliance as well as increased LV mass and left atrial area, cardiomyocyte hypertrophy and increased interstitial fibrosis. Levosimendan decreased systemic arterial pressures, raised cardiac index, and enhanced LV relaxation and diastolic compliance in both acute and chronic experiments. ZSF1 Ob + Levo showed pronounced attenuation of hypertrophy and interstitial fibrosis alongside increased effort tolerance (endured workload raised 38 %) and maximum O2 consumption. Skinned cardiomyocytes from ZSF 1 Ob + Levo showed a downward shift in sarcomere length-passive tension relationship and intact cardiomyocytes showed decreased diastolic Ca2+ levels and enhanced Ca2+ sensitivity. On molecular grounds, levosimendan enhanced phosphorylation of phospholamban and mammalian target of rapamycin. The observed effects encourage future clinical trials with levosimendan in a broad population of HFpEF patients.

Comprehensive characterization of protein modifications using mass spectrometry and dry blood spots.

PURPOSE: The main objective of this study is to characterize and analyze modified peptides in DBS samples. This includes deciphering their specific PTMs and understanding their potential impact on the population or disease cohort under study. EXPERIMENTAL DESIGN: Using mass spectrometry-based proteomic approaches, we performed a comprehensive analysis of DBS samples. Our focus was on the identification and quantification of modified peptides. We also took advantage of recent advances in DBS mass spectrometry to ensure accurate detection and quantification. RESULTS: A comprehensive analysis identified 972 modified peptides in DBS samples. Of these, a subset of 211 peptides was consistently present in all samples, highlighting their potential biological importance and relevance. This indicates a diverse spectrum of PTMs in the proteome of DBS samples. CONCLUSIONS AND CLINICAL RELEVANCE: Integration of mass spectrometry and proteomics has revealed a broad spectrum of modified peptides in DBS samples and highlighted their importance in biological processes and disease progression. Accurate detection of these PTMs may be critical for risk stratification and disease management. This study improves the understanding of molecular mechanisms underlying biological processes and disease development, providing important insights for clinical applications.

Association of metabolic syndrome components and NAFLD with quality of life: Insights from a cross-sectional study.

AIM: Metabolic syndrome (MetS) is associated with higher cardiovascular and metabolic risks, as well as with psychosocial disorders. Data regarding quality of life (QoL) in patients with MetS, point towards a significative association between MetS and a worse QoL. It remains unclear whether MetS components and non-alcoholic fatty liver disease (NAFLD) are associated with QoL in these individuals. We aimed to evaluate the association between QoL of patients with MetS and prespecified metabolic parameters (anthropometric, lipidic and glucose profiles), the risk of hepatic steatosis and fibrosis, and hepatic elastography parameters. METHODS: Cross-sectional study including patients from microDHNA cohort. This cohort includes patients diagnosed with MetS, 18 to 75 years old, followed in our tertiary center. The evaluation included anamnesis, physical examination, a QoL questionnaire (Short-Form Health Survey, SF-36), blood sampling and hepatic elastography. We used ordered logistic regression models adjusted to sex, age and body mass index to evaluate the associations between the QoL domains evaluated by SF-36 and the prespecified parameters. RESULTS: We included a total of 65 participants with MetS, with 54% being female and the mean age 61.9 ± 9.6 years old. A worse metabolic profile, specifically higher waist circumference, lower HDL, higher triglycerides, and more severe hepatic steatosis, were associated with worse QoL scores in several domains. We found no significant association of hepatic fibrosis with QoL. CONCLUSION: Our data suggests that there is a link between a worse metabolic profile (specifically poorer lipidic profile and presence of hepatic steatosis) and a worse QoL in patients with MetS.

The impact of echocardiographic indexation to evaluate cardiac reverse remodeling throughout pregnancy and postpartum.

INTRODUCTION AND OBJECTIVES: Echocardiography guidelines suggest normalizing left ventricular (LV) volumes and mass (LVM) to body size. During pregnancy, continuous weight variation impacts on body surface area (BSA) calculation, limiting the longitudinal analysis of cardiac remodeling (CR) and reverse remodeling (RR) variables. Our aim was to identify the most common indexing methodologies in the literature on pregnant populations through a systematic review; and, to compare four scaling methods: (i) none (absolute values); (ii) indexing to the BSA before pregnancy; (iii) allomeric indexing; and (iv) indexing to BSA measured at the same day of cardiac assessment, using an illustrative example. METHODS: We performed a systematic review of CR and RR during pregnancy and post-partum, using two databases. We included studies reporting longitudinal echocardiographic analysis of cardiac chamber volumes in humans. We used a prospective cohort study of healthy pregnant women who underwent four echocardiographic evaluations during pregnancy and postpartum, as an illustrative example. RESULTS: Twenty-seven studies were included, most studies indexed to BSA measured at each evaluation moment (n=21). Within-subjects design was the most reported to analyse longitudinal data (n=17). Indexation to the pre-pregnancy BSA or application of allometric indexes revealed a higher effect than BSA measured at each evaluation and an equal effect to not indexing using within-subjects design. The within-subjects designs also revealed a higher effect size value than the between-subjects design for longitudinal analysis of LVM adaptations during pregnancy and postpartum. CONCLUSION(S): This study concludes that indexation methods do not impact the clinical interpretation of longitudinal echocardiographic assessment but highlights the need to harmonize normalization procedures during pregnancy.

The additive effects of anaemia and transfusion on long-term survival after coronary artery bypass surgery.

OBJECTIVES: To compare the independent and combined effects of anaemia and red blood cell transfusion on late survival after isolated coronary artery bypass grafting. METHODS: Retrospective analysis of 5243 consecutive patients undergoing primary isolated coronary artery bypass grafting, performed from 2000 to 2015, in a Portuguese Academic Hospital. We identified 1649 patients with preoperative anaemia (A+) and 1422 patients who received a perioperative transfusion (T+)-the 4 possible combinations allowed for the creation of 4 subgroups (A-/T-, A-/T+, A+/T- and A+/T+). The primary endpoint was all-cause mortality at 10 years. We employed inverse probability weighting to control for confounding variables. RESULTS: Thirty-one percent of the patients had preoperative anaemia, and 27.0% had at least one packed red blood cell transfusion. Inverse probability weighting was effective in eliminating differences in all significant baseline characteristics. The primary endpoint of all-cause mortality at 10 years occurred in 568 patients (20.5%) in the A-/T- group, as compared with 204 (24.4%) in the A-/T+ group (hazard ratio, 1.14; 95% confidence interval, 1.00 to 1.31; P = 0.053), 358 (33.8%) in the A+/T- group (hazard ratio, 1.53; 95% confidence interval, 1.38 to 1.71; P < 0.001), 254 (43.6%) in the A+/T+ group (hazard ratio, 2.25; 95% confidence interval, 1.97 to 2.56; P < 0.001). CONCLUSIONS: This longitudinal, population-level study emphasizes the adverse long-term outcomes of preoperative anaemia and perioperative red blood cell transfusion. It stresses the importance of an evidence-based, multimodal and multidisciplinary approach to conserving blood resources and optimizing outcomes in patients at high risk for transfusion.

Digital flashcards and medical physiology performance: a dose-dependent effect.

Use of digital flashcards promotes active recall, spaced repetition, and self-assessment academic principles. This work explores the association and dose-dependent effect of this study method and locomotor (LP) and cardiovascular physiology (CP) grades. A single-faculty cohort study of medical LP and CP students was conducted, and 155 and 676 flashcards, respectively, were created through Moodle. An exploratory analysis examined three exam results (2019), and a confirmatory study used a fourth exam (2021) in another CP cohort. Of 685 students enrolled, 558 participated in the exploratory analysis: 319 (69%) for LP and 311 (84%) for CP, of which 203 LP and 267 CP students were flashcard users. Median grades were higher among flashcard users, and the number of cards reviewed was positively correlated with grades (r = 0.275 to 0.388 for LP and r = 0.239 to 0.432 for CP, P < 0.001). Multiple linear regression models confirmed a positive dose-dependent association between results and the number of flashcards studied: for every 100 LP cards reviewed, exam grades increased 0.44-0.75 on a 0-20 scale range (P < 0.001), and for every 1,000 CP flashcards, results raised 0.81-1.08 values (P < 0.05). These findings were confirmed in the 2021 CP cohort of 269 participants, of whom 67% were flashcard users. Digital flashcard revision has a consistent positive dose-dependent association on LP and CP grades.NEW & NOTEWORTHY Implementing flashcard-based strategies is a feasible way to promote active recall, spaced repetition, and self-assessment, and students are highly adherent to these initiatives. There is a positive dose-dependent association between the number of flashcards reviewed and physiology grades. These results are consistent across different physiology subjects, under different cohorts, over short and medium terms.

Prognostic value of flow-status in severe aortic stenosis patients undergoing percutaneous intervention.

PURPOSE: Low-flow status is a mortality predictor in severe aortic stenosis (SAS) patients, including after transcatheter aortic valve implantation (TAVI) treatment. However, the best parameter to assess flow is unknown. Recent studies suggest that transaortic flow rate (FR) is superior to currently used stroke volume index (SVi) in defining low-flow states. Therefore, we aimed to evaluate the prognostic value of FR and SVi in patients undergoing TAVI. METHODS: A single-centre retrospective analysis of all consecutive patients treated with TAVI for SAS between 2011 and 2019 was conducted. Low-FR was defined as < 200 mL/s and low-SVi as < 35 mL/m2. Primary endpoint was all-cause five-year mortality, analyzed using Kaplan-Meier curves and Cox regression models. Secondary endpoint was variation of NYHA functional class six months after procedure. Patients were further stratified according to ejection fraction (EF < 50%). RESULTS: Of 489 cases, 59.5% were low-FR, and 43.1% low-SVi. Low-flow patients had superior surgical risk, worse renal function, and had a higher prevalence of coronary artery disease. Low-FR was associated with mortality (hazard ratio 1.36, p = 0.041), but not after adjustment to EuroSCORE II. Normal-SVi was not associated with survival, despite a significative p-trend for its continuous value. No associations were found for flow-status and NYHA recovery. When stratifying according to preserved and reduced EF, both FR and SVi did not predict all-cause mortality. CONCLUSION: In patients with SAS undergoing TAVI, a low-FR state was associated with higher mortality, as well as SVi, but not at a 35 mL/m2 cut off.

A Minimally Invasive Model of Aortic Stenosis in Swine.

Large animal models of heart failure play an essential role in the development of new therapeutic interventions due to their size and physiological similarities to humans. Efforts have been dedicated to creating a model of pressure-overload induced heart failure, and ascending aortic banding while still supra-coronary and not a perfect mimic of aortic stenosis in humans, closely resembling the human condition. The purpose of this study is to demonstrate a minimally invasive approach to induce left ventricular pressure overload by placing an aortic band, precisely calibrated with percutaneously introduced high-fidelity pressure sensors. This method represents a refinement of the surgical procedure (3Rs), resulting in homogenous trans-stenotic gradients and reduced intragroup variability. Additionally, it enables swift and uneventful animal recovery, leading to minimal mortality rates. Throughout the study, animals were followed for up to 2 months after surgery, employing transthoracic echocardiography and pressure-volume loop analysis. However, longer follow-up periods can be achieved if desired. This large animal model proves valuable for testing new drugs, particularly those targeting hypertrophy and the structural and functional alterations associated with left ventricular pressure overload.

Myocardial stretch-induced compliance is abrogated under ischemic conditions and restored by cGMP/PKG-related pathways.

Introduction: Management of acute myocardial infarction (MI) mandates careful optimization of volemia, which can be challenging due to the inherent risk of congestion. Increased myocardial compliance in response to stretching, known as stretch-induced compliance (SIC), has been recently characterized and partly ascribed to cGMP/cGMP-dependent protein kinase (PKG)-related pathways. We hypothesized that SIC would be impaired in MI but restored by activation of PKG, thereby enabling a better response to volume loading in MI. Methods: We conducted experiments in ex vivo rabbit right ventricular papillary muscles under ischemic and non-ischemic conditions as well as pressure-volume hemodynamic evaluations in experimental in vivo MI induced by left anterior descending artery ligation in rats. Results: Acutely stretching muscles ex vivo yielded increased compliance over the next 15 min, but not under ischemic conditions. PKG agonists, but not PKC agonists, were able to partially restore SIC in ischemic muscles. A similar effect was observed with phosphodiesterase-5 inhibitor (PDE5i) sildenafil, which was amplified by joint B-type natriuretic peptide or nitric oxide donor administration. In vivo translation revealed that volume loading after MI only increased cardiac output in rats infused with PDE5i. Contrarily to vehicle, sildenafil-treated rats showed a clear increase in myocardial compliance upon volume loading. Discussion: Our results suggest that ischemia impairs the adaptive myocardial response to acute stretching and that this may be partly prevented by pharmacological manipulation of the cGMP/PKG pathway, namely, with PDE5i. Further studies are warranted to further elucidate the potential of this intervention in the clinical setting of acute myocardial ischemia.