Remarkable advances have been made in the treatment of cardiovascular diseases (CVD), however, CVD still accounts for the most deaths in industrialized nations. Ischemic heart disease (IHD) can lead to acute coronary syndrome (ACS) (myocardial infarction [MI]). The standard of care is reperfusion therapy followed by pharmacological intervention to attenuate clinical symptoms related to the MI. While survival from MI has dramatically increased with the implementation of reperfusion therapy, these individuals will inevitably suffer progressive pathological remodeling leaving them predispose to develop heart failure (HF). HF is a clinical syndrome defined as the impairment of the heart to maintain organ perfusion at rest and/or during times of exertion (i.e. exercise intolerance). Clinically, this is accompanied by dyspnea, pulmonary or splanchnic congestion and peripheral edema. Physiologically, there is neurohormal activation through the classical β–adrenergic and PKA–dependent signalin / Physiology

<p>  </p> <p><strong>Background: </strong></p> <p>Torsades de pointes (TdP) is a polymorphic ventricular tachycardia (VT) associated with heart rate-corrected QT interval (QTc) prolongation on the electrocardiogram (ECG). TdP can cause sudden cardiac arrest (SCA), a catastrophic outcome. The antiarrhythmic drugs dofetilide and sotalol can cause QTc prolongation and arrhythmias, as can more than 200 other medications available on global markets. Heart failure (HF) with reduced ejection fraction (HFrEF) is a risk factor for drug-induced TdP, and HFrEF heightens sensitivity to drug-induced QTc lengthening. However, ~55% of patients with HF have preserved, rather than reduced, ejection fraction. It remains unknown whether patients with HF with preserved ejection fraction (HFpEF) are at increased risk for drug-induced VT/SCA. Assessment of the risk of drug-induced VT/SCA in HFpEF patients is important, so that recommendations can be made regarding the safety of QTc-prolonging drugs and need for enhanced ECG monitoring in this population. </p> <p><strong>Objective:</strong></p> <p>In aim 1, we sought to determine the risk of VT and SCA associated with dofetilide and sotalol in patients with HFpEF. In aim 2, we were able to use QTc interval to determine the odds of dofetilide/sotalol-associated QT interval prolongation in patients with HFpEF. In Aim 3, we investigated the influence of HFpEF on VT and SCA associated with a broader group of drugs known to cause TdP (“known “TdP drugs”), as designated by the QT drugs list at www.crediblemeds.org. </p> <p><strong>Methods:</strong></p> <p>In aim 1, we used Medicare claims (2014-2016) and ICD-9/10 codes to identify patients taking the QT interval-prolonging drugs dofetilide or sotalol, which are used commonly in patients with HF and atrial fibrillation, as well as non-dofetilide or sotalol users among 3 groups: HFpEF, HFrEF, and no HF. Multinomial propensity score-matching was performed. Cochran–Mantel–Haenszel statistics and standardized differences were used to compare baseline characteristics. A generalized Cox proportional hazards model was used to estimate hazard ratios (HRs) and test the association of VT and SCA among dofetilide/sotalol users, HFpEF, HFrEF, and no HF.</p> <p>In Aim 2, the data source was electronic health records from the Indiana Network for Patient Care (February 2010 to May 2021). After removing patients with overlapping diagnoses of HFpEF and HFrEF, no diagnosis code, absence of QT interval records, and no validated record of using dofetilide or sotalol, we identified patients taking dofetilide or sotalol among three groups: HFrEF, HFpEF, and no HF. Cochran–Mantel–Haenszel statistics were used to compare baseline characteristics. QT interval prolongation was defined as heart rate-corrected QT (QTc) > 500 ms during dofetilide/sotalol therapy. Unadjusted odds ratios (OR) of QT interval prolongation were determined by univariate analysis, and adjusted ORs were determined by generalized estimating equations (GEE) with logit link to account for an individual cluster with different times of hospitalization and covariates.</p> <p>In aim 3, we used Medicare enrollment in fee-for-service medical and pharmacy benefits (2014 to 2016) and ICD-9/10 codes, we identified patients taking drugs known to cause torsades de pointes (TdP drugs; www.crediblemeds.org) and non-TdP drug users among three groups: HFrEF, HFpEF, and no HF. Multinomial propensity score-matching was performed to minimize baseline differences in covariates (patient demographics, comorbidities, health care utilization and drug history). Cochran–Mantel–Haenszel statistics and standardized differences were used to compare baseline characteristics. A generalized Cox proportional hazards model was used to estimate HRs and test the association of VT and SCA among TdP drug users with HFpEF, HFrEF, and no HF.</p> <p><strong>Results:</strong></p> <p>In Aim 1, VT and SCA occurred in 166 (10.68%) and 16 (1.03%), respectively, of 1,554 dofetilide/sotalol users with HFpEF, 543 (38.76%) and 40 (2.86%) of 1,401 dofetilide/sotalol users with HFrEF, and 245 (5.06%) and 13 (0.27%) of 4,839 dofetilide/sotalol users with no HF. The adjusted HR for VT in patients with HFrEF was 7.00 (95% CI 6.12-8.02) and in patients with HFpEF was 1.99 (1.71-2.32). The risk of VT associated with dofetilide/sotalol was increased across the overall study population (HR: 2.47 [1.89-3.23]). Use of dofetilide/sotalol increased the risk of VT in patients with HFrEF (HR: 1.53 [1.07-2.20]) and in those with HFpEF (HR: 2.34 [1.11-4.95]). However, while the overall risk of SCA was increased in patients with HFrEF (HR: 5.19 [4.10-6.57]) and HFpEF (HR: 2.53 [1.98-3.23]) compared to patients with no HF, dofetilide/sotalol use was not significantly associated with an increased risk of SCA.</p> <p>In Aim 2, QTc prolongation associated with dofetilide/sotalol occurred in 51.2% of patients with HFpEF, 70.1% of patients with HFrEF, and 29.4% of patients with no HF. After adjusting for age, sex, race, serum potassium and magnesium concentrations, kidney function, concomitant drug therapy, and comorbid conditions, the adjusted odds of having QTc interval larger than 500ms during the hospital stay were 5.23 [3.15-8.67] for HFrEF and 1.98 [1.17-3.33] for HFpEF with no HF as the reference group. </p> <p>In Aim 3, of 23,910 known TdP drug users with HFrEF, VT and SCA occurred in 4,263 (17.8%) and 493 (2.1%) patients, respectively. In comparison, among 31,359 known TdP drug users with HFpEF, VT and SCA occurred in 1,570 (5.0%) and 340 (1.1%) patients. VT and SCA occurred in 3,154 (0.8%) and 528 (0.1%) of 384,824 known TdP drug users without HF. The overall HR of both VT and SCA was increased in patients with HFrEF (HR: 7.18 [6.13-8.40])  and in those with HFpEF (HR: 2.09 [1.80-2.42]). The risk of VT associated with known TdP drugs was increased across the overall population (HR: 1.34 [1.20-1.51]). Use of known TdP drugs significantly increased the risk of VT and SCA in patients with HFrEF (HR: 1.34 [1.07-1.67]), but not in patients with HFpEF.</p> <p><strong>Conclusion:</strong></p> <p>HFpEF may exhibit an enhanced response to drug-associated VT, and is associated with a higher risk of drug-associated QTc interval prolongation. Further study is needed to identify methods to minimize this risk for patients with HFpEF requiring therapy with dofetilide, sotalol, or drugs known to cause TdP. </p>

No description available.

Background and aims Heart failure (HF) is a major cause of serious morbidity and death in the population and one of the leading medical causes of hospitalization among people older than 60 years. The aim of this thesis was to describe how to create and how to analyze a Heart Failure Registry with emphasis on Anemia and Quality of Life. (Paper I) We described the creation of the Swedish Heart Failure Registry (SwedeHF) as an instrument, which may help to optimize the handling of HF patients and show how the registry can be used to improve the management of patients with HF. (Paper II) In order to show how to analyze a HF registry we investigated the prevalence of anemia, its predictors, and its association with mortality and morbidity in a large cohort of unselected patients with HFrEF included in the SwedeHF, and to explore if there are subgroups of HF patients identifying high--‐risk patients in need of treatment. (Paper III) In order to show another way of analyzing a HF registry we assessed the prevalence of, associations with, and prognostic impact of anemia in patients with HFmrEF and HFpEF. (Paper IV) Finally we examined the usefulness of EQ--‐ 5D as a measure of patient--‐reported outcomes among HF patients using different analytical models and data from the SwedeHF, and comparing results about HRQoL for patients with HFpEF and HFrEF. Methods An observational study based on the SwedeHF database, consisting of about 70 variables, was undertaken to describe how a registry is created and can be used (Paper I). One comorbidity (anemia) was applied to different types of HF patients, HFrEF (EF &lt;40%) (II) and HFmrEF (EF 40--‐49% ) or HFpEF (&gt; 50%) (III) analyzing the data with different statistical methods. The usefulness of EQ--‐5D as measure of patient--‐ reported outcomes was studied and the results about HRQoL were compared for patients with HFpEF and HFrEF (IV). Results In the first paper (Paper I) we showed how to create a HF registry and presented some characteristics of the patients included, however not adjusted since this was not the purpose of the study. In the second paper (Paper II) we studied anemia in patients with HFrEF and found that the prevalence of anemia in HFrEF were 34 % and the most important independent predictors were higher age, male gender and renal dysfunction. One--‐year survival was 75 % with anemia vs. 81 % without (p&lt;0,001). In the matched cohort after propensity score the hazard ratio associated with anemia was for all--‐cause death 1.34. Anemia was associated with greater risk with lower age, male gender, EF 30--‐39%, and NYHA--‐class I--‐II. In the third paper (Paper III) we studied anemia in other types of HF patients and found that the prevalence in the overall cohort in patients with EF &gt; 40% was 42 %, in HFmrEF 38 % and in HFpEF (45%). Independent associations with anemia were HFpEF, male sex, higher age, worse New York Heart Association class and renal function, systolic blood pressure &lt;100 mmHg, heart rate ≥70 bpm, diabetes, and absence of atrial fibrillation. One--‐year survival with vs. without anemia was 74% vs. 89% in HFmrEF and 71% vs. 84% in HFpEF (p&lt;0.001 for all). Thus very similar results in paper II and III but in different types of HF patients. In the fourth paper (Paper IV) we studied the usefulness of EQ--‐5D in two groups of patients with HF (HFpEF and HFrEF)) and found that the mean EQ--‐5D index showed small reductions in both groups at follow--‐up. The patients in the HFpEF group reported worsening in all five dimensions, while those in the HFrEF group reported worsening in only three. The Paretian classification showed that 24% of the patients in the HFpEF group and 34% of those in the HFrEF group reported overall improvement while 43% and 39% reported overall worsening. Multiple logistic regressions showed that treatment in a cardiology clinic affected outcome in the HFrEF group but not in the HFpEF group (Paper IV). Conclusions The SwedeHF is a valuable tool for improving the management of patients with HF, since it enables participating centers to focus on their own potential for improving diagnoses and medical treatment, through the online reports (Paper I). Anemia is associated with higher age, male gender and renal dysfunction and increased risk of mortality and morbidity (II, III). The influence of anemia on mortality was significantly greater in younger patients in men and in those with more stable HF (Paper II, III). The usefulness of EQ--‐5D is dependent on the analytical method used. While the index showed minor differences between groups, analyses of specific dimensions showed different patterns of change in the two groups of patients (HFpEF and HFrEF). The Paretian classification identified subgroups that improved or worsened, and can therefore help to identify needs for improvement in health services (Paper IV).

No description available.

L’insuffisance cardiaque (IC) est définie comme l’incapacité du cœur à fournir un débit cardiaque suffisant lorsque la demande augmente. L’IC survient lors d’une diminution 1) de la fonction contractile, définie comme l’IC à fraction d’éjection réduite (IC-FER) ou 2) de remplissage reliée à une rigidité du myocarde ou du péricarde, définie comme l’IC à FE préservée (IC-FEP). Les altérations de la fonction cardiaque contribuent à l’activation neuro-hormonale et à l’inflammation sous-clinique lors de l’apparition et l’évolution de l’IC. L’IC est caractérisée par de multiples anomalies du système vasculaire et musculaire périphériques. La diminution de la perfusion périphérique peut causer de multiples désordres au niveau vasculaire et musculaire chez les IC. L’inflammation sous-clinique contribue significativement à la progression de l’IC. Puisque les neutrophiles sont les principaux acteurs dans la sécrétion de cytokines inflammatoires, l’objectif de cette thèse est de caractériser le profil pro- et anti-inflammatoire dérivé des neutrophiles chez les patients souffrant d’IC-FER et IC-FEP, ainsi que l’impact du diabète (DM) sur ce profil. Les biomarqueurs plasmatiques et relâchés par les neutrophiles isolés à partir du sang provenant de 20 volontaires sains (CTL), 52 IC-FER et 25 IC-FEP et 22 DM ont été quantifiés. L’observation majeure de notre étude est la réduction importante (>90%) des taux circulants de Vascular endothelial growth factor (VEGF) chez les patients IC-FER et IC-FEP avec ou sans DM par rapport aux CTL. En parallèle, nous avons observé une diminution significative de la sécrétion du VEGF par les neutrophiles des patients IC-FER et IC-FEP avec une réduction maximale (92%) chez les IC-FEP+DM comparé aux CTL après une stimulation avec des médiateurs pro-inflammatoires. La diminution du VEGF associée à une inflammation accrue de l'endothélium micro-vasculaire coronarien conduit à une dérégulation de la génération de l’oxyde nitrique (NO). Une diminution marquée des taux circulants de NO a été observée chez les patients diabétiques et atteints d'IC comparé aux CTL. Les niveaux circulants d'IL-6 et d'IL-8 sont significativement augmentés chez les patients IC et DM et de manière synergique chez les IC-FEP avec DM. Ces données, combinées à une diminution du VEGF et du NO, suggèrent une altération significative de la fonction macro-vasculaire et micro-vasculaire chez les patients IC-FEP, qui est intensifiée par la présence de diabète. La libération d’IL-8 et d’IL-6 par les neutrophiles était significativement augmentée chez les patients DM et IC-FEP+DM après un traitement au lipopolysaccharide (LPS). Nous avons aussi démontré une augmentation de l'IL-1RA circulante, une cytokine anti-inflammatoire dans toutes les cohortes de patients. Cependant, la sécrétion de l’IL-1RA par les neutrophiles était diminuée dans toutes les cohortes par rapport aux CTL, indépendamment de l’agoniste utilisé. Ces observations suggèrent que les neutrophiles ne sont pas les principales cellules qui secrètent l'IL-1RA, mais bien les monocytes, les hépatocytes, les cellules épithéliales et les adipocytes. Les données scientifiques provenant de ces études nous ont permis de mieux caractériser le rôle du neutrophile dans l’IC et permettront de valider l’hypothèse stipulant que les biomarqueurs dérivés des neutrophiles jouent un rôle significatif dans l’IC. / Heart failure (HF) is characterized by the inability of the heart to provide sufficient cardiac output when there is an increase in demand. This may result from a decrease in 1) contractile function, defined as heart failure with reduced ejection fraction (HF-REF) or 2) filling related to stiffness of the myocardium or pericardium, defined as HF with preserved EF (HF-PEF). Alterations in cardiac function contribute to neuro-hormonal activation and subclinical inflammation during the onset and progression of HF. HF is characterized by multiple abnormalities in the peripheral vascular and muscular system. Decreased peripheral perfusion can cause vascular and peripheral muscular disorders in HF-REF and HF-PEF. However, the cellular mechanisms involved in these observations remain unknown. Subclinical inflammation significantly contributes to the progression of HF. Since neutrophils are the first players for the inflammatory cytokines release, the main objective of this doctoral thesis is to characterize the pro and anti-inflammatory profile derived from neutrophils in patients suffering from HF-REF and HF-PEF, as well as the impact of diabetes (DM) on this profile. The plasma and neutrophil released biomarkers from the blood of 20 healthy control volunteers (CTL), 52 HF-REF and 25 HF-PEF and 22 DM were quantified. The major finding of our study is the significant reduction (>90%) of the circulating levels of vascular endothelial growth factor (VEGF) in HF-REF and HF-PEF patients with or without diabetes compared to CTL. In parallel, we observed a significant decrease of the VEGF secretion by the neutrophils from HF-REF and HF-PEF patients with a maximal reduction (92%) in HF-PEF+DM compared to CTL after pro-inflammatory agonists stimulation. The decrease of VEGF associated with an increased inflammation of the coronary microvascular endothelium leads to a deregulation of nitric oxide (NO) generation. A marked decrease in circulating NO levels was indeed observed in diabetic and HF patients compared to CTL. Circulating levels of IL-6 and IL-8 increased significantly in HF and DM patients, being maximal in HFPEF+DM. These data, when combined with a decrease in VEGF and NO, support a significant impairment of macrovascular and microvascular function in HF-PEF patients, which is increased by the presence of diabetes. The release of IL-8 and IL-6 from neutrophils was significantly increased in DM and HF-PEF+DM patients after treatment with lipopolysaccharide (LPS). We also observed an increase in circulating IL-1RA, an anti-inflammatory cytokine in all patients’ cohorts. However, IL-1RA secretion by the neutrophils was decreased in all cohorts compared to CTL, independently of the agonist used. These observations suggest that neutrophils are not the main cells that secrete IL-1RA, but rather monocytes, hepatocytes, epithelial cells and adipocytes. The scientific data from these studies have allowed us to better characterize the role of neutrophils in HF and will validate the hypothesis that biomarkers derived from neutrophils play a significant role in the HF.