Cardiorespiratory Fitness and Risk of Cardiovascular Events and Mortality in Middle Age Patients without Known Cardiovascular Disease.

BACKGROUND: Low cardiorespiratory fitness is an established risk predictor for chronic non-communicable diseases. We aimed to investigate the prognostic significance of fitness level on the risk of major adverse cardiac events (MACE, the composite of myocardial infarction, stroke, or all-cause death), in a contemporary cohort of middle-aged subjects without cardiovascular disease. METHODS: Retrospective analysis of patients aged 40-60 years without a history of cardiovascular disease. Degree of fitness was determined according to a graded, maximal treadmill exercise stress testing (EST) time achieved, classified into age- and sex-specific quintiles (Q), and categorized as low (Q1), moderate (Q2-Q4) or high (Q5) fitness groups. A multivariable Cox proportional hazard regression model was used to assess the association of fitness level with the risk of MACE. RESULTS: A total of 6836 patients were included, of which 44.5% were women, and the mean age was 52 years. Overall, 289 MACE events occurred during a median follow-up of 7 years. Level of fitness was inversely associated with the presence of cardiovascular risk factors. The multivariable adjusted hazard ratio (95% confidence interval) for MACE was 1.65 (1.12-2.44) and 2.17 (1.40-3.38) in those at moderate and low fitness levels, compared to the high-fitness group (reference), respectively. For each decrease of one metabolic equivalent (MET) unit achieved at peak exercise, the relative risk for MACE increased by 18%. The association between low fitness and MACE was not modified by other risk factors (P-for-interaction non-significant). CONCLUSIONS: Low fitness level, as captured by a maximal treadmill EST, is an independent risk predictor for MACE among middle-age individuals without known cardiovascular disease. The association of low fitness with high burden of cardiometabolic risk factors highlight the importance of lifestyle intervention in this patient population.

Heart Failure Therapies following Acute Coronary Syndromes with Reduced Ejection Fraction: Data from the ACSIS Survey.

BACKGROUND: Guideline-directed medical therapies for heart failure (HF) may benefit patients with reduced left ventricular ejection fraction (LVEF) following acute coronary syndromes (ACS). Few real-world data are available regarding the early implementation of HF therapies in patients with ACS and reduced LVEF. METHODS: Data collected from the 2021 nationwide, prospective ACS Israeli Survey (ACSIS). Drug classes included: (a) angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB) or angiotensin receptor-neprilysin inhibitors (ARNI); (b) beta-blockers; (c) mineralocorticoid receptor antagonist (MRA) and (d) sodium-glucose cotransporter-2 inhibitors (SGLT2I). The utilization of HF therapies at discharge or 90 days following ACS was analyzed in relation to LVEF [reduced ≤40% (n = 406) or mildly-reduced 41-49% (n = 255)] and short-term adverse outcomes. RESULTS: History of HF, anterior wall myocardial infarction and Killip class II-IV (32% vs. 14% p < 0.001) were more prevalent in those with reduced compared to mildly-reduced LVEF. ACEI/ARB/ARNI and beta-blockers were used by the majority of patients in both LVEF groups, though ARNI was prescribed to only 3.9% (LVEF ≤ 40%). MRA was used by 42.9% and 12.2% of patients with LVEF ≤40% and 41-49%, respectively, and SGLT2I in about a quarter of both LVEF groups. Overall, ≥3 HF drug classes were documented in 44% of the patients. A trend towards higher rates of 90-day HF rehospitalizations, recurrent ACS or all-cause death was noted in those with reduced (7.6%) vs. mildly-reduced (3.7%) LVEF, p = 0.084. No association was observed between the number of HF drug classes or the use of ARNI and/or SGLT2I with adverse clinical outcomes. CONCLUSIONS: In current clinical practice, the majority of patients with reduced and mildly-reduced LVEF are treated by ACEI/ARB and beta-blockers early following ACS, whereas MRA is underutilized and the adoption of SGLT2I and ARNI is low. A greater number of therapeutic classes was not associated with reduced short-term rehospitalizations or mortality.

Sequencing and titrating approach of therapy in heart failure with reduced ejection fraction following the 2021 European Society of Cardiology guidelines: an international cardiology survey.

AIMS: In symptomatic patients with heart failure and reduced ejection fraction (HFrEF), recent international guidelines recommend initiating four major therapeutic classes rather than sequential initiation. It remains unclear how this change in guidelines is perceived by practicing cardiologists versus heart failure (HF) specialists. METHODS AND RESULTS: An independent academic web-based survey was designed by a group of HF specialists and posted by email and through various social networks to a broad community of cardiologists worldwide 1 year after the publication of the latest European HF guidelines. Overall, 615 cardiologists (38 [32-47] years old, 63% male) completed the survey, of which 58% were working in a university hospital and 26% were HF specialists. The threshold to define HFrEF was ≤40% for 61% of the physicians. Preferred drug prescription for the sequential approach was angiotensin-converting enzyme inhibitors or angiotensin receptor-neprilysin inhibitors first (74%), beta-blockers second (55%), mineralocorticoid receptor antagonists third (52%), and sodium-glucose cotransporter 2 inhibitors (53%) fourth. Eighty-four percent of participants felt that starting all four classes was feasible within the initial hospitalization, and 58% felt that titration is less important than introducing a new class. Age, status in training, and specialization in HF field were the principal characteristics that significantly impacted the answers. CONCLUSION: In a broad international cardiology community, the 'historical approach' to HFrEF therapies remains the preferred sequencing approach. However, accelerated introduction and uptitration are also major treatment goals. Strategy trials in treatment guidance are needed to further change practices.

Adherence to Guidelines in Heart Failure, Is It Valid for Elderly Patients?

BACKGROUND: Current guidelines for the treatment of heart failure with reduced ejection fraction (HFrEF) are based on studies that have excluded or underrepresented older patients. OBJECTIVES: To assess the value of guideline directed medical therapy (GDMT) in HFrEF patients 80 years of age and older. METHODS: A single-center retrospective study included patients hospitalized with a first and primary diagnosis of acute decompensated heart failure (ADHF) and ejection fraction (EF) of ≤ 40%. Patients 80 years of age and older were stratified into two groups: GDMT, defined as treatment at hospital discharge with at least two drugs of the following groups: beta-blockers, angiotensin converting enzyme inhibitor (ACEI), angiotensin receptor blocker (ARB), or mineralocorticoid antagonists; and a personalized medicine group, which included patients who were treated with up to one of these drug groups. The primary outcomes were 90-day all-cause mortality, 90-day rehospitalization, and 3-years mortality. RESULTS: The study included 1152 patients with HFrEF. 254 (22%) patients who were at least 80 years old. Of the group, 123 were GDMT at discharge. When GDMT group was compared to the personalized medicine group, there were no statistically significant differences in terms 90-day mortality (17% vs. 13%, P = 0.169), 90-day readmission (51 % vs. 45.6%, P = 0.27), or 3-year mortality (64.5% vs. 63.3%, P = 0.915). CONCLUSIONS: Adherence to guidelines in the older adult population may not have the same effect as in younger patients who were studied in the randomized clinical trials. Larger prospective studies are needed to further address this issue.

IV Sodium Ferric Gluconate Complex in Patients With Iron Deficiency Hospitalized due to Acute Heart Failure-Investigator Initiated, Randomized Controlled Trial.

ABSTRACT: Patients with heart failure (HF) with iron deficiency (ID) have worse New York Heart Association class and are at a higher risk of recurrent hospitalizations. Intravenous (IV) iron has been shown to improve exercise ability and reduce hospitalizations. IV sodium ferric gluconate complex (SFGC) has been found to be safe and affordable but has not been studied in this population in a randomized trial. This was a prospective, single-blind, investigator-initiated, randomized controlled trial. Patients admitted for acute heart failure with ID were randomly assigned 1:1 to receive IV SFGC on top of optimal medical treatment. The primary outcome was the change in the 6-minute walk test (6MWT) from baseline to 3 and 6 months. Between September 2019 and May 2021, 34 patients were randomized. 19 patients (55%) were randomized to the treatment arm receiving 125 mg of IV SFGC per day for 3-5 days. COVID-19 was a major barrier to the implementation of the study follow-up protocol, which caused the study to end early. Both groups of patients had similar clinical characteristics, comorbidities, median left ventricular ejection fraction, and rate of death and readmissions due to HF. A higher level of NT-proBNP was observed in patients treated with IV iron (7902 pg/mL vs. 3158, P = 0.04). There was no difference in 6MWT change between groups at 3 months (improvement of 21.6 vs. 24.1 meters) or 6 months (-5 meters vs. 46 meters). In conclusion, IV SFGC-treated patients had a comparable 6-minute walk at 3 and 6 months despite suffering from more severe HF with higher baseline NT-proBNP (NCT04063033).

The prognostic value of heart rate at discharge in acute decompensation of heart failure with reduced ejection fraction.

AIMS: The effect of elevated heart rate (HR) on morbidity and mortality is evident in chronic stable heart failure; data in this regard in acute decompensated heart failure (ADHF) setting are scarce. In this single-centre study, we sought to address the prognostic value of HR and beta-blocker dosage at discharge on all-cause mortality among patients with heart failure and reduced ejection fraction and ADHF. METHODS AND RESULTS: In this retrospective observational study, 2945 patients were admitted for the first time with the primary diagnosis of ADHF between January 2008 and February 2018. Patients were divided by resting HR at discharge into three groups (HR < 70 b.p.m., HR 70-90 b.p.m., and HR > 90 b.p.m.). Evidence-based beta-blockers were defined as metoprolol, bisoprolol, and carvedilol. The doses of prescribed beta-blockers were calculated into a percentage target dose of each beta-blocker and divided to four quartiles: 0 < Dose ≤ 25%, 25% < Dose ≤ 50%, 50% < Dose ≤ 75%, and >75% of the target dose. Cox regression was used to calculate the hazard ratio for various HR categories and adjusting for clinical and laboratory variables. At discharge, 1226 patients had an HR < 70 b.p.m., 1347 patients had an HR at range 70-90 b.p.m., and 372 patients with an HR > 90 b.p.m. The 30 day mortality rate was 2.2%, 3.7%, and 12.1% (P < 0.001), respectively. Concordantly, 1 year mortality rate was 14.6%, 16.7%, and 30.4% (P < 0.001) among patients with HR < 70 b.p.m., HR 70-90 b.p.m., and HR > 90 b.p.m., respectively. The adjusted hazard ratio was significantly increased only in HR above 90 b.p.m. category (hazard ratio, 2.318; 95% confidence interval, 1.794-2.996). CONCLUSIONS: Patients with ADHF and an HR of <90 b.p.m. at discharge had significantly a lower 1 year mortality independent of the dosage of beta-blocker at discharge. It is conceivable to discharge these patients with lower HR.

SOFA score and short-term mortality in acute decompensated heart failure.

Acute decompensated heart failure (ADHF) is one of the leading causes for hospitalization and mortality. Identifying high risk patients is essential to ensure proper management. Sequential Organ Function Assessment Score (SOFA) is considered an excellent score to predict short-term mortality in sepsis and other life-threatening conditions. To assess the capability of SOFA score in predicting short-term mortality in ADHF. We retrospectively identified patients with first hospitalization with primary diagnosis of ADHF between the years (2008-2018). The SOFA score was calculated for all patients. A total 3232 patients were included in the study. The SOFA score was significantly associated with in-hospital mortality and 30-day mortality. The odds ratios for 1-point increase in the SOFA score were 1.86 (95% CI 1.68-1.96) and 1.627 (95% CI 1.523-1.737) respectively. The SOFA Score demonstrated a good predictive accuracy. The areas under the curve of receiver operating characteristic curves for in-hospital mortality and 30-day mortality were 0.765 (95% CI 0.733-0.798) and 0.706 (95% CI 0.676-0.736) respectively. SOFA score is associated with increased risk of short-term mortality in ADHF. SOFA can be used as a complementary risk score to screen high risk patients who need strict monitoring.

Prognostic value of cardiac troponin levels in patients presenting with supraventricular tachycardias.

BACKGROUND: An association between paroxysmal supraventricular tachycardias (PSVT) and elevated cardiac troponin I (cTnI) has been reported in small studies, even in the absence of significant coronary artery or structural heart disease. We sought to explore the prognostic significance of elevated cTnI among patients presenting with PSVT. METHODS: This is a retrospective single-center observational study conducted between January 2014 and Decemebr 2016. 165 patients (60% men, mean age 55 ± 17 year-old) with an acute episode of regular supraventricular tachyarrhythmia were admitted to the emergency department at Rambam Medical Center. 131 patients had at least one serum cTnI value measured. Of those, 57 had a positive result, defined as serum cTnI of more than 0.028 ng/dL. RESULTS: Multivariate analysis showed that heart rate > 150 beats per minute (bpm) on admission (OR = 3.9; 95% CI 1.1.6-9.5; p < 0.003) and history of coronary artery disease (CAD) (OR = 3.4; 95% CI 1.2-10.1; p = 0.026) were the only independent predictors of cTnI elevation. After mean follow-up period of 23 ± 7 months, the combined primary outcome of death, coronary intervention (PCI) or myocardial infarction (MI) occurred in 7 patients (12.3%) out of 57 patients with positive cTnI and in zero patients with negative cTn (p = 0.002). Cox proportional hazard model showed that elevated cTnI on admission was an independent predictor of adverse outcomes only in patients with known coronary artery disease (CAD) (HR = 3.3, p = 0.05). CONCLUSION: Elevated cTnI among patients presenting with PSVT appears to have prognostic significance only in patients with history of CAD. In this patient group elevated cTnI is associated with increased risk of adverse cardiac outcomes. We therefore believe serum cTnI should be measured selectively, such as in patients with symptoms of ischemic chest pain and a high pretest likelihood of having CAD.

Blood urea nitrogen variation upon admission and at discharge in patients with heart failure.

AIMS: Heart failure (HF) is one of the leading causes for hospitalization and mortality. After first admission with acute decompensated HF, some patients are in high risk for short-term and long-term mortality. These patients should be identified, closely followed up, and treated. It has been observed that blood urea nitrogen (BUN) on admission is a predictive marker for short-term mortality. Recently, it has been shown that higher BUN levels on discharge are also a bad prognostic predictor. However, the prognostic value of BUN alteration during hospital stay was not investigated; therefore, we aimed to investigate the effect of BUN variation during hospitalization on mortality. METHODS AND RESULTS: A retrospective study included patients with first hospitalization with the primary diagnosis of HF. The patients were divided into four groups on the basis of the values of BUN on admission and discharge, respectively: normal-normal, elevated-normal, normal-elevated, and elevated-elevated. Four thousand seven hundred sixty-eight patients were included; 2567 were male (53.8%); the mean age was 74.7 ± 12.7 years. The 90 day mortality rate in the normal-normal group was 7% lower than that in the elevated-normal (14.6%) and normal-elevated (19.3%) groups; P value < 0.01. The 90 day mortality in the elevated-elevated group (28.8%) was significantly higher than that in the other groups; P < 0.001. During the 36 month follow-up, these results are maintained. While sub-dividing BUN levels into <30, 30-39, and >40 mg/dL, higher BUN levels correlated with higher 90 day mortality rate regardless of creatinine levels, brain natriuretic peptide, or age. Moreover, BUN on admission and on discharge correlated better with mortality than did creatinine and glomerular filtration rate at the same points. CONCLUSIONS: The BUN both on admission and on discharge is a prognostic predictor in patients with HF; however, patients with elevated levels both on admission and on discharge have the worst prognosis. Moreover, worsening or lack of improvement in BUN during hospitalization is a worse prognostic predictor. To the best of our knowledge, this is the first trial to discuss the BUN change during hospitalization in HF.

Involvement of Cytokines in the Pathogenesis of Salt and Water Imbalance in Congestive Heart Failure.

Congestive heart failure (CHF) has become a major medical problem in the western world with high morbidity and mortality rates. CHF adversely affects several systems, mainly the kidneys and the lungs. While the involvement of the renin-angiotensin-aldosterone system and the sympathetic nervous system in the progression of cardiovascular, pulmonary, and renal dysfunction in experimental and clinical CHF is well established, the importance of pro-inflammatory mediators in the pathogenesis of this clinical setting is still evolving. In this context, CHF is associated with overexpression of pro-inflammatory cytokines, such as tumor necrosis factor-α, interleukin (IL)-1, and IL-6, which are activated in response to environmental injury. This family of cytokines has been implicated in the deterioration of CHF, where it plays an important role in initiating and integrating homeostatic responses both at the myocardium and circulatory levels. We and others showed that angiotensin II decreased the ability of the lungs to clear edema and enhanced the fibrosis process via phosphorylation of the mitogen-activated protein kinases p38 and p42/44, which are generally involved in cellular responses to pro-inflammatory cytokines. Literature data also indicate the involvement of these effectors in modulating ion channel activity. It has been reported that in heart failure due to mitral stenosis; there were varying degrees of vascular and other associated parenchymal changes such as edema and fibrosis. In this review, we will discuss the effects of cytokines and other inflammatory mediators on the kidneys and the lungs in heart failure; especially their role in renal and alveolar ion channels activity and fluid balance.

Relation between changes in red cell distribution width and clinical outcomes in acute decompensated heart failure.

BACKGROUND: Increased red blood cell distribution (RDW) has been associated with adverse outcomes in patients with heart failure. We studied the association between baseline RDW and changes in RDW during hospital course with clinical outcomes in acute decompensated heart failure (ADHF) patients. METHODS AND RESULTS: We prospectively studied 614 patients with ADHF. Baseline RDW and RDW change during hospital course were determined. The relationship between RDW and clinical outcomes after hospital discharge was tested using Cox regression models, adjusting for clinical characteristics, echocardiographic findings and brain natriuretic peptide levels. During follow up (1 year), 286 patients (46.6%) died and 84 were readmitted for ADHF (13.7%). Median RDW was significantly higher among patients who died compared to patients who survived (15.6% interquartile range [14.5 to 17.1] vs. 14.9% mg/L interquartile range [14.1 to 16.1], P<0.0001). Compared with patients in the 1st RDW quartile, the adjusted hazard ratio [HR] for death or rehospitalization was 1.9 [95% CI 1.3-2.6] in patients in the 4th quartile. Changes in RDW during hospitalization were strongly associated with changes in mortality risk. Compared with patients with persistent normal RDW (<14.5%), the adjusted HR for mortality was 1.9 [95% CI 1.1-3.1] for patients in whom RDW increased above 14.5% during hospital course, similar to patients with persistent elevation of RDW (HR was 1.7, 95% CI 1.2-2.3). CONCLUSION: In patients hospitalized with ADHF, RDW is a strong independent predictor of greater morbidity and mortality. An increase in RDW during hospitalization also portends adverse clinical outcome.

Restrictive left ventricular filling pattern and risk of new-onset atrial fibrillation after acute myocardial infarction.

Mechanisms for atrial arrhythmias that occur in the context of acute myocardial infarction (AMI) have not been well characterized. AMI often leads to alterations in left ventricular (LV) filling dynamics, which may result in advanced diastolic dysfunction. Diastolic dysfunction may produce increased left atrial (LA) pressure and initiate LA remodeling, promoting the progression to atrial fibrillation (AF). We studied 1,169 patients admitted with AMI. Advanced diastolic dysfunction was defined as a restrictive filling pattern (RFP), defined as ratio of early to late transmitral velocity of mitral inflow >1.5 or deceleration time <130 ms. The relation between RFP and the primary end point of new-onset AF occurring within 6 months was analyzed using multivariable Cox models. Of 1,169 patients (70% men, mean ± SD 64 ± 10 years of age), 110 (9.4%) developed new-onset AF (19.6% and 7.5% in patients with and without RFP, respectively, p <0.0001). RFP was associated with a hazard ratio of 2.72 for AF (95% confidence interval 1.83 to 4.05, p <0.0001). After multivariable adjustments for clinical variables, LV ejection fraction (EF) and LA size, RFP remained an independent predictor of AF (hazard ratio 2.17, 95% confidence interval 1.42 to 3.32, p <0.0001). Risk of AF was higher in patients with RFP for preserved (≥45%, hazard ratio 2.14, 95% confidence interval 1.09 to 4.20, p = 0.03) or decreased (hazard ratio 2.80, 95% confidence interval 1.63 to 4.82, p <0.0001) LVEF. In contrast, decreased LVEF in the absence of RFP was similar to that of patients with preserved LVEF and without RFP. In conclusion, in patients with AMI, presence of advanced diastolic dysfunction was independently associated with new-onset AF, suggesting that increased filling pressures may contribute to the development of AF after AMI.

Relationship of functional mitral regurgitation to new-onset atrial fibrillation in acute myocardial infarction.

BACKGROUND/OBJECTIVE: The role of factors that increase left atrial pressure or cause acute left atrial dilatation is frequently emphasised in the pathogenesis of atrial fibrillation (AF) in patients with acute myocardial infarction (AMI). This study was designed to test the hypothesis that functional mitral regurgitation (FMR) occurring after AMI may promote AF by producing left atrial volume overload. SETTING: Intensive care unit of a tertiary care hospital. PATIENTS AND METHODS: 1920 patients admitted with AMI were studied. Patients with known AF were excluded. FMR was classified using echocardiography into three groups: none; mild FMR and moderate or severe FMR. The relationship between FMR and AF occurring at any time during the hospital course was examined using multivariable logistic regression. RESULTS: Mild FMR was present in 744 patients (38.8%) and moderate or severe FMR was present in 150 patients (7.8%). AF developed in 51 (5.0%), 83 (11.2%) and 28 (18.7%) patients with no FMR, mild FMR and moderate or severe FMR, respectively (p trend <0.001). In multivariable logistic regression, both mild (odds ratio (OR) 1.6; 95% CI 1.1 to 2.3, p=0.02) and moderate or severe FMR (OR 2.1; 95% CI 1.2 to 3.6, p=0.007) were independent predictors of AF. There was a significant interaction between the left ventricular ejection fraction and FMR (p=0.003) such that mild FMR was predictive of AF only in patients with a reduced (<45%) ejection fraction. CONCLUSIONS: There is a graded independent association between the severity of FMR and the new onset of AF in patients with AMI.