Atrial fibrillation in patients with systolic heart failure: pathophysiology mechanisms and management

Heart failure (HF) and atrial fibrillation (AF) demonstrate a constantly increasing prevalence during the 21^st century worldwide, as a result of the aging population and the successful interventions of the clinical practice in the deterioration of adverse cardiovascular outcomes. HF and AF share common risk factors and pathophysiological mechanisms, creating the base of a constant interrelation. AF impairs systolic and diastolic function, resulting in the increasing incidence of HF, whereas the structural and neurohormonal changes in HF with preserved or reduced ejection fraction increase the possibility of the AF development. The temporal relationship of the development of either condition affects the diagnostic algorithms, the prognosis and the ideal therapeutic strategy that leads to euvolaemia, management of non-cardiovascular comorbidities, control of heart rate or restoration of sinus rate, ventricular synchronization, prevention of sudden death, stroke, embolism, or major bleeding and maintenance of a sustainable quality of life. The indicated treatment for the concomitant HF and AF includes rate or/and rhythm control as well as thromboembolism prophylaxis, while the progress in the understanding of their pathophysiological interdependence and the introduction of the genetic profiling, create new paths in the diagnosis, the prognosis and the prevention of these diseases.

Heart failure (HF) and atrial fibrillation (AF) have become epidemics of the 21st century, as a result of the increased longevity and the successful reduction of the cardiovascular (CV) mortality.^[1] The prevalence of both conditions is constantly rising, increasing significantly the cost of treatment to the healthcare systems worldwide.^[2-4] It is estimated that the incidence of AF (2%) is double compared to the last decade. AF is present in 0.12%−0.16% of those < 49 years of age, in 3.7%−4.2% of those aged 60−70 years, and in 10%−17% of those aged ≥ 80 years, occurring more frequently in males, with a male to female ratio of 1.2: 1.^[5] By the year 2030 in Europe alone it is estimated that the patients with AF will be 14−17 million, with an annual number of 120−215,000 new cases,^[5] while the prevalence in the American population will be 12 million.^[6] HF affects approximately 1%−2% of adults in developed countries.^[7] Few individuals under 50 years of age are diagnosed with HF, whereas the prevalence in those aged 75 years or above is more than 10%.^[7,8] The prevalence of HF globally in AF individuals is 33% in patients with paroxysmal AF, 44% in those with persistent and 56% in those with permanent AF.^[9] Among the 5.8 million US adults with heart failure with reduced ejection fraction (HFrEF) or preserved EF (HFpEF), the prevalence of AF is up to 40%.^[10,11] It is clear that the combination of these two conditions will have a significant impact on healthcare and the management of cardiovascular (CV) disease as it is performed so far.^[12,13] The pathophysiology and risk factors for HF and AF are closely related and the coexistence of HF and AF affects elderly patients with a significant burden of comorbidities.^{[9, 14]} The development of AF is connected with complex interactions that lead to impairment of systolic and diastolic function, that are not present in sinus rhythm (SR), resulting in a three-fold increased risk of HF incidence compared with SR.^[15] Conversely, the structural and neurohormonal changes in HF increase the possibility of the AF incidence^[16] both in HFrEF and in HFpEF.^[1] Previous studies have also demonstrated differences in atrial remodeling, prognosis and outcomes^[17] associated with AF development among the HF subtypes,^[18] with greater eccentric LA remodeling in HFrEF, and increased LA stiffness in HFpEF predisposing more evidently in AF.^[19] Regardless which condition develops first, their combined incidence is associated with a worse prognosis than either condition alone.^[20-22] Concerning the adverse outcomes that are associated with HF and AF, an important target of clinical studies is the development of effective therapies for these patients but also an arduous one as the so far applied treatments on either of these conditions alone are shown to be effective or provoke safety concerns in patients with HF and AF.^{[23, 24]}     

Beta-blocker treatment in heart failure patients with atrial fibrillation: challenges and perspectives

Heart failure (HF) and atrial fibrillation (AF) are common conditions that share similar clinical phenotype and frequently coexist. The classification of HF in patients with preserved ejection fraction (> 50%, HFpEF), mid-range reduced EF (40%−49%, HFmrEF) and reduced EF (< 40%, HFrEF) are crucial for optimising the therapeutic approach, as each subgroup responds differently. Beta-blocker constitute an important component of our pharmacological regimen for chronic HF. Beta-blocker administration is reccomended in patients with HF with reduced ejection fraction in stable sinus rhythm, due to improvement of symptoms, the better long term-outcome and survival. The beneficial role of beta-blocker use in patients with preserved EF still remain unclear, as no treatment showed a positive impact, regarding morbidity or mortality reduction. The presence of AF in HF patients increases as the disease severity evolves and is associated with a higher rate of cardiovascular morbidity and mortality. But more question is the use of betablocker in HF patients irrespective of EF and concomitant AF. There are many conflicting data and publications, regarding the beta blocker benefit in this population. Generally, it is supported an attenuation of beta-blockers beneficial effect in HF patients with AF. A design of more randomised trials/studies with HF patients and concomitant AF may improve our clinical approach of beta-blockers use and identify the patients with HF, who mostly profit from an invasive approach.

Atrial fibrillation (AF) and heart failure (HF) with or without systolic dysfunction constitute common cardiac conditions, that frequently coexist and overlap.^[1] These entities share multiple risk factors such as age, hypertension, diabetes, obesity, as well as cardiac substrates as valvular, ischemic, and non ischemic structural heart disease.^{[1, 2]} Their coexistence can be partially explained by the presence of the common risk factors.^[3]The definition of heart failure revised in 2016, based on the measurement of left ventricular ejection fraction (EF).^[4] Especially, HF can be divided in three groups: heart failure with preserved EF(> 50%, HFpEF), mid-range reduced EF (40%−49%, HFmrEF) and reduced EF (< 40%, HFrEF).^[4] Interestingly, up to 50% of chronic HF patients present normal or only mildly impaired left ventricular EF.^[5] The prevalence of AF in HF patients increases as the disease severity evolves.^[6] Specifically, in patients with New York Heart Association (NYHA) I−II is typically about 5%, NYHA III approximately 26% and NYHA IV is presented up to 50%.^[6] According to the data from randomized clinical trials and registries, the presence of AF in HFpEF patients ranges between 15% and 41%.^[7] Patients with HFpEF are more likely to demonstrate prevalent AF or AF at any time up to twice, compared with those with HFrEF.^[7] Data from the natiowide Swedish heart failure registry reported the prevelance of AF among LVEF ranges, specifically 53% in HFrEF, 60% HFmrEF, and 65% inHFpEF.^[8] The presence of AF in HFrEF patients was 27% in an anaylsis of ESC-HF long term registry.^[9] Notably, AF occurs in 24%−44% of patients in the setting of acute HF and in one third of those with chronic HF.^{[10, 11]} Atrial fibrillation is also found in more than half (57%) of patients with new onset of HF.^[12] Furthermore, HF is present in 33%, 44% and 56% of ambulatory patients with paroxysmal, persistent and permanent AF, respectively and in more than one third (37%) of those with new onset AF.^{[12, 13]}     

Association of time-varying changes in physical activity with cardiac death and all-cause mortality after ICD or CRT-D implantation

OBJECTIVETo evaluate the association of longitudinal changes in physical activity (PA) with long-term outcomes after implantable cardioverter-defibrillator (ICD) or cardiac resynchronization therapy defibrillator (CRT-D) implantation.METHODSPatients with ICD/CRT-D implantation from SUMMIT registry were retrospectively analyzed. Accelerometer-derived PA changes over 12 months post implantation were obtained from the archived home monitoring data. The primary endpoints were cardiac death and all-cause mortality. The secondary endpoints were the first ventricular arrthymia (VA) and first appropriate ICD shock.RESULTSIn 705 patients, 446 (63.3%) patients showed improved PA over 12 months after implantation. During a mean 61.5-month follow-up duration, 99 cardiac deaths (14.0%) and 153 all-cause deaths (21.7%) occurred. Compared to reduced/unchanged PA, improved PA over 12 months could result in significantly reduced risks of cardiac death (improved PA ≤ 30 min: hazard ratio (HR) = 0.494, 95% CI: 0.288−0.848; > 30 min: HR = 0.390, 95% CI: 0.235−0.648) and all-cause mortality (improved PA ≤ 30 min: HR = 0.467, 95%CI: 0.299−0.728; > 30 min: HR = 0.451, 95% CI: 0.304−0.669). No differences in the VAs or ICD shocks were observed across different groups of PA changes. PA changes can predict the risks of cardiac death only in the low baseline PA group, but improved PA was associated with 56.7%, 57.4%, and 62.3% reduced risks of all-cause mortality in the low, moderate, and high baseline PA groups, respectively, than reduced/unchanged PA.CONCLUSIONSImproved PA could protect aganist cardiac death and all-cause mortality, probably reflecting better clinical efficacy after ICD/CRT-D implantation. Low-intensity exercise training might be encouraged among patients with different baseline PA levels.

Physical activity (PA), which reflects the individual health status, is a strong independent predictor of cardiovascular diseases, hospitalizations for heart failure, atrial arrhythmia events, cardiovascular death, and all-cause mortality.^[1-5] However, in most studies, PA was only accessed at baseline using a self-reported questionnaire over the preceding months or an accelerometer recording during the first 30−60 days after device implantation.^[6] Time-varying changes in PA could reflect the longitudinal changes in respiratory and cardiovascular functions, muscle mass and strength, health-related quality of life, and lifestyle modification.^[6-8]In patients after implantable cardioverter-defibrillator (ICD) or cardiac resynchronization therapy defibrillator (CRT-D) implantation, PA changes were indicated associated with CRT response or heart-focused anxiety after defibrillation implantation.^[9-11] Promoting PA during the early stages after implantation is encouraged to improve cardiovascular rehabilitation.^[12] Cardiac death remains as the leading cause in ICD/CRTD recipients.^[13-16] However, it is controversial about the association of increasing PA post device implantation with cardiac death and all-casue mortality.^[9] Lack of evidence supported that increasing PA after ICD/CRT-D implantation was beneficial to the long-term clinical outcomes without additional risks of ventricular arrhythmias (VAs) and ICD shocks.^[9,17]In this cohort study, patients received ICD or CRT-D implantation, which was equipped with a remote home monitoring system capable of providing continuous PA recording.^[18] We collected the changes in PA and aimed: (1) to demonstrate the PA changes over 12 months after ICD or CRT-D implantation; (2) to determine whether increasing PA could reduce the risks of cardiac death and all-cause mortality without inducing further VAs or ICD shocks; and (3) to explore the effects of increasing PA on long-term outcomes in patients with different levels of baseline PA.     

Chronic kidney disease and risks of adverse clinical events in patients with atrial fibrillation

BACKGROUNDChronic kidney disease (CKD) is highly prevalent in patients with atrial fibrillation (AF). However, the association between CKD and clinical consequences in AF patients is still under debate.METHODSWe included 19,079 nonvalvular AF patients with available estimated glomerular filtration rate (eGFR) values in the Chinese Atrial Fibrillation Registry from 2011 to 2018. Patients were classified into no CKD (eGFR ≥ 90 mL/min per 1.73 m²), mild CKD (60 ≤ eGFR < 90 mL/min per 1.73 m ²), moderate CKD (30 ≤ eGFR < 60 mL/min per 1.73 m ²), and severe CKD (eGFR < 30 mL/min per 1.73 m ²) groups. The risks of thromboembolism, major bleeding, and cardiovascular mortality were estimated with Fine-Gray regression analysis according to CKD status. Cox regression was performed to assess the risk of all-cause mortality associated with CKD. RESULTSOver a mean follow-up of 4.1 ± 1.9 years, there were 985 thromboembolic events, 414 major bleeding events, 956 cardiovascular deaths, and 1,786 all-cause deaths. After multivariate adjustment, CKD was not an independent risk factor of thromboembolic events. As compared to patients with no CKD, those with mild CKD, moderate CKD, and severe CKD had a 45%, 47%, and 133% higher risk of major bleeding, respectively. There was a graded increased risk of cardiovascular mortality associated with CKD status compared with no CKD group: adjusted hazard ratio [HR] was 1.34 (95% CI: 1.07−1.68,P = 0.011) for mild CKD group, 2.17 (95% CI: 1.67−2.81,P < 0.0001) for moderate CKD group, and 2.95 (95% CI: 1.97−4.41, P < 0.0001) for severe CKD group, respectively. Risk of all-cause mortality also increased among patients with moderate or severe CKD. CONCLUSIONSCKD status was independently associated with progressively higher risks of major bleeding and mortality, but didn’t seem to be an independent predictor of thromboembolism in AF patients.

Atrial fibrillation (AF) is the most common arrhythmia worldwide, being associated with increased risks of cardiovascular diseases and death. Chronic kidney disease (CKD) often coexists with AF,^[1,2] present in 10% to 40% of AF patients.^[3,4] Besides, CKD is an independent risk factor of incident AF^[5] and shares common risk factors with AF, such as older age, hypertension and diabetes mellitus.^[6,7] Both CKD and AF were associated with poor prognosis, bringing growing burden to healthcare systems.^[8,9]Nevertheless, whether CKD independently confers increased risks of cardiovascular outcomes and mortality in AF patients remains controversial.^[10-14] Although studies have indicated that CKD was an independent predictor of stroke,^{[10, 11, 15]} the widely-used CHA₂DS₂-VASc stroke score recommended by the current guidelines did not include CKD.^{[6, 16]} Abnormal renal function was also precluded from a biomarker-based death score,^[17] but was incorporated into the HAS-BLED score for bleeding risk prediction. Thus, a better understanding of the relationship between CKD and adverse outcomes is essential to the comprehensive management of AF patients. Using data from the large, prospective Chinese Atrial Fibrillation Registry (China-AF) cohort, we intend to determine the risks of thromboembolism, major bleeding, cardiovascular mortality and all-cause mortality associated with CKD in individuals with AF.     

Biomarkers in the clinical management of patients with atrial fibrillation and heart failure

Atrial fibrillation (AF) and heart failure (HF) are two cardiovascular diseases with an increasing prevalence worldwide. These conditions share common pathophysiologiesand frequently co-exit. In fact, the occurrence of either condition can ‘cause’ the development of the other, creating a new patient group that demands different management strategies to that if they occur in isolation. Regardless of the temproral association of the two conditions, their presence is linked with adverse cardiovascular outcomes, increased rate of hospitalizations, and increased economic burden on healthcare systems. The use of low-cost, easily accessible and applicable biomarkers may hasten the correct diagnosis and the effective treatment of AF and HF. Both AF and HF effect multiple physiological pathways and thus a great number of biomarkers can be measured that potentially give the clinician important diagnostic and prognostic information. These will then guide patient centred therapeutic management. The current biomarkers that offer potential for guiding therapy, focus on the physiological pathways of miRNA, myocardial stretch and injury, oxidative stress, inflammation, fibrosis, coagulation and renal impairment. Each of these has different utility in current clinincal practice.

Atrial fibrillation (AF) is the most common type of arrhythmia having an annual prevalence of 33 million patients worldwide, along with a three times higher prevalence in women than in men.^[1] There are a number associated risk factors including heart failure, diabetes, hypertension, hyperthyroidism, obesity, structural and ischemic heart disease. However, up to 20% of AF cases cannot be connected with those factors.^[2] The development of AF involves a complex interplay between genetic, molecular and environmental factors. Their better identificationcould alter the possible management and treatment of symptomatic and asymptomatic patients, incuding those that are yet diagnosed via the ECG.^[3-5] Atrial fibrosis is likely play a key role in the development and prognsosi of AF. The extent of the fibrotic process can predict the response to the use of ablation as a treatment.^[6-8] The fibrotic mechanism is not yet fully clarified, but according to some studies, the renin-angiotensin axis^[9] and transforming growth factor (TGF) β1, play a key role in the cardiac fibrosis.^[10]Atrial fibrillation is linked with cardiovascular diseases, mortality, central nervous system side effects.^[11] Most specifically, AF often precedes or follows the development of HF, both share pathophysiological paths that contribute to cardiac remodelling and the combined presence of the two conditions is connected with an adverse prognosis.^[12]Heart failure (HF) is a clinical syndrome presenting with typical symptoms (breathlessness on exertion, paroxysmal nocturnal dyspnea, orthopnea and fatigue) and signs (elevated jugular venous pressure, pulmonary oedema and peripheral oedema) as a result of a structural and/or functional cardiac abnormalities. These lead to a reduced cardiac output and/or elevated intracardiac pressures at rest or during stress, which result in many physiological changes, including multiple morphological, biochemical and molecular alterations referred to cardiac remodeling.^[13,14] The current definition includes stages based on the symptoms observed in the patients requiring medical assistance, however prior to any clinical symptoms patients can present with asymptomatic structural or functional cardiac abnormalities [systolic or diastolic left ventricular (LV) dysfunction]. The early recognition of these precursors can lead to better outcomes, in terms of both hospitalization and mortality in patients with HF. The prevalence of HF varies according to the definition used, but is approximately 1%–2% of the adult population in developed countries, rising to ≥ 10% among people > 70 years of age worldwide. ^[15-18] Among people > 65 years old presenting to primary care with breathlessness on exertion, one in six will have undiagnosed HF. ^[19,20] The lifetime possibility of developing HF at age 55 is 33% for men and 28% for women.^[17] The pathophysiology of HF is mediated by a variety of biological mechanisms, with complex interactions between endothelial cells, monocytes, macrophages, cardiomyocytes, fibrocytes and the neuro-endocrine system. On top is the interplay with systemic conditions such as diabetes, advanced age, hypertension, obesity, dyslipidemia and chronic kidney disease. Cardiac troponins and natriuretic peptides are the most widely used diagnostic biomarkers in the management of HF,^[21] although there are a number of novel ones are also available, but not widely used in clinical practice.     

The incidence and predictors of high-degree atrioventricular block in patients with bicuspid aortic valve receiving self-expandable transcatheter aortic valve implantation

BACKGROUNDThe high-degree atrioventricular block (HAVB) in patients with bicuspid aortic valve (BAV) treated with transcatheter aortic valve implantation (TAVI) remains high. The study aims to explore this poorly understood subject of mechanisms and predictors for HAVB in BAV self-expandable TAVI patients.METHODSWe retrospectively included 181 BAV patients for analysis. Using computed tomography data, the curvature of ascending aorta (AAo) was quantified by the angle (AAo angle) between annulus and the cross-section at 35 mm above annulus (where the stent interacts with AAo the most). The valvular anatomy and leaflet calcification were also characterized.RESULTSThe 30-day HAVB rate was 16.0% (median time to HAVB was three days). Type-1 morphology was found in 79 patients (43.6%) (left- and right-coronary cusps fusion comprised 79.7%). Besides implantation below membrane septum, large AAo angle [odds ratio (OR) = 1.08, P = 0.016] and type-1 morphology (OR = 4.97, P = 0.001) were found as the independent predictors for HAVB. Together with baseline right bundle branch block, these predictors showed strong predictability for HAVB with area under the cure of 0.84 (sensitivity = 62.1%, specificity = 92.8%). Bent AAo and calcified raphe had a synergistic effect in facilitating high implantation, though the former is associated with at-risk deployment (device implanted above annulus + prothesis pop-out, versus straight AAo: 9.9% vs. 2.2%, P = 0.031). CONCLUSIONSAAo curvature and type-1 morphology are novel predictors for HAVB in BAV patients following self-expandable TAVI. For patients with bent AAo or calcified raphe, a progressive approach to implant the device above the lower edge of membrane septum is favored, though should be done cautiously to avoid pop-out.

Bicuspid aortic valve (BAV) is the commonest adult congenital cardiac anomaly and affects approximately half of the younger population requiring surgical valve replacement.^[1–3] Transcatheter aortic valve implantation (TAVI) is an increasingly important alternative to surgical aortic valve replacement and has been shown non-inferior or superior to open heart surgery across different risk spectrums by multiple pivotal trials.^[4–8] The subsequent trend of expanding TAVI toward the younger population has led to increased use of TAVI in BAV patients.^[9] Recent findings from several clinical trials suggest that with contemporary device iteration and strategy optimization, TAVI in BAV population may secure satisfactory outcomes in terms of procedural success, paravalvular leak and 30-day mortality.^[10–14] However, the incidence of high-degree atrioventricular block (HAVB) remains relatively high (12.2%−17.9%).^{[10,12,13,15]} Post-procedural HAVB is associated with increased re-admission and impaired long-term prognosis, and its minimization in BAV patients is of profound clinical significance in this population with longer life expectancy.^[16,17] As most of the major trials have excluded BAV patients, little is known about the mechanism for HAVB in this population. For now, only the classic predictors of HAVB including implant depth and expansion rate have been validated in a few small sample trials.^[15,18] However, compared with tricuspid aortic valve (TAV), BAV presents with singularity in anatomy in terms of leaflet (presence of raphe and heavy calcification) and ascending aorta (AAo) morphology. These anatomical features may influence the interaction between stent frame and conduction tissue and therefore are potential risk factors for HAVB.^[10,12] To elucidate the post-TAVI HAVB mechanism in the BAV population and therefore further refine the procedural strategy and improve clinical outcome, we characterized the leaflet and AAo morphology in BAV patients through computed tomography (CT) and explored in depth the potential association between these risk factors and HAVB.     

Beta-blockers and 1-year clinical outcomes in hospitalized heart failure patients with atrial fibrillation

OBJECTIVETo assess the association between beta-blockers and 1-year clinical outcomes in heart failure (HF) patients with atrial fibrillation (AF), and further explore this association that differs by left ventricular ejection fraction (LVEF) level.METHODSWe enrolled hospitalized HF patients with AF from China Patient-centered Evaluative Assessment of Cardiac Events Prospective Heart Failure Study. COX proportional hazard regression models were employed to calculate hazard ratio of beta-blockers. The primary outcome was all-cause death.RESULTSAmong 1762 HF patients with AF (756 women [41.4%]), 1041 (56%) received beta-blockers at discharge and 1272 (72.2%) had an LVEF > 40%. During one year follow up, all-cause death occurred in 305 (17.3%), cardiovascular death occurred in 203 patients (11.5%), and rehospitalizations for HF occurred in 622 patients (35.2%). After adjusting for demographic characteristics, social economic status, smoking status, medical history, anthropometric characteristics, and medications used at discharge, the use of beta-blockers at discharge was not associated with all-cause death [hazard ratio (HR): 0.86; 95% Confidence Interval (CI): 0.65−1.12; P = 0.256], cardiovascular death (HR: 0.76, 95% CI: 0.52−1.11; P = 0.160), or the composite outcome of all-cause death and HF rehospitalization (HR: 0.97, 95% CI: 0.82−1.14; P = 0.687) in the entire cohort. There were no significant interactions between use of beta-blockers at discharge and LVEF with respect to all-cause death, cardiovascular death, or composite outcome. In the adjusted models, the use of beta-blockers at discharge was not associated with all-cause death, cardiovascular death, or composite outcome across the different levels of LVEF: reduced (< 40%), mid-range (40%−49%), or preserved LVEF (≥ 50%). CONCLUSIONAmong HF patients with AF, the use of beta-blockers at discharge was not associated with 1-year clinical outcomes, regardless of LVEF.

Heart failure (HF) is a leading cause of death and there are approximately 64.3 million patients with HF worldwide.^[1] Among them, atrial fibrillation (AF) is the most common arrhythmia and presents in up to half of HF patients; its prevalence is even higher in those with preserved left ventricular ejection fraction (LVEF).^[2] Given the association between AF and worse prognosis in HF patients,^[3] we need to consider the presence of AF in the treatment of such patients. Beta-blockers are important medications to improve outcomes in HF patients with reduced ejection fraction (HFrEF).^[4] However, an individual-level meta-analysis suggested beta-blockers did not improve survival of HFrEF patients with concomitant AF.^[5] Moreover, current trials have not found sufficient evidence of survival benefits of beta-blockers in HF patients with preserved ejection fraction (HFpEF).^[6,7] But the use of beta-blockers was common in HFpEF patients,^[8,9] partly because the treatment for complications, such as AF.^[4,10] Whether beta-blockers would appear to be ineffective in long-term prognosis in HFrEF patients with AF, and whether this also holds true in those with preserved LVEF are uncertain. The individual-level meta-analysis of 11 randomized controlled trials mainly consisted of HFrEF patients with AF, and only included 73 HFpEF patients with AF, which could make it difficult to draw a reliable conclusion.^[6] Despite lack of evidence, the current guidelines recommend beta-blockers as first-line heart rate control treatment in HFrEF/HFpEF patients with AF. ^[4,10]To fill these knowledge gaps, we explored the association between use of beta-blockers at discharge and 1-year clinical outcomes in a large prospective cohort study of hospitalized HF patients with AF, and further explored this association that differs by LVEF level.     

Usefulness of the Japanese version of Rapid Dementia Screening Test for mild cognitive impairment in older patients with cardiovascular disease: a cross-sectional study

BACKGROUND Cognitive decline is common among older patients with cardiovascular disease(CVD) and can decrease their self-management abilities. However, the instruments for identifying mild cognitive impairment(MCI) are not always feasible in clinical practice. Therefore, this study evaluated whether MCI could be detected using the Japanese version of the Rapid Dementia Screening Test(RDST-J), which is a simple screening tool for identifying cognitive decline.METHODS This retrospective single-center study included patients who were ≥ 65 years old and hospitalized because of CVD.Patients with a pre-hospitalization diagnosis of dementia were excluded. Each patient's cognitive function had been measured at discharge using the RDST-J and the Japanese version of the Montreal Cognitive Assessment(Mo CA-J), which is a standard tool for MCI screening. The correlation between the two scores was evaluated using Spearman's rank correlation coefficient. Receiver operating characteristic(ROC) analysis was also to evaluate whether the RDST-J could identify MCI, which was defined as a Mo CA-J score of ≤ 25 points.RESULTS The study included 78 patients(mean age: 77.2 ± 8.9 years). The RDST-J and Mo CA-J scores were strongly correlated(r = 0.835, P < 0.001). The ROC analysis revealed that an RDST-J score of ≤ 9 points provided 75.4% sensitivity and 95.2% specificity for identifying MCI, with an area under the curve of 0.899(95% CI: 0.835-0.964). The same cut-off value was identified when excluding patients with a high probability of dementia(RDST-J score of ≤ 4 points).CONCLUSIONS The RDST-J may be a simple and effective tool for identifying MCI in older patients with CVD.     

Epidemiology,etiology, and outcomes of in-hospital cardiac arrest in Lebanon

BACKGROUNDIn-hospital cardiac arrest (IHCA) constitutes a significant cause of morbidity and mortality. As data is scarce in the Middle East and Lebanon, we devised this study to shed some light on it to better inform both hospitals and policymakers about the magnitude and quality of IHCA care in Lebanon.METHODSWe analyzed retrospective data from 680 IHCA events at the American University of Beirut Medical Center between July 1, 2016 and May 2, 2019. Sociodemographic variables included age and sex, in addition to the comorbidities listed in the Charlson comorbidity index. IHCA event variables were day, event location, time from activation to arrival, initial cardiac rhythm, and the total number of IHCA events. We also looked at the months and years. We considered the return of spontaneous circulation (ROSC) and survival to discharge (StD) to be our outcomes of interest.RESULTSThe incidence of IHCA was 6.58 per 1,000 hospital admissions (95% CI: 6.09−7.08). Non-shockable rhythms were 90.7% of IHCAs. Most IHCA cases occurred in the closed units (87.9%) (intensive care unit, respiratory care unit, neurology care unit, and cardiology care unit) and on weekdays (76.5%). ROSC followed more than half the IHCA events (56%). However, only 5.4% of IHCA events achieved StD. Both ROSC and StD were higher in cases with a shockable rhythm. Survival outcomes were not significantly different between day, evening, and nightshifts. ROSC was not significantly different between weekdays and weekends; however, StD was higher in events that happened during weekdays than weekends (6.7%vs. 1.9%, P = 0.002). CONCLUSIONSThe incidence of IHCA was high, and its outcomes were lower compared to other developed countries. Survival outcomes were better for patients who had a shockable rhythm and were similar between the time of day and days of the week. These findings may help inform hospitals and policymakers about the magnitude and quality of IHCA care in Lebanon.

In-hospital cardiac arrest (IHCA) constitutes a significant cause of morbidity and mortality.^[1] Based on the American Heart Association’s Get With The Guidelines-Resuscitation (GWTG-R) registry data from 2003 to 2007, the approximated incidence of IHCAs in the United States was 211,000 annually or roughly 6 to 7 cardiac arrests per 1,000 hospital admissions.^[2,3] Data from 2008 to 2017 showed the incidence of IHCA increased to 292,000 annually or 9 to 10 IHCAs per 1,000 hospital admissions.^[1,4] In contrast, data from the United Kingdom National Cardiac Arrest Audit showed an incidence of 1.6 IHCAs per 1,000 hospital admissions in the United Kingdom from 2011 to 2013.^[1] Despite progress in resuscitation technology and care, survival outcomes following IHCA remain low at 15%−25% and vary radically between 0% and 42% worldwide.^[5,6] Sandroni, et al.^[5] showed that various patient and healthcare-related factors are associated with the survival outcomes of IHCA. The main patient-related factors are age, sex, initial cardiac rhythm, underlying medical condition, comorbidities, and the time of the IHCA event. In contrast, major healthcare-related factors are the protocols for IHCA care, duration and method of resuscitation, skills of healthcare professionals, time from code activation and the arrival of the code response team, and the location of the IHCA event.^[5,7] The study by Chen, et al.^[8] suggests that improving the quality of resuscitation care and minimizing other healthcare-related risk factors can markedly increase survival outcomes from IHCAs.^[6,9]Consistent and updated estimates of the magnitude and outcomes of IHCA are fundamental for monitoring and improving the delivery and quality of IHCA care in any healthcare setting. In Lebanon, studies have shown low survival rates (5.5%) from out-of-hospital cardiac arrest.^[10]The reported incidence of IHCA in the United Arab Emirates was 11.7 per 1,000 hospital admissions,^[6] and in Saudi Arabia was 7.76 per 1,000 hospital admissions.^[11] The reported survival to hospital discharge in the United States was only 10.4%,^[12] and it was only 7.9% in the United Kingdom.^[13] However, unlike European countries and the United States, the epidemiology of IHCA is unknown in Lebanon, suggesting the need for research in this area. Therefore, this study aimed to produce the first estimates of the incidence, characteristics, and outcomes of IHCA at a tertiary-care hospital in Lebanon.     

Association of changes in waist circumference with cardiovascular disease and all-cause mortality among the elderly Chinese population: a retrospective cohort study

BACKGROUNDTo examine the association of baseline waist circumference (WC) and changes in WC with cardiovascular disease (CVD) and all-cause mortality among elderly people.METHODSA total of 30,041 eligible participants were included from a retrospective cohort in China. The same questionnaire, anthropometric and laboratory measurements were performed at baseline (2010) and the first follow-up (2013). The percent change in WC between baseline and the first follow-up was calculated to evaluate three years change of WC. We collected the occurrence of CVD and all-cause death from the first follow-up to December 31, 2018. Restricted cubic splines and Cox proportional-hazards regression models were used to evaluate the relationship between baseline WC/ changes in WC and mortality.RESULTSThe dose-response relationships between baseline WC and CVD mortality were U- or J-shaped. In low WC group, compared with stable group, the fully adjusted hazard ratio (aHR) for CVD mortality was 1.60 (95% CI: 1.24−2.06) in WC gain group among men. In normal WC group, the CVD mortality risk increased with WC gain (men: aHR = 1.86, 95% CI: 1.36−2.56; women: aHR = 1.83, 95% CI: 1.29−2.58). In moderate-high WC group, the CVD mortality risk increased with WC gain (men: aHR = 1.76, 95% CI: 1.08−2.88; women: aHR = 1.46, 95% CI: 1.04−2.05) and risk decreased with WC loss (men: aHR = 0.54, 95% CI: 0.30−0.98; women: aHR = 0.59, 95% CI: 0.37−0.96).CONCLUSIONSFor the elderly population, WC gain may increase CVD mortality risk regardless of baseline WC, whereas WC reduction could decrease the risk only in the moderate-high WC group.

Obesity is a major risk factor for many chronic diseases, such as high blood pressure, diabetes and dyslipidemia. Further, more serious obesity could cause cardiovascular disease (CVD) and death.^[1-3] However, recent evidence shows that there is a more obvious obesity paradox in elderly people; namely, overweight and obesity are more beneficial to CVD disease.^[4] The relationship between obesity and CVD in elderly people is controversial. Most of the studies indicating the existence of an obesity paradox only have used body mass index (BMI) as an indicator of obesity.^[5] Obesity is commonly measured by BMI and waist circumference (WC).^{[6, 7]} WC increases at a faster rate than BMI; as a result, the obesity-related health burden may be underestimated by using BMI alone and may contribute to the obesity paradox.^{[8, 9]} Abdominal obesity defined by WC may be a better indicator than overall obesity defined by BMI with respect to predicting CVD and all-cause mortality.^{[10, 11]}However, most studies are often based on WC at a certain point, ignoring the changes in WC during follow-up.^[12] Previous studies on the effect of WC change in European and American populations were limited and conflicting.^[13-17] Some studies of Chinese populations only explored the association of changes in WC and chronic disease, without considering the time of outcome variable.^[18-20] Most studies based on cross-sectional study design cannot determine whether WC changes had taken place before CVD and all-cause mortality, and the purpose of cause and effect inference could not be achieved. To our knowledge, only a few cohort studies assessed the relationship between changes in BMI and the risk of CVD death in Chinese populations.^[21] However, the risk of CVD mortality with changes in WC has not been studied in the Chinese population. Thus, the purpose of this study was to explore the risk of CVD mortality and all-cause mortality with baseline WC and WC change and to identify dose-response relationships among baseline WC and WC change and CVD mortality and all-cause mortality in an elderly Chinese population.     

Prognostic relevance of normocytic anemia in elderly patients affected by cardiovascular disease

BACKGROUNDAnemia associated with cardiovascular diseases (CVD) is a common condition in older persons. Prevalence and prognostic role of anemia were extensively studied in patients with myocardial infarction (MI) or congestive heart failure (CHF) whereas limited data were available on patients with atrial fibrillation (AF). This study was conducted to assess the clinical prevalence and prognostic relevance of anemia in elderly patients affected by AF and other CVDs.METHODSA total of 866 elderly patients (430 men and 436 women, age: 65−98 years, mean age: 85 ± 10 years) were enrolled. Among these patients, 267 patients had acute non-ST-segment elevation MI (NSTEMI), 176 patients had acute CHF, 194 patients had acute AF and 229 patients were aged-matched healthy persons (CTR). All parameters were measured at the hospital admission and cardiovascular mortality was assessed during twenty-four months of follow-up.RESULTSThe prevalence of anemia was higher in NSTEMI, CHF and AF patients compared to CTR subjects (50% vs. 15%, P < 0.05), with normocytic anemia being the most prevalent type (90%). Adjusted mortality risk was higher in anemic patient versus non-anemic patient in all the groups of patients [NSTEMI: hazard ratio (HR) = 1.81, 95% CI: 1.06−2.13; CHF: HR = 2.49, 95% CI: 1.31−4.75; AF: HR = 1.98, 95% CI: 1.01−3.88]. Decreased hemoglobin levels ( P = 0.001) and high reticulocyte index (P = 0.023) were associated with higher mortality in CVD patients. CONCLUSIONSThe significant associations between CVD and anemia and the prognostic relevance of anemia for elderly patients with CVD were confirmed in this study. The presence of anemia in AF patients is associated with a two-fold increased mortality risk compared with non-anemic AF patients. Low hemoglobin and high reticulocyte count independently predict mortality in elderly patients with CVD.

The prevalence of anemia significantly rises with advancing age in both men and women. Patients over 75 years have a 10% incidence of anemia, while those over 90 years have an incidence higher than 25%.^[1–3] Numerous causes may explain an anemic state in older persons, including macro-/micro-hemorrhages, iron deficiency, and chronic inflammation. Interestingly, the puzzling entity of unexplained anemia in the elderly represents 30% to 46% of elderly patients.^[4]An anemic state in older individuals is associated with a number of negative outcomes, including heart disease, hospitalization, and death.^[5,6] It has been recently shown that a pre-existing state of anemia is correlated with the development and progression of acute coronary syndrome.^[7] For example, anemic patients who develop acute myocardial infarction (AMI) have an increased risk of death and in-hospital cardiovascular complications.^[8,9] In addition, the unfavorable impact of anemia has been reported also in patients with AMI undergoing percutaneous coronary intervention.^[10] It is also widely recognized that a high prevalence of anemia is common in heart failure (HF) patients and is associated with significantly higher mortality rates.^[11,12]Atrial fibrillation (AF) is the most common cardiac arrhythmia in older persons and it is associated with increased morbidity and mortality.^[3] AF is also a potent risk factor for ischemic stroke and reduces physical and cardiac performance as well as patient quality of life.^[13,14] However, only few reports have investigated the prevalence of anemia in patients with AF and its relevance on the clinical outcomes. It has been recently reported that anemia was associated with increased mortality and hospitalization in elderly patients with AF.^[15] However, in this previous study, anemia was defined based on hematocrit (Hct) levels and not hemoglobin (Hb) levels (< 13 g/dL in men and < 12 g/dL in women) as currently recommended by World Health Organization (WHO).^[16] The Hct value depends on plasma volume and consequently can be modulated from many different variables, including hemodynamic compensation, pharmacological treatment, hydro-electrolytic balance, hydration state, which are highly variable in patients with chronic heart disease. Thus, we aimed at investigating the association between anemia (defined by Hb level) and commonly observed heart diseases [congestive HF (CHF), AMI and AF] in a large sample of older patients. We also aimed at testing the prognostic value of anemia on mortality over time. According to current AF management guidelines, oral anticoagulant therapy (OAT) is the cornerstone for the prevention of severe outcomes. However, OAT increases the risk of severe bleeding affecting the mortality rate, especially in elderly patients.^[17] Thus, to reduce the possible bias related to different AF pharmacological treatments, we included in the survival analysis only patients with OAT therapy.     

Association between serum cystatin C level and hemodynamically significant aortic stenosis: a prospective cohort study

BACKGROUNDCystatin C (CysC) is a cysteine protease inhibitor involved in proteins catabolism and plays an essential role in human vascular pathophysiology. CysC may also increase the risk of aortic stenosis (AS), but limited studies have reported on this association. This study aimed to investigate if elevated serum CysC levels are associated with hemodynamically significant AS.METHODSSerum CysC levels were estimated in 4,791 participants, samples were collected in 1990−1992. The study population was divided into quintile groups. Follow-up continued in 2011–2013 when participants returned for echocardiography examination. Incidence of aortic valve disease (AVD) was ascertained by Doppler echocardiography through the end of 2013. AVD defined in hemodynamic progression was assessed and classified as aortic sclerosis, mild stenosis, and moderate-to-severe stenosis.RESULTSOverall, a total of 4,791 participants (mean age: 54.8 ± 5.0 years, females: 57.6%, blacks: 8.2%) were included in this study. During a follow-up of 21 years, we identified 736 cases (15.4%) of aortic sclerosis, 194 cases (4.0%) of mild stenosis, and 42 cases (0.7%) of moderate-to-severe stenosis. Compared with serum CysC levels within individual quintile groups, the odds ratio (OR) was per standard deviation associated with an increased incidence of AVD (OR = 1.15, 95% CI: 1.05−1.26,P = 0.002). CONCLUSIONSIn this large population-based study, an increased serum CysC levels is independently associated with the incidence of hemodynamically significant AS. However, this association appears not to extend to patients with extremely high serum CysC levels and necessitate further investigation.

Aortic stenosis (AS) is the most common aetiology of aortic valve disease (AVD), affecting 3% of people > 65 years of age and has a high prevalence among developed countries. ^[1–3] AS has been strongly related to adverse outcomes and an increased risk of cardiovascular morbidity.^[1] Despite the limitation in prognosis, aortic valve replacement treatment remains its first-line treatment option for elderly and high-risk patients.^[4,5] Various coronary heart disease (CHD) and chronic kidney disease (CKD) risk factors are reported to show a strong correlation with AS incidence.^[2,6,7] Cystatin C (CysC) is a cysteine protease inhibitor involved in catabolism and plays an essential role in human vascular pathophysiology.^[8] In addition, it is produced by all nucleated cells and eliminated from the bloodstream by glomerular filtration.^[8] Circulating CysC levels have been proven an alternative surrogate parameter of renal dysfunction.^[9,10] It is suggested as a more sensitive renal impairment marker, particularly in subjects with creatinine levels within normal limits. Similarly, CysC is a pro-inflammatory biomarker essential for the prognosis of coronary artery calcification and adverse CHD outcome in elderly patients.^[8,11,12]However, research is still needed for clarifying the association between AVD, AS and elevated serum CysC levels among individuals at high-risk in the general population. Therefore, the purpose of this study was to test the hypothesis that an increase in serum CysC levels would increase the risk of AS independent of other traditional risk factors in the Atherosclerosis Risk in Communities (ARIC) cohort, a community-based study of cardiovascular disease in the United States.     

Difficulty of falling asleep and non-high-density lipoprotein cholesterol level among Canadian older adults: a cross-sectional analysis of the Canadian Longitudinal Study for Aging baseline data

OBJECTIVETo examine whether difficulty of falling asleep (DoFA) is associated with non-high-density lipoprotein cholesterol (non-HDL-C) level among Canadian older adults.METHODS26,954 individuals aged 45–85 years from the baseline data of the Canadian Longitudinal Study for Aging were included in this study. DoFA was categorized into five groups by answer to the question “Over the last month, how often did it take you more than 30 min to fall asleep?” Response options are “Never, < 1 time/week, 1−2 times/week, 3−5 times/week, or 6−7 times/week”. Non-HDL-C, the difference of total cholesterol and HDL-C, were categorized into five categories based on these cut-offs (< 2.6 mmol/L, 2.6−3.7 mmol/L, 3.7−4.8 mmol/L, 4.8−5.7 mmol/L, and ≥ 5.7 mmol/L). Ordinal logistic regression (logit link) continuation ratio models were used to estimate the odds of higher non-HDL-C levels for DoFA status. Adjusted means of non-HDL-C by DoFA status were estimated by general linear models. All analyses were sex separately using analytic weights to ensure generalizability.RESULTSThe proportions of DoFA in five categories were 41.6%, 25.7%, 13.6%, 9.4%, 9.7% for females and 52.9%, 24.9%, 10.5%, 6.1%, 5.6% for males, respectively. After adjustment of demographical and other covariates (such as depression, comorbidity, sleeping hour, etc.) compared to those who reported never having DoFA, the ORs (95% CIs) of higher levels of non-HDL-C for those whose DoFA status in < 1 time/week, 1−2 times/week, 3−5 times/week, and 6−7 times/week were 1.12 (1.05−1.21), 1.09 (0.99−1.18), 1.20 (1.09−1.33), 1.29 (1.17−1.43) in females and 1.05 (0.98−1.13), 0.95 (0.87−1.05), 1.21 (1.08−1.37), 0.97 (0.85−1.09) in males, respectively. The adjusted means of non-HDL-C among the five DoFA status were 3.68 mmol/L, 3.73 mmol/L, 3.74 mmol/L, 3.82 mmol/L, 3.84 mmol/L for females and 3.54 mmol/L, 3.58 mmol/L, 3.51 mmol/L, 3.69 mmol/L, 3.54 mmol/L for males, respectively.CONCLUSIONSThe results of this study have identified a risk association pattern between DoFA status and non-HDL-C levels in females but not in males. Further research is needed to confirm these findings.

The increased level of non-high-density lipoprotein cholesterol (non-HDL-C) is a reliable risk predictor for future coronary heart disease (CHD).^[1–3] Evidence from studies of the relationship between non-HDL-C reduction and CHD risk has suggested that non-HDL-C is an important target of therapy for CHD prevention.^[4] Non-HDL-C, the difference between total cholesterol (TC) and HDL-C, includes low-density lipoprotein cholesterol (LDL-C), intermediate-density lipoprotein cholesterol, and very-low-density lipoprotein cholesterol; they are all proatherogenic lipoproteins containing apolipoproteins B (Apo B).^[5] Currently, LDL-C is the primary target of treatment of CHD since it contains the majority of Apo B and lowering its level reduces CHD risk.^[6] However, LDL-C level in clinic is most likely estimated indirectly and its levels depend on fasting status and the levels of triglycerides.^[7] The level of non-HDL-C is not related to triglycerides measurement and not affected by fasting status, thus, it is considered superior to LDL-C as a treatment target for CHD risk management. Sleep disorders are conditions that changes the way people sleep and affects the overall health and quality of life. In a study conducted among 2,000 Canadians aged 18 years or older, 40.2% of individuals reported having either trouble falling or staying asleep, or early morning awakening for at least three nights per week in a previous month.^[8] Serious sleep disorders not only affects persons’ life quality,^[9,10] and increases risk for motor vehicle accidents,^[11] but also found to be associated with an increased risk for cardiovascular diseases (CVD).^[12–14] Sleep disturbance was observed to be highly associated with the increased risk of CVD, it was considered as a potential risk predictor of CVD.^[13] However, whether sleep disorders are associated with dyslipidemia is uncertain since studies showed contradictory results.^[15] Short sleep duration was found to be associated with an increased risk of CVD,^[16,17] but there is no conclusion whether sleep duration is linked to dyslipidemia.^[18] Furthermore, there is no study examined the relationship between sleep disorders and non-HDL-C levels. Therefore, the aim of this study is to examine how sleep disturbance is associated with lipid profile, particularly the levels of non-HDL-C among older adults. To explore this association, we used the baseline data collected by the Canadian Longitudinal Study on Aging (CLSA), a large population-based cohort study.     

Cardiac hybrid imaging: novel tracers for novel targets

Non-invasive cardiac imaging has explored enormous advances in the last few decades. In particular, hybrid imaging represents the fusion of information from multiple imaging modalities, allowing to provide a more comprehensive dataset compared to traditional imaging techniques in patients with cardiovascular diseases. The complementary anatomical, functional and molecular information provided by hybrid systems are able to simplify the evaluation procedure of various pathologies in a routine clinical setting. The diagnostic capability of hybrid imaging modalities can be further enhanced by introducing novel and specific imaging biomarkers. The aim of this review is to cover the most recent advancements in radiotracers development for SPECT/CT, PET/CT, and PET/MRI for cardiovascular diseases.

During the last decades, the emergence of new technologies able to integrate dual imaging modalities into hybrid systems and to combine the acquisition of different data sets (e.g., positron emission tomography (PET)/computed tomography (CT)) has dramatically improved the management of oncologic patients compared to stand-alone CT and PET images.^[1] Moreover, hybrid imaging techniques in cardiovascular field combining either single-photon emission computed tomography (SPECT) or PET with CT may simultaneously capture morphological abnormalities and related pathophysiological processes.^[2] Therefore, hybrid systems are able to provide a more comprehensive dataset compared to traditional imaging techniques in patients with cardiovascular diseases.^[3,4] Since 2010, when the first hybrid PET/magnetic resonance imaging (MRI) platform equipped with sequential and integrated scanners has been introduced, hybrid imaging protocols have been increasingly included in clinical practice.^[5,6] Complementary information obtained from hybrid systems simplifies the evaluation procedure of various pathologies in a routine clinical setting. The diagnostic capability of hybrid imaging modalities can be further enhanced by introducing novel and specific imaging biomarkers.^[7]Conventional nuclear cardiology evaluates myocardial perfusion, viability, function, and scar in order to assess the severity of the disease after an initial injury.^[4] The development of new molecular-targeted imaging probes offers the potential to deepen our understanding of the physiology and the underlying molecular physiology of various cardiovascular diseases, enabling imaging at an earlier stage of the disease. This allows a timely intervention, an improved patient risk stratification, therapeutic guidance, optimized diagnostic accuracy, and ultimately improves prognosis.^[8,9] This paper will review the most recent advancements in radiotracer development for SPECT/CT, PET/CT, and PET/MRI to evaluate the main pathophysiological processes of cardiomyopathies.     

Cognitive impairment and its association with circulating biomarkers in patients with acute decompensated heart failure

BACKGROUNDCognitive impairment (CI) is common in patients with heart failure (HF), but the association between CI and biomarkers related to HF or cognitive decline in patients with HF remains unclear.METHODSThis prospective observational study investigated the incidence of CI, subsequent cognitive changes, and the association between CI and novel biomarkers in patients with left ventricular ejection fraction < 40% who were hospitalized for acute decompensated HF. Patients were evaluated for CI, depressive symptoms, and quality of life with the Mini-Mental State Examination (MMSE) and the Mini-Cog, Beck Depression Inventory (BDI)-II, and Kansas City Cardiomyopathy Questionnaire (KCCQ), respectively. The primary endpoint was a composite of all-cause mortality or hospitalization for HF at one year.RESULTSAmong the 145 patients enrolled in this study, 54 had CI (37.2%) at baseline. The mean MMSE increased significantly at the 3-month and 1-year follow-up, accompanied by decreased BDI-II and increased KCCQ scores. The improvement in the MMSE scores mainly occurred in patients with CI. Among the biomarkers assayed, only growth/differentiation factor (GDF)-15 > 1621.1 pg/mL was significantly associated with CI (area under the curve = 0.64; P = 0.003). An increase in GDF-15 per 1000 units was associated with an increased risk of the primary endpoint (hazard ratio = 1.42; 95% confidence interval: 1.17–1.73; P < 0.001). CONCLUSIONSIn patients with HF with CI, cognitive function, depression, and quality of life measures improved at the 3-month and 1-year follow-up. GDF-15 predicted CI with moderate discrimination capacity and was associated with worse HF outcomes.

With increased longevity and improved survival from coronary artery disease, the prevalence and health care burden of heart failure (HF) have been growing considerably over time. Cognitive impairment (CI) is a common geriatric condition in patients with HF, with an incidence of 25%–85%.^[1,2] In a cross-sectional survey of subjects aged 65 years or older, HF conferred an approximately 2-fold increased risk of CI.^[3] CI in patients with HF may impair their somatic awareness, self-management, and adherence to guideline-recommended therapies, leading to increased risks of mortality and hospitalization.^[4] Compared with ambulatory patients with HF, patients who are hospitalized for acute decompensated HF (ADHF) may be more frequently underrecognized for the coexisting CI^[5] due to the worsening symptoms and concomitant acute illnesses that may demand more medical attention than CI. Given its adverse impact on medication compliance and long-term outcomes, CI should be incorporated into the multidisciplinary care of these patients. The pathophysiologic link between HF and CI remains unclear. The concept of heart–brain connection proposes that cardiovascular risk factors, such as diabetes, hypertension, dyslipidemia, atrial fibrillation, and smoking, can lead to the development of cerebrovascular disease and its sequelae, including CI and dementia.^[6,7] Patients with HF often have at least one of these risk factors and thus tend to develop concomitant CI. HF per se may also lead to cognitive decline through systemic and cerebral hypoperfusion.^[8] In addition, raised inflammatory mediators in HF, such as interleukin-1, interleukin-6, and tumor necrosis factor-α, impair cognitive processes by modulating neurogenesis, synaptic plasticity, and neurotransmitter cascades involved in learning and memory.^[9] The associations between clinical parameters and cognitive function in patients with HF have been extensively analyzed. Reduced left ventricular ejection fraction (LVEF) or cardiac output,^[10] advanced New York Heart Association (NYHA) functional class,^[11] and elevated B-type natriuretic peptide (BNP) levels^[12] reflect an increased severity of CI. However, novel HF biomarkers, such as growth/differentiation factor-15 (GDF-15), galectin-3, and clusterin, or biomarkers that are mechanistically linked to CI or dementia, such as tau^[13] and amyloid-beta 1–40 (Aβ40) and 1–42 (Aβ42),^[14] have rarely been evaluated for their association with CI in the HF population. This prospective observational study investigated the incidence of CI in patients who were admitted for ADHF and observed their cognitive changes over the treatment course of HF. Given the interconnected pathophysiology between HF and CI, we hypothesized that incorporating biomarkers related to HF or cognitive dysfunction may improve the risk stratification of CI and clinical outcomes beyond the traditional risk predicting models for patients with HF.     

Acute heart failure in elderly patients: a review of invasive and non-invasive management

Acute heart failure (AHF) is a major cause of unplanned hospitalisations in the elderly and is associated with high mortality. Its prevalence has grown in the last years due to population aging and longer life expectancy of chronic heart failure patients. Although international societies have provided guidelines for the management of AHF in the general population, scientific evidence for geriatric patients is often lacking, as these are underrepresented in clinical trials. Elderly have a different risk profile with more comorbidities, disability, and frailty, leading to increased morbidity, longer recovery time, higher readmission rates, and higher mortality. Furthermore, therapeutic options are often limited, due to unfeasibility of invasive strategies, mechanical circulatory support and cardiac transplantation. Thus, the in-hospital management of AHF should be tailored to each patient’s clinical situation, cardiopulmonary condition and geriatric assessment. Palliative care should be considered in some cases, in order to avoid unnecessary diagnostics and/or treatments. After discharge, a strict follow-up through outpatient clinic or telemedicine is can improve quality of life and reduce rehospitalisation rates. The aim of this review is to offer an insight on current literature and provide a clinically oriented, patient-tailored approach regarding assessment, treatment and follow-up of elderly patients admitted for AHF.

Heart failure (HF) is a growing health issue affecting around 2% of the adult population in developed countries.^[1] HF predominantly concerns elderly patients, since its incidence doubles in men and triples in women with each decade after the age of 65 years.^[2] HF is a common cause of hospitalisation, accounting for an estimated annual expense of at least 108 billion dollars in direct and indirect costs for health economies worldwide.^[3] This disease may develop insidiously or presenting in an emergent fashion with rapidly progressive signs and symptoms, in the constellation of acute HF (AHF). Depending on the clinical profile, patients hospitalised with AHF may require loop diuretics to treat congestion, vasodilators, inotropic or vasopressor therapy, and non-invasive ventilation. Advanced interventions such as mechanical ventilation or mechanical circulatory support necessitate admission to an intensive care unit.^[4,5] Since elderly patients with HF commonly differ from younger patients in terms of comorbidities, disability and drug therapy, they are often excluded from invasive and complex interventions, requiring tailored therapeutic pathways based on their clinical status and life expectancy. Furthermore, hospitalisation for AHF in the aged population is associated with higher rates of mortality, rehospitalisation, and decline in physical activity.^[6–8] Earlier data suggested a 1-year all-cause mortality of 56% in patients aged > 75 years. ^[9] Finally, these patients have a greater symptom burden and a worse quality of life (QoL) than age-matched individuals with stable HF.^[10]Several attempts to improve the outcomes of geriatric patients have been done in the last years, although they are often excluded from HF clinical trials and underrepresented in clinical registries.^[7,11] Thus, the information about the clinical profile and prognosis of patients hospitalised for AHF at extreme ranges of age is scarce. The purpose of this review is to offer an insight on current literature and provide a clinically oriented, patient-tailored approach regarding assessment, treatment and follow-up of elderly patients admitted for AHF.     

Association between non-culprit healed plaque and plaque progression in acute coronary syndrome patients: an optical coherence tomography study

BACKGROUNDHealed plaques are frequently found in patients with acute coronary syndrome, but the prognostic value is debatable. This study investigated the clinical features of non-culprit healed plaques detected by optical coherence tomography (OCT) with the aim of predicting plaque progression of healed plaques.METHODSThis study retrospectively analyzed 113 non-culprit lesions from 85 patients who underwent baseline OCT imaging and follow-up angiography from January 2015 to December 2019. Plaque progression predictors were assessed by multivariate analysis.RESULTSAmong 113 non-culprit lesions, 27 healed plaques (23.9%) were identified. Patients with non-culprit healed plaques had prior antiplatelet therapy (65.0% vs. 33.8%, P = 0.019), hypertension (85.0% vs. 50.7%, P = 0.009), and dyslipidemia (70.0% vs. 41.5%, P = 0.04) which were more frequently than those without healed plaques. The thickness (r = 0.674, P < 0.001), arc ( r = 0.736, P < 0.001), and volume ( r = 0.541, P = 0.004) of healed plaque were correlated with minimum lumen diameter changes. At a mean follow-up of 11.5 months, the non-culprit healed plaques had a lower minimum lumen diameter (1.61 ± 0.46 mm vs. 1.91 ± 0.73 mm, P = 0.016), lower average lumen diameter (1.86 mm vs. 2.10 mm, P = 0.033), and a higher degree of diameter stenosis (41.4% ± 11.9% vs. 35.5% ± 13.1%, P = 0.031) when compared to baseline measurements. The plaque progression rate was higher in the healed plaque group (33.3% vs. 8.1%, P = 0.002), and multivariate analysis identified healed plaques [odds ratio (OR) = 8.49, 95% CI: 1.71−42.13] and lumen thrombus (OR = 10.69, 95% CI: 2.21−51.71) as predictors of subsequent lesion progression. CONCLUSIONSHealed plaques were a predictor for rapid plaque progression. The quantitative parameters of healed plaque showed a good agreement with plaque progression. Patients with healed plaque were associated with prior antiplatelet therapy and high level of low-density lipoprotein cholesterol. Bifurcation lesions might be the predilection sites of healed plaques.

Coronary artery diseases originate from pathological changes in the vessel endothelium, present as plaque development and lumen stenosis, that finally lead to clinical coronary symptoms.^[1] Finding the ideal time to intervene in the atherosclerosis process is difficult, especially with non-culprit lesions.^[2–4] Revascularization benefits are challenged by the quick progression of previously untreated mild to moderate lesions.^[2] Several clinical trials suggested that the rapid step-wise pattern of plaque growth may play an important role in lumen narrowing.^[5,6] This mechanism was described as a healing process that was initiated by a plaque rupture or erosion to protect the integrity of the vessel structure.^[7,8] Re-endothelialization results in a new layer of organized thrombus and collagen distinguished from the underlying ruptured or eroded site,^[9] and plaques with two or more layers of different densities are called healed plaques or layered plaques.^[8,10] Autopsy studies found that healed plaques were frequent in patients dying of sudden death or asymptomatic myocardial infarction.^[11] Optical coherence tomography (OCT) is a high-resolution intravascular imaging tool that is highly sensitive and specific for in vivo identification of layered plaque patterns by histopathology.^[12,13] A previous OCT study suggested that layered plaques at the culprit site were associated with more vulnerable features and a high degree of lumen stenosis in patients with acute coronary syndrome (ACS).^[14] However, serial observations of plaque progression at the exact site were only reported in rare cases.^[15] In this study, we investigated the OCT features, quantitative parameters, and predictive value of non-culprit healed plaques, which may help minimize plaque progression and stenosis risk.     

Associations of body mass index and hospital-acquired disability with post-discharge mortality in older patients with acute heart failure

OBJECTIVESTo investigate the effect of hospital-acquired disability (HAD) on all-cause mortality after discharge according to the body mass index (BMI) in older patients with acute decompensated heart failure.METHODSWe included 408 patients aged ≥ 65 years who were hospitalized for acute decompensated heart failure and had undergone an acute phase of cardiac rehabilitation at the Sakakibara Heart Institute between April 2013 and September 2015 (median age: 82 years, interquartile range (IQR): 76–86; 52% male). Patients were divided into three groups based on BMI at hospital admission: underweight (< 18.5 kg/m²), normal weight (18.5 to 25 kg/m²), and overweight (≥ 25 kg/m²). HAD was defined as a decrease of at least five points at discharge compared to before hospitalization according to the Barthel Index. RESULTSThe median follow-up period was 475 (IQR: 292–730) days, and all-cause mortality during the follow-up period was 84 deaths (21%). According to multivariate Cox regression analysis, being underweight (HR: 1.941, 95% CI: 1.134−3.321,P = 0.016) or overweight (HR: 0.371, 95% CI: 0.171−0.803,P = 0.012), with normal BMI as the reference, and HAD (HR: 1.857, 95% CI: 1.062−3.250,P = 0.030) were independently associated with all-cause mortality. Patients with HAD exhibited a significantly lower cumulative survival rate in the underweight group (P = 0.001) and tended to have a lower cumulative survival rate in the normal weight group (P = 0.072). HAD was not significantly associated with cumulative survival in the overweight group (P = 0.392). CONCLUSIONSBMI and HAD independently predicted all-cause mortality after discharge in older patients with acute decompensated heart failure. Furthermore, HAD was significantly associated with higher all-cause mortality after discharge, especially in the underweight group.

In recent years, the prevalence of patients with heart failure has increased rapidly.^[1] As the population ages in Japan, there is a growing concern that the prevalence of heart failure will continue to increase.^[2] Therefore, there is an urgent need to treat and manage older patients with heart failure by determining the risk factors associated with poor prognoses. Being overweight and obese are associated with all-cause and cardiovascular mortality.^{[3, 4]} Moreover, individuals who are overweight or obese reportedly have a higher risk of developing heart failure than those with normal body weight.^[5] Conversely, the “obesity paradox” shows that being underweight, rather than being overweight or obese, is associated with a poorer prognosis in patients with heart failure.^{[6, 7]}A decline in physical function during hospitalization is called hospital-acquired disability (HAD), and has a reported incidence rate of approximately 35% in older patients.^[8] HAD is a poor prognostic factor in older patients with heart disease.^[9] In a previous study, underweight patients with heart failure had low scores for activities of daily living measured at admission, and the decline tended to continue even at discharge.^[10] However, it remains unclear whether HAD influences patient prognosis according to the body mass index (BMI) after discharge. This study aimed to investigate the association of HAD with all-cause mortality after discharge according to BMI categories in patients with acute decompensated heart failure.     

Atypical antipsychotics and oxidative cardiotoxicity: review of literature and future perspectives to prevent sudden cardiac death

Oxidative stress is considered the principal mediator of myocardial injury under pathological conditions. It is well known that reactive oxygen (ROS) or nitrogen species (RNS) are involved in myocardial injury and repair at the same time and that cellular damage is generally due to an unbalance between generation and elimination of the free radicals due to an inadequate mechanism of antioxidant defense or to an increase in ROS and RNS. Major adverse cardiovascular events are often associated with drugs with associated findings such as fibrosis or inflammation of the myocardium. Despite efforts in the preclinical phase of the development of drugs, cardiotoxicity still remains a great concern. Cardiac toxicity due to second-generation antipsychotics (clozapine, olanzapine, quetiapine) has been observed in preclinical studies and described in patients affected with mental disorders. A role of oxidative stress has been hypothesized but more evidence is needed to confirm a causal relationship. A better knowledge of cardiotoxicity mechanisms should address in the future to establish the right dose and length of treatment without impacting the physical health of the patients.

Second-generation (atypical) antipsychotics are used in the treatment of mental disorders (schizophrenia, bipolar disorder, major depressive disorder). Since marketed, clozapine was widely used because of its efficacy in drug-resistant schizophrenia and freedom from extrapyramidal effects. After clozapine, other antipsychotics were introduced (olanzapine, quetiapine, risperidone) with similar effects and the same safer profile and soon became the mainstay of the treatment of schizophrenia.^[1] The therapeutic effect of second-generation antipsychotic agents is related to dopaminergic D2 receptor antagonism and to the blockage of serotonin receptors. Major cardiovascular adverse effects (tachycardia, bradycardia, hypertension, hypotension, syncopal episodes) and electrocardiographic abnormalities (prolonged QT interval) are reported in patients suffering from mental disorders and treated with antipsychotics.^[2–8] An increased risk of sudden death has been also reported but the risk of underreporting is concrete because of the lack of a systematic post-mortem examination.^[9–13] In addition, individuals with schizophrenia are known to be at greater risk of cardiac death, in part linked to inadequate lifestyles that predispose to cardiovascular disease, in part due to poor compliance with health care.^[14–16] However, many typical and atypical antipsychotic drugs have been reported in the literature to significantly increase the risk of sudden cardiac death in patients with psychiatric disorders,^[17] and this has led to restrictions in clinical practice or the withdrawal of these molecules from the market. A retrospective cohort study showed that the incidence of sudden cardiac death in subjects taking antipsychotics is increased (dose-related increase) compared to non-users of antipsychotics, regardless of the pharmacological class.^[18]Sudden antipsychotic cardiac death appears to be linked to arrhythmic mechanisms, dilated heart disease, and myocarditis.^[19–21] In the pathogenesis of the aforementioned cardiological alterations, an involvement of oxidative stress has been suggested, with an increase in reactive oxygen (ROS).^[22] ROS modulates multiple cellular signaling pathways in physiological conditions. However, when the production of intracellular ROS is excessive it causes damage to the molecular components of the cell, favoring the pathogenesis of various diseases with particular reference to cardiovascular ones. Despite the large use, factors underlying cardiovascular disease in patients treated with antipsychotics are still far to be completely understood and need to be deeply studied.^[23–27] Growing interest is aimed at understanding the contribution of antipsychotic therapy in the genesis of cardiac toxicity in schizophrenic patients. The purpose of the present study is to review the scientific literature on the topic and propose a possible explanation of antipsychotics-related cardiotoxicity.