Heart Failure Group Research Articles

Prognostic significance of addition of electrocardiographic findings to the MAGGIC heart failure risk score

Abstract Funding Acknowledgements Type of funding sources: None. Main funding source(s): Researchers Background The Meta-analysis Global Group in Chronic Heart Failure (MAGGIC) is a scoring system that is easy to use in outpatient or inpatient settings and was developed to predict the survival of heart failure (HF) patients after hospitalization. Aim This study aims to determine the prognostic significance of MAGGIC risk score combined with electrocardiography (ECG) parameters in decompensated patients with heart failure with reduced left ventricular ejection fraction (HFrEF) who were hospitalized for worsening HF. Methods A total of 562 HF patients with New York Heart Association (NYHA) II-IV functional class who were discharged after hospitalization for decompensated HF between 2013 and 2018 in a single center were included. MAGGIC risk scores of all participating patients were calculated according to baseline characteristics gathered using data from the initial hospitalization for HF. In addition, electrocardiographic findings of all patients were examined. Results During the follow-up period (4.5 ± 1.2 years) 177 patients died. MAGGIC scores were observed to be higher in non-survivors compared to surviving patients (28.69 ± 7.01 vs. 22.82 ± 6.05, p < 0.001). After a multivariate analysis, MAGGIC score (OR:1.090, p < 0.001), development of cardio-renal syndrome (OR:2.035, p < 0.001), presence of left bundle branch block (LBBB) (OR:1.931, p < 0.001), atrial fibrillation (AF) (OR:1.817, p < 0.001), and fragmented QRS (fQRS) (OR:1.671, p = 0.002) on ECG were found to be independent predictors of mortality. While the MAGGIC score was shown to predict mortality (AUC = 0.739), its predictive power was improved when combined with AF (AUC = 0.752), LBBB (AUC = 0.745), and fQRS (AUC = 0.757) respectively, as well as in the combined final model (MAGGIC score, AF, LBBB, fQRS) (AUC = 0.787). Conclusions Our findings showed that addition of electrocardiographic findings to the MAGGIC heart failure risk score has prognostic significance in decompensated patients with HFrEF.

Retinal vascular density change in patients with heart failure

PurposeThe aim of this study is to assess choroid thickness, retinal vessel density in the superficial capillary plexus layer and deep capillary plexus layer in heart failure (HF) using optical coherence tomography angiography (OCT-A). Methods36 healthy participants (group 1), 33 patients with HF were assessed for this study. HF patients had a left ventricular ejection fraction (LVEF) <50%. HF patients were divided into 2 groups according to the New York Heart Association (NYHA). 15 patients were evaluated as group 2 according to NYHA and 18 patients as group 3 according to NYHA. Choroid thickness, superficial and deep capillary plexus perfusion were analyzed between groups using OCT-A. ResultsChoroid thicknesses were found to be significantly decrease in the HF groups. Superficial capillary plexus density was compared with the control group, no statistically significant difference was found between the HF groups. But among the HF groups, a statistically significant decrease was found in group 3 patients. Deep capillary plexus density was compared with the control group, a statistically significant decrease was found in group 3. In addition, deep capillary plexus density a statistically significant difference was found between the groups HF. ConclusionsPatients with HF showed decreased flow density compared with healthy controls. In addition, significant changes were found in flow densities among the HF groups. Retinal perfusion measured using OCT-A may give an idea about the hemodynamic status and microperfusion of HF patients.

Blood flow kinetic energy is a novel marker for right ventricular global systolic function in patients with left ventricular assist device therapy.

Right ventricular (RV) failure remains a major concern in heart failure (HF) patients undergoing left ventricular assist device (LVAD) implantation. We aimed to measure the kinetic energy of blood in the RV outflow tract (KE-RVOT) - a new marker of RV global systolic function. We also aimed to assess the relationship of KE-RVOT to other echocardiographic parameters in all subjects and assess the relationship of KE-RVOT to hemodynamic parameters of RV performance in HF patients. Fifty-one subjects were prospectively enrolled into 4 groups (healthy controls, NYHA Class II, NYHA Class IV, LVAD patients) as follows: 11 healthy controls, 32 HF patients (8 NYHA Class II and 24 Class IV), and 8 patients with preexisting LVADs. The 24 Class IV HF patients included 21 pre-LVAD and 3 pre-transplant patients. Echocardiographic parameters of RV function (TAPSE, St', Et', IVA, MPI) and RV outflow color-Doppler images were recorded in all patients. Invasive hemodynamic parameters of RV function were collected in all Class IV HF patients. KE-RVOT was derived from color-Doppler imaging using a vector flow mapping proprietary software. Kruskal-Wallis test was performed for comparison of KE-RVOT in each group. Correlation between KE-RVOT and echocardiographic/hemodynamic parameters was assessed by linear regression analysis. Receiver operating characteristic curves for the ability of KE-RVOT to predict early phase RV failure were generated. KE-RVOT (median ± IQR) was higher in healthy controls (55.10 [39.70 to 76.43] mW/m) than in the Class II HF group (22.23 [15.41 to 35.58] mW/m, p < 0.005). KE-RVOT was further reduced in the Class IV HF group (9.02 [5.33 to 11.94] mW/m, p < 0.05). KE-RVOT was lower in the LVAD group (25.03 [9.88 to 38.98] mW/m) than the healthy controls group (p < 0.005). KE-RVOT had significant correlation with all echocardiographic parameters and no correlation with invasive hemodynamic parameters. RV failure occurred in 12 patients who underwent LVAD implantation in the Class IV HF group (1 patient was not eligible due to death immediately after the LVAD implantation). KE-RVOT cut-off value for prediction of RV failure was 9.15 mW/m (sensitivity: 0.67, specificity: 0.75, AUC: 0.66). KE-RVOT, a novel noninvasive measure of RV function, strongly correlates with well-established echocardiographic markers of RV performance. KE-RVOT is the energy generated by RV wall contraction. Therefore, KE-RVOT may reflect global RV function. The utility of KE-RVOT in prediction of RV failure post LVAD implantation requires further study.

Sodium-Glucose Cotransporter 2 Inhibitor Use in Early-Phase Acute Coronary Syndrome with Severe Heart Failure.

Sodium-glucose cotransporter 2 inhibitor (SGLT2i) improves clinical outcomes in patients with heart failure (HF), but has limited evidence of SGLT2i use on early-phase acute coronary syndrome (ACS). We determined association of early SGLT2i use compared with either non-SGLT2i or dipeptidyl peptidase 4 inhibitor (DPP4i) in hospitalized patients with ACS. This retrospective cohort study that used the Japanese nationwide administrative claims database included patients hospitalized with ACS aged≥20 years between April 2014 and March 2021. The primary outcome was a composite of all-cause mortality or HF/ACS rehospitalization. Using 1:1 propensity score matching, the association with outcomes of the early SGLT2i use (≤14 days after admission) compared with non-SGLT2i or DPP4i was determined according to the HF treatment. Among 388185 patients included, 115612 and 272573 with and without severe HF, respectively. Compared to non-SGLT2i users, the SGLT2i users had a lower hazard ratio (HR) with the primary outcome (HR: 0.83, 95% confidence interval [CI]: 0.76-0.91, p<0.001) in the severe HF group; however, there was no significant difference in the non-severe HF group (HR: 0.92, 95% CI: 0.82-1.03, p=0.16). SGLT2i use showed a lower risk of the outcome in patients with severe HF and diabetes compared with DPP4i (HR: 0.83, 95% CI: 0.69-1.00, p=0.049). SGLT2i use in patients with early-phase ACS showed a lower risk of primary outcome in patients with severe HF but the effect was not apparent in patients without severe HF.

Trainability for cardiopulmonary fitness is low in patients with peripheral artery disease.

In patients with peripheral arterial disease (PAD), exercise therapy is recommended to relieve leg symptoms, as noted in the 2016 AHA/ACC and 2017 ESC/ESVS guidelines. We assessed the trainability for cardiopulmonary fitness (CPF) and quality of life (QOL); three distinct patient types, namely, PAD, heart failure (HF), and stroke, were compared. This is a multicentre, retrospective analysis of prospectively collected data from three clinical studies. Data collected from 123 patients who completed 36 sessions of supervised aerobic training of moderate intensity were analysed, with 28 PAD, 55 HF, and 40 stroke patients totalling 123. Before and after training, cardiopulmonary exercise testing with non-invasive cardiac output monitoring and QOL evaluation using a 36-Item Short Form Survey (SF-36) were performed. Non-response was defined as a negative change in the post-training value compared with that in the pre-training value. The result showed an improvement in CPF in all three groups. However, cardiorespiratory fitness (CRF) increased by a lesser extent in the PAD group than in the HF and stroke groups; the physical and mental component scores (MCS) of SF-36 exhibited a similar pattern. Non-response rates of peak V˙O2, oxygen uptake efficiency slope, and MCS were higher in the PAD group. In the PAD group, non-responders regarding peak V˙O2 had a higher pulse wave velocity than responders. In patients with PAD following exercise therapy, CRF and QOL improved to a lesser extent on average; their non-response rate was also higher compared with that of HF or stroke patients. Therefore, a higher dose of exercise might be needed to elicit adaptation in PAD patients, especially those with high pulse wave velocity.

Mortality After the First Hospital Admission for Acute Heart Failure, De Novo Versus Acutely Decompensated Heart Failure With Reduced Ejection Fraction

It is not clear to date whether a first admission in heart failure (HF) marks a worse evolution in patients not previously diagnosed with HF ("de novo HF") than those already diagnosed as outpatients ("acutely decompensated HF"). The aim of the study was to analyze whether survival in patients admitted for de novo HF differs from the survival in those admitted for a first episode of decompensation but with a previous diagnosis of HF. This study includes an analysis of 1,728 patients admitted for decompensated HF during 9years. Readmissions and patients with left ventricular ejection fraction ≥50% were excluded (finally, 524 patients analyzed). We compared de novo HF (n=186) in patients not diagnosed with HF, although their structural heart disease was defined, versus acutely decompensated HF (n=338). The clinical profiles in both groups were similar. The de novo HF group more frequently presented with normal right ventricular function, with less presence of severe tricuspid regurgitation. The probability of survival was low in both groups. Thus, the median life in the de novo HF group was 2.1years and in the acutely decompensated HF group, 3.5years. There was a lower probability of long-term survival in the de novo HF group (p=0.035). The variables associated with mortality were age (p <0.0001), ischemic heart disease (p <0.0001), hypertension (p=0.009), obesity (p=0.025), diabetes (p=0.001), and N-terminal pro-brain natriuretic peptide at admission (p <0.0001). A higher glomerular filtration rate was associated with better survival (p=0.033). De novo HF was associated with a higher mortality than chronic HF with acute decompensation (hazard ratio 1.53, 95% confidence interval 1.03 to 2.27, p=0.036). In conclusion, the first admission for HF decompensation in patients with no previous diagnosis of HF identifies a subgroup of patients with higher long-term mortality.

Combination of cardiac color Doppler ultrasound, serum MR-ProANP and NT-ProBNP forecasted hypertensive LVH and LFH

ABSTRACT To analyze the value of the combined test of the cardiac color Doppler ultrasound, the serum middle receptor pro-atrial natriuretic peptide (MR-ProANP) and the N-terminal pro-brain natriuretic peptide (NT-ProBNP) in forecasting the hypertensive left ventricular hypertrophy (LVH) and left heart failure (LHF). All patients were subjected to cardiac color Doppler ultrasound examination to obtain left atrium volume index (LAVI), left ventricular end-diastolic diameter (LVEDD), early-diastolic peak flow velocity (E), early-diastolic mean flow velocity (e’), early-diastolic peak flow velocity/early-diastolic mean flow velocity (E/e’) and left ventricular ejection fraction (LVEF). Biomarkers were performed to obtain serum MR-ProANP and NT-ProBNP concentrations, and statistical analysis was performed. The LVEF was obviously lower than that in the control group (P<0.01). The area under the receiver operating characteristic (ROC) curve (AUC) values of LVEF, E/e’, serum MR-ProANP and NT-ProBNP alone were in the range of 0.7–0.8. The AUC, sensitivity and specificity of LVEF and E/e’ combined with MR-ProANP and NT-ProBNP to diagnose hypertensive LVH and LHF were 0.892, 89.14% and 78.21%, which were higher than those of single diagnosis. In the heart failure group, LVEF was negatively correlated with serum MR-ProANP and NT-ProBNP concentrations (P<0.05), and E/e’ was positively correlated with serum MR-ProANP and NT-ProBNP concentrations (P<0.05). Pump function and ventricular remodeling in patients with hypertensive LVH and LHF are closely related to serum MR-ProANP and NT-ProBNP levels. Combination of the two testing can improve the prediction and diagnostic efficacy of LHF.

The serum soluble scavenger with 5 domains levels: A novel biomarker for individuals with heart failure.

Background: We aimed to explore the relationship between the serum Soluble Scavenger with 5 Domains (SSC5D) levels and heart failure (HF). Methods and Results: We retrospectively enrolled 276 patients diagnosed with HF or normal during hospitalization in Shanghai General Hospital between September 2020 and December 2021. Previously published RNA sequencing data were re-analyzed to confirm the expression profile of SSC5D in failing and non-failing human and mouse heart tissues. Quantitative real-time polymerase chain reaction assay was used to quantify Ssc5d mRNA levels in murine heart tissue after myocardial infarction and transverse aortic constriction surgery. To understand the HF-induced secreted proteins profile, 1,755 secreted proteins were investigated using human dilated cardiomyopathy RNA-seq data, and the results indicated that SSC5D levels were significantly elevated in failing hearts compared to the non-failing. Using single-cell RNA sequencing data, we demonstrated that Ssc5d is predominantly expressed in cardiac fibroblasts. In a murine model of myocardial infarction or transverse aortic constriction, Ssc5d mRNA levels were markedly increased compared with those in the sham group. Similarly, serum SSC5D levels were considerably elevated in the HF group compared with the control group [15,789.35 (10,745.32-23,110.65) pg/mL, 95% CI (16,263.01-19,655.43) vs. 8,938.72 (6,154.97-12,778.81) pg/mL, 95% CI (9,337.50-11,142.93); p < 0.0001]. Moreover, serum SSC5D levels were positively correlated with N-terminal pro-B-type natriuretic peptide (R = 0.4, p = 7.9e-12) and inversely correlated with left ventricular ejection fraction (R = -0.46, p = 9.8e-16). Conclusion: We concluded that SSC5D was a specific response to HF. Serum SSC5D may function as a novel biomarker and therapeutic target for patients with HF.

The Usefulness of Bioelectrical Impedance as a Marker of Fluid Status in Patients With Congestive Heart Failure: A Systematic Review and Meta-Analysis.

Bioelectrical impedanceanalysis (BIA) is a method that measures electrical currents conducted through water, which assesses fluid status by measuring extracellular water (ECW), total body water (TBW), and resistance (R). Limited studies are done to evaluate the utility of BIA in patients with congestive heart failure (CHF), and therefore, we performed a systematic review and meta-analysis to evaluate this.A comprehensive literature search was performed at Medline and Embase until March 2022. Our primary outcome was a comparison of TBW and ECW between patients with CHF and controls. Our secondary outcome was to compare R between the groups. All analysis was conducted using RevMan 5.4 software.Six studies with 1,046 patients met our inclusion criteria. Out of 1,046 patients, 526 had CHF and 538 had no CHF. Among patients with CHF, all 526 had decompensated CHF. There was no significant difference in TBW between patients with heart failure and the control group (mean deviation (MD) = 1.42 (-0.44-3.27), percent of variation (I2) = 0%,p = 0.13). ECW was significantly higher with an assessment of BIA in heart failure patients compared to patients in the control group (MD = 1.62 (0.82-2.42), I2 = 0%, p < 0.0001). Resistance of extracellular fluid was significantly lower in the heart failure group (MD = -45.64 (-72.88--18.41), I2 = 83%, p = 0.001). Publication bias was deferred as the number of included studies was less than 10. BIA can be helpful in ambulatory and inpatient setting to identify patients' fluid status, which can improve outcomes. However, larger prospective studies are needed to further evaluate the usefulness of BIA in the CHF population.

Prevalence, hematological parameters, and coagulation profiles: Cardiovascular diseases statistics in the Asir region, Saudi Arabia.

To determine the prevalence of cardiovascular disease (CVD) types in the Asir region of Saudi Arabia and the importance of hematological testing for CVD patients in the context of disease management. This retrospective study comprised 416 CVD patients, and samples were divided based the type of CVD. The Mann Whitney U test was used to compare patients' hematological markers and coagulation profiles to those of healthy controls. The rate of ischemic heart disease (IHD) was 80.7% that of other CVDs, and the rate of ST-elevation myocardial infarction (STEMI) was 37.3% the rate of CVD. Significant differences were observed in the hematological and coagulation parameters of CVD patients compared to the control group. White blood cells (WBC) were significantly higher in STEMI, non-ST-elevation myocardial infarction (NSTEMI), unstable angina (UA), and heart failure (HF) groups. Red blood cells (RBC) were significantly lower in STEMI, NSTEMI, UA, chronic coronary syndrome (CCS), HF, dilated cardiomyopathy (DCM), and ischemic cardiomyopathy (ICM). Red distribution width (RDW) was significantly greater in the HF, DCM, and ICM groups. Prothrombin time (PT) was significantly higher in the STEMI, HF, and DCM groups. ST-elevation myocardial infarction has a higher prevalence rate among CVD patients in the Asir region. Both coagulation and hematological indicators have high potential utility as CVD diagnostic and prognostic markers.

Linagliptin exacerbates heart failure due to energy deficiency via downregulation of glucose utilization and absorption in a mouse model

Use of dipeptidyl peptidase-4 (DPP4) inhibitor in some clinical trials might have caused heart failure (HF), leading to increased hospitalizations. The aim of the present study was to determine whether linagliptin has any effect on chronic dilated HF, and its underlying mechanisms. Physiologic and pathologic studies were conducted on heart/muscle-specific manganese superoxide dismutase-deficient mice, which exhibited dilated cardiomyopathy, and were randomized to receive a low dose (1 mg/kg, HF-L group) or high dose (10 mg/kg, HF–H group) mixed with food, or normal food (HF group), for 8 weeks. Linagliptin increased mortality and heart/body weight ratio in mice with HF. Cardiac contractility and fibrosis worsened, whereas hepatic glycogen content and individual carbohydrate consumption decreased significantly in the HF–H group, when compared with the HF control group. Therefore, we performed a complementary experiment by supplementing glucose to the mice treated with high-dose linagliptin (HF-HG group). Adequate glucose supplementation reduced heart/body weight ratio and cardiac fibrosis, and improved cardiac contractility, without changing mortality. Following oral administration of 13C glucose, the respiratory 13C decreased in the HF–H and HF-HG groups, when compared with that in the HF group; the fecal 13C increased, suggesting that linagliptin inhibited glucose absorbance in the intestine. In addition, the expression of GLUT2, a glucose transporter was downregulated in the small intestine. Linagliptin treatment exacerbated HF, which increased mortality, cardiac function, and fibrosis. DPP4 inhibitors might boost cardiac cachexia and exacerbate HF, at least in part, through the modification of glucose utilization and absorption.

Deep phenotyping as a contribution to personalized depression therapy: the GEParD and DaCFail protocols

Depressive patients suffer from a complex of symptoms of varying intensity compromising their mood, emotions, self-concept, neurocognition, and somatic function. Due to a mosaic of aetiologies involved in developing depression, such as somatic, neurobiological, (epi-)genetic factors, or adverse life events, patients often experience recurrent depressive episodes. About 20–30% of these patients develop difficult-to-treat depression. Here, we describe the design of the GEParD (Genetics and Epigenetics of Pharmaco- and Psychotherapy in acute and recurrent Depression) cohort and the DaCFail (Depression-associated Cardiac Failure) case–control protocol. Both protocols intended to investigate the incremental utility of multimodal biomarkers including cardiovascular and (epi-)genetic markers, functional brain and heart imaging when evaluating the response to antidepressive therapy using comprehensive psychometry. From 2012 to 2020, 346 depressed patients (mean age 45 years) were recruited to the prospective, observational GEParD cohort protocol. Between 2016 and 2020, the DaCFail case–control protocol was initiated integrating four study subgroups to focus on heart-brain interactions and stress systems in patients > 50 years with depression and heart failure, respectively. For DaCFail, 120 depressed patients (mean age 60 years, group 1 + 2), of which 115 also completed GEParD, and 95 non-depressed controls (mean age 66 years) were recruited. The latter comprised 47 patients with heart failure (group 3) and 48 healthy subjects (group 4) of a population-based control group derived from the Characteristics and Course of Heart Failure Stages A–B and Determinants of Progression (STAAB) cohort study. Our hypothesis-driven, exploratory study design may serve as an exemplary roadmap for a standardized, reproducible investigation of personalized antidepressant therapy in an inpatient setting with focus on heart comorbidities in future multicentre studies.

Clinical Value of Novel Echocardiographic Biomarkers Assessing Myocardial Work in Acute Heart Failure-Rationale and Design of the "Beyond Myo-HF Study".

Despite ongoing treatment advancements in chronic heart failure (HF), mortality and readmission rates remain high for patients hospitalized for decompensated acute HF. These patients represent a distinct HF group, which requires emergent echocardiographic evaluation in an attempt to provide optimal and individualized acute care. The role of serial advanced echocardiographic assessment in acute HF for risk stratification and treatment guidance has not been thoroughly explored. The "Beyond Myo-HF Study" is a prospective, non-interventional cohort trial designed to enroll acutely admitted patients with symptoms and/or signs of HF. The aim of this study is to investigate whether intrahospital changes of conventional and novel echocardiographic indices of myocardial function and congestion-related markers can predict early mortality, late mortality, and HF rehospitalization. As per the protocol, all patients undergo a pair of state-of-the-art echocardiographic assessments, with a rigorous protocol including speckle tracking analysis of all cardiac chambers and myocardial work analysis for the left and right ventricle, upon admission and pre-discharge. Their laboratory profile is captured at those two time-points, and their therapeutic management is recorded. Patients will be followed-up for a median period of 12 months after enrollment. The "Beyond Myo-HF" study is an ongoing, prospective trial aspiring to provide deep insight into the pathophysiology of acute HF, to enlighten the reverse cardiac functional and anatomical remodeling during hospitalization, and to recognize echocardiographic patterns capable of predicting adverse outcomes during and post decompensation of acute HF.

Association of Chronic Heart Failure with Frailty, Malnutrition, and Sarcopenia Parameters in Older Patients—A Cross-Sectional Study in a Geriatric Ward

The need to assess sarcopenia and frailty in patients with chronic heart failure (HF) has recently been raised. This cross-sectional study of 416 geriatric ward patients (median age (Me)-82 (IQR, 77-86) years, 77.4% female, 96.9% community dwelling) aimed to assess the prevalence of dynapenia, frailty syndrome, functional and nutritional health, and co-morbidity regarding their HF status. We collected data from comprehensive geriatric assessment. We observed HF in 162 (38.9%) patients, with 80 (49.4%) classified as New York Heart Association (NYHA) class III or IV. HF patients were significantly older, more frequently male, obese, hospitalized in the previous year, burdened with multimorbidity and polypharmacy, classified as frail, dependent on daily living activities, and physically non-active. Ischemic heart disease, atrial fibrillation, diabetes, peripheral arterial disease, anemia, chronic kidney disease, history of myocardial infarction, and stroke were found significantly more often in the HF group. A considerably higher percentage of HF patients had dynapenia (54.9% versus 41.9%, p = 0.02), but the difference was significant only in women. We found no significant difference between HF and no-HF groups regarding muscle performance, except for lower median gait speed in the HF group-0.53 m/s (0.35-0.89 m/s) versus 0.68 m/s (0.44-0.99 m/s), p = 0.02). HF patients significantly more often had low grip strength accompanied by slow gait, suggesting probable severe sarcopenia (40.4% vs. 29% in patients without HF, p = 0.046). In the regression analysis, significantly higher odds for HF were observed for lower mid-arm circumference (MAC) and dynapenia when controlling for age, sex, body mass index (BMI), calf circumference (CC), peripheral arterial disease, history of stroke, ischemic heart disease, atrial fibrillation, and diabetes mellitus. Conclusions: HF geriatric patients are often burdened with frailty, obesity, multimorbidity, and polypharmacy. As a result, they are more likely to present low muscle strength (potential sarcopenia), which is frequently accompanied by functional limitations (suggestive of more advanced stages of sarcopenia). This tendency is evident mainly in older women. Nevertheless, sarcopenia can be independently associated with HF in older patients with multimorbidity and disability who are hospitalized in a geriatric department, as a multivariable logistic regression analysis demonstrated.

Prevalence of Neutralizing Antibodies against Adeno-Associated Virus Serotypes 1, 2, and 9 in Non-Injected Latin American Patients with Heart Failure—ANVIAS Study

Neutralizing antibody (NAb) activity against the viral capsid of adeno-associated viral (AAV) vectors decreases transduction efficiency, thus limiting transgene expression. Several reports have mentioned a variation in NAb prevalence according to age, AAV serotype, and, most importantly, geographic location. There are currently no reports specifically describing the anti-AAV NAb prevalence in Latin America. Here, we describe the prevalence of NAb against different serotypes of AAV vectors (AAV1, AAV2, and AAV9) in Colombian patients with heart failure (HF) (referred to as cases) and healthy individuals (referred to as controls). The levels of NAb were evaluated in serum samples of 60 subjects from each group using an in vitro inhibitory assay. The neutralizing titer was reported as the first dilution inhibiting ≥50% of the transgene signal, and the samples with neutralizing titers at ≥1:50 dilution were considered positive. The prevalence of NAb in the case and control groups were similar (AAV2: 43% and 45%, respectively; AAV1 33.3% in each group; AAV9: 20% and 23.2%, respectively). The presence of NAb for two or more of the serotypes analyzed was observed in 25% of the studied samples, with the largest amount in the positive samples for AAV1 (55-75%) and AAV9 (93%), suggesting serial exposures, cross-reactivity, or coinfection. Moreover, patients in the HF group exhibited more common combined seropositivity for NAb against AAV1 d AAV9 than those in the control group (91.6% vs. 35.7%, respectively; p = 0.003). Finally, exposure to toxins was significantly associated with the presence of NAb in all regression models. These results constitute the first report of the prevalence of NAb against AAV in Latin America, being the first step to implementing therapeutic strategies based on AAV vectors in this population in our region.

Relationship between disorders of the intestinal microbiota and heart failure in infants with congenital heart disease.

There is a close relationship between the intestinal microbiota and heart failure, but no study has assessed this relationship in infants with congenital heart disease. This study aimed to explore the relationship between heart failure and intestinal microbiota in infants with congenital heart disease. Twenty-eight infants with congenital heart disease with heart failure admitted to a provincial children's hospital from September 2021 to December 2021 were enrolled in this study. A total of 22 infants without heart disease and matched for age, sex, and weight were selected as controls. Faecal samples were collected from every participant and subjected to 16S rDNA gene sequencing. The composition of the intestinal microbiota was significantly disordered in infants with heart failure caused by congenital heart disease compared with that in infants without heart disease. At the phylum level, the most abundant bacteria in the heart failure group were Firmicutes, Actinobacteria, Proteobacteria, and Bacteroidetes, and the most abundant bacteria in the control group were Firmicutes, Proteobacteria, Actinobacteria, and Bacteroidetes. At the genus level, the most abundant bacteria in the heart failure group were Enterococcus, Bifidobacterium, Subdoligranulum, Shigella, and Streptococcus, and the most abundant bacteria in the control group were Bifidobacterium, Blautia, Bacteroides, Streptococcus, and Ruminococcus. The alpha and beta diversities of the gut bacterial community in the heart failure group were significantly lower than those in the control group (p<0.05). Compared with the control group, retinol metabolism was significantly downregulated in the heart failure group. Heart failure in infants with congenital heart disease caused intestinal microbiota disorder, which was characterised by an increase in pathogenic bacteria, a decrease in beneficial bacteria, and decreases in diversity and richness. The significant downregulation of retinol metabolism in the intestinal microbiota of infants with heart failure may be related to the progression of heart failure, and further study of the underlying mechanism is needed.

The effect of heart failure on gut microbial richness and diversity

Introduction and objectiveWith recent advances in genome sequencing technology, a large body of evidence has accumulated over the last few years linking alterations in microbiota with cardiovascular disease. In this study, we aimed to compare gut microbial composition using 16S ribosomal DNA (rDNA) sequencing techniques in patients with coronary artery disease (CAD) and stable heart failure (HF) with reduced ejection fraction and patients with CAD but with normal ejection fraction. We also studied the relationship between systemic inflammatory markers and microbial richness and diversity. MethodsA total of 40 patients (19 with HF and CAD, 21 with CAD but without HF) were included in the study. HF was defined as left ventricular ejection fraction <40%. Only stable ambulatory patients were included in the study. Gut microbiota were assessed from the participants’ fecal samples. The diversity and richness of microbial populations in each sample were assessed by the Chao1-estimated OTU number and the Shannon index. ResultsThe Chao1-estimated OTU number and Shannon index were similar between HF and control groups. There was no statistically significant relationship between inflammatory marker levels (tumor necrosis factor-alpha, interleukin 1-beta, endotoxin, C-reactive protein, galectin-3, interleukin 6, and lipopolysaccharide-binding protein) and microbial richness and diversity when analyzed at the phylum level. ConclusionIn the current study, compared to patients with CAD but without HF, stable HF patients with CAD did not show changes in gut microbial richness and diversity. At the genus level Enterococcus sp. was more commonly identified in HF patients, in addition to certain changes in species levels, including increased Lactobacillus letivazi.

Integrated whole-genome gene expression analysis reveals an atlas of dynamic immune landscapes after myocardial infarction.

Myocardial infarction (MI) is a deadly medical condition leading to irreversible damage to the inflicted cardiac tissue. Elevated inflammatory response marks the severity of MI and is associated with the development of heart failure (HF), a long-term adverse outcome of MI. However, the efficacy of anti-inflammatory therapies for MI remains controversial. Deciphering the dynamic transcriptional signatures in peripheral blood mononuclear cells (PBMCs) is a viable and translatable route to better understand post-MI inflammation, which may help guide post-MI anti-inflammatory treatments. In this work, integrated whole-genome gene expression analysis was performed to explore dynamic immune landscapes associated with MI. GSEA and GSVA showed that pathways involved in the inflammatory response and metabolic reprogramming were significantly enriched in PBMCs from MI patients. Based on leukocyte profiles generated by xCell algorithm, the relative abundance of monocytes and neutrophils was significantly increased in PBMCs from MI patients and had positive correlations with typical inflammation-associated transcripts. Mfuzz clustering revealed temporal gene expression profiles of PBMCs during the 6-month post-MI follow-up. Analysis of DEGs and gene sets indicated that PBMCs from HF group were characterized by elevated and lasting expression of genes implicated in inflammation and coagulation. Consensus clustering generated 4 metabolic subtypes of PBMCs with molecular heterogeneity in HF patients. In summary, integrated whole-genome gene expression analysis here outlines a transcriptomic framework that may improve the understanding of dynamic signatures present in PBMCs, as well as the heterogeneity of PBMCs in MI patients with or without long-term clinical outcome of HF. Moreover, the work here uncovers the diversity and heterogeneity of PBMCs from HF patients, providing novel bioinformatic evidence supporting the mechanistic implications of metabolic reprogramming and mitochondrial dysfunction in the post-MI inflammation and HF. Therefore, our work here supports the notion that individualized anti-inflammatory therapies are needed to improve the clinical management of post-MI patients.

Artificial Intelligence–Derived Electrocardiogram Assessment of Cardiac Age and Molecular Markers of Senescence in Heart Failure

ObjectiveTo ascertain whether heart failure (HF) itself is a senescent phenomenon independent of age, and how this is reflected at a molecular level in the circulating progenitor cell niche, and at a substrate level using a novel electrocardiogram (ECG)–based artificial intelligence platform. Patients and MethodsBetween October 14, 2016, and October 29, 2020, CD34+ progenitor cells were analyzed by flow cytometry and isolated by magnetic-activated cell sorting from patients of similar age with New York Heart Association functional classes IV (n = 17) and I-II (n = 10) heart failure with reduced ejection fraction and healthy controls (n = 10). CD34+ cellular senescence was quantitated by human telomerase reverse transcriptase expression and telomerase expression by quantitative polymerase chain reaction, and senescence-associated secretory phenotype (SASP) protein expression assayed in plasma. An ECG-based artificial intelligence (AI) algorithm was used to determine cardiac age and difference from chronological age (AI ECG age gap). ResultsCD34+ counts and telomerase expression were significantly reduced and AI ECG age gap and SASP expression increased in all HF groups compared with healthy controls. Expression of SASP protein was closely associated with telomerase activity and severity of HF phenotype and inflammation. Telomerase activity was more closely associated with CD34+ cell counts and AI ECG age gap. ConclusionWe conclude from this pilot study that HF may promote a senescent phenotype independent of chronological age. We show for the first time that the AI ECG in HF shows a phenotype of cardiac aging beyond chronological age, and appears to be associated with cellular and molecular evidence of senescence.

Myocardial Metabolomics of Human Heart Failure With Preserved Ejection Fraction.

The human heart primarily metabolizes fatty acids, and this decreases as alternative fuel use rises in heart failure with reduced ejection fraction (HFrEF). Patients with severe obesity and diabetes are thought to have increased myocardial fatty acid metabolism, but whether this is found in those who also have heart failure with preserved ejection fraction (HFpEF) is unknown. Plasma and endomyocardial biopsies were obtained from HFpEF (n=38), HFrEF (n=30), and nonfailing donor controls (n=20). Quantitative targeted metabolomics measured organic acids, amino acids, and acylcarnitines in myocardium (72 metabolites) and plasma (69 metabolites). The results were integrated with reported RNA sequencing data. Metabolomics were analyzed using agnostic clustering tools, Kruskal-Wallis test with Dunn test, and machine learning. Agnostic clustering of myocardial but not plasma metabolites separated disease groups. Despite more obesity and diabetes in HFpEF versus HFrEF (body mass index, 39.8 kg/m2 versus 26.1 kg/m2; diabetes, 70% versus 30%; both P<0.0001), medium- and long-chain acylcarnitines (mostly metabolites of fatty acid oxidation) were markedly lower in myocardium from both heart failure groups versus control. In contrast, plasma levels were no different or higher than control. Gene expression linked to fatty acid metabolism was generally lower in HFpEF versus control. Myocardial pyruvate was higher in HFpEF whereas the tricarboxylic acid cycle intermediates succinate and fumarate were lower, as were several genes controlling glucose metabolism. Non-branched-chain and branched-chain amino acids (BCAA) were highest in HFpEF myocardium, yet downstream BCAA metabolites and genes controlling BCAA metabolism were lower. Ketone levels were higher in myocardium and plasma of patients with HFrEF but not HFpEF. HFpEF metabolomic-derived subgroups were differentiated by only a few differences in BCAA metabolites. Despite marked obesity and diabetes, HFpEF myocardium exhibited lower fatty acid metabolites compared with HFrEF. Ketones and metabolites of the tricarboxylic acid cycle and BCAA were also lower in HFpEF, suggesting insufficient use of alternative fuels. These differences were not detectable in plasma and challenge conventional views of myocardial fuel use in HFpEF with marked diabetes and obesity and suggest substantial fuel inflexibility in this syndrome.