Heart Failure Subjects Research Articles

A Novel Approach Using Continuous Monitoring Of Peripheral Edema In Heart Failure Patients Allows Recognition Of Acute Decompensation Early In The Window Of Intervention

<h3>Introduction</h3> Peripheral edema is a common clinical sign along with weight gain, dyspnea, jugular distention, and elevated brain natriuretic peptides (BNP) of cardiac insufficiency associated with impending decompensation and hospitalization. Pitting edema is used in the clinical setting to classify edema severity. And patients occasionally use various subjective measures such as visibility of foot tendons, depth of sandal strap depression, and watch band tension to assess the degree of fluid retention. A better method is needed. A continuous, reliable, quantitative measurement of peripheral edema in the patient setting provides the early recognition necessary for diagnosis and treatment of the underlying causes of decompensation required to prevent the unnecessary cycle of crisis hospitalization. <h3>Hypotheses</h3> Continuous monitoring of ankle circumference will establish a normal baseline and allow detection of "ankle swelling" (peripheral edema) associated with fluid retention. We hypothesize that fluid retention presents as deviations from a normal baseline or "dry state" and can be characterized to distinguish between compensated events and decompensation trends. <h3>Methods</h3> A method of continuously measuring ankle circumference with 1 mm accuracy in the patient setting was employed, allowing us to test the feasibility of detecting changes in ankle swelling (peripheral edema) associated with fluid retention. An open pilot study was performed which collected ankle circumference and orientation data from both healthy normal and heart failure subjects. This data was enhanced using Subject Information Logs which tracked medication adherence, activity, salt intake, and daily weight. Continuous monitoring of the Daily Swelling Profile (DSP) allows definition of a Normal Baseline for each subject. Changes in fluid retention is identified as the difference between the Ankle Circumference Daily Rolling Average (DRA) compared to the Normal Baseline. Events from the Subject Information Logs were mapped to the Ankle Circumference Data. <h3>Results</h3> The following results were documented. Well-managed heart failure subjects present a DSP and Normal Baseline substantially equivalent to healthy normal subjects. Each subject's DSP represented as the change in ankle circumference from a horizontal position (sleeping) to standing or sitting throughout the day is 5-8 mm. Fluid retention or loss presents as a shift in the Ankle Circumference DRA. Compensated fluid retention such as missed medication or isolated high salt intake are observed as an increase in the Ankle Circumference DRA and return to normal after the subject corrects the anomalous behavior. Decompensated fluid retention is observed as an increasing trend in Ankle Circumference DRA and indicates a medical assessment and intervention may be needed. <h3>Conclusion</h3> A continuous, reliable, quantitative measurement of peripheral edema in the patient setting is a feasible method to recognize acute decompensation early in the window of intervention.

A Phase I, Open-label, Single-Dose Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of AMG 986 in Healthy Japanese Subjects.

Background and ObjectiveAMG 986 is a first-in-class, novel apelin receptor small molecule agonist initially developed as a treatment for patients with heart failure (HF). Previously, a first-in-human study of AMG 986 was conducted in healthy and HF subjects; however, AMG 986 was not evaluated in Japanese subjects.MethodsThis was a phase I, open-label, single-dose, single-center study conducted to evaluate the safety and pharmacokinetics (PK) of AMG 986 200 mg and 400 mg in 12 healthy Japanese subjects. Six subjects received AMG 986 200 mg and six subjects received AMG 986 400 mg.ResultsFollowing oral administration, median time to maximum observed plasma concentration (tmax) was 1.0 h for both the AMG 986 200 mg and 400 mg groups, and mean terminal half-life (t½) was 15.1 h and 17.6 h, respectively. When comparing the AMG 986 200 mg and 400 mg groups, 1.33-fold and 1.18-fold higher maximum observed plasma concentration (Cmax) and AUC∞, respectively, were observed for the 2-fold increase in dose. AMG 986 exhibited an acceptable safety and tolerability profile; all adverse events were mild in severity.ConclusionAMG 986 exposure increased with increasing dose, and the increase was less than dose proportional in healthy Japanese subjects. The results of this study could facilitate the subsequent clinical development of AMG 986 for the treatment of Japanese patients with HF.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40268-022-00386-3.

Cardioprotective Effect of Growth Differentiation Factor 15 Against Isoproterenol-Induced Cardiomyocyte Apoptosis via Regulation of the Mitochondrial Fusion

Abstract Objective: Pressure overload-induced myocardial apoptosis is a critical pathologically initiated process leading to heart failure (HF). Growth differentiation factor 15 (GDF15) dramatically increases during cardiac hypertrophy and dysfunction, but its functions and mechanisms are barely known. This study aims to elucidate the role and mechanism of GDF15 in HF. Methods: Between January 2017 and August 2018, 57 patients diagnosed with chronic HF (aged &gt;18 years, with left ventricular ejection fraction (LVEF) ≤35%) and 57 non-HF patients (aged &gt;18 years, LVEF &gt;35%) were prospectively enrolled in this study based on the balance of the baseline characteristics. Other acute or chronic diseases and pregnant/lactating women were excluded. The serum concentrations of GDF15 were detected. Isoproterenol (ISO)-induced HF mouse model was established by pumping with ISO (30 mg/(kg·day)) for 4 weeks, and the GDF15 expression in serum and heart tissue was evaluated in vivo. Primary cardiomyocytes were cultured and treated with ISO to induce cardiomyocytes damage. The apoptosis of cardiomyocytes and the effect of GDF15 on ISO-induced cardiomyocytes injury was evaluated in vitro. Results: After adjusting the baseline characteristic, serum levels of GDF15 were significantly higher in HF subjects than in non-HF patients. Similarly, in the ISO-induced HF mouse model, the significant increase in GDF15 was associated with the process of HF in vivo. Moreover, the elevation of GDF15 occurred prior to heart remodeling in the ISO-induced HF mouse model. Furthermore, using primary cardiomyocytes, we demonstrated that the GDF15 was remarkably enhanced in serum from pathological HF patients and cardiac tissue from the ISO-induced mouse model. Reducing GDF15 exaggerated the ISO-induced cell apoptosis by blocking mitochondrial fusion and increasing oxidative stress. In contrast, the silence of GDF15 aggravated the ISO-induced cardiomyocytes damage. Conclusions: GDF15 acts as a protective factor against cardiomyocyte apoptosis by improving mitochondria fusion during HF. These findings indicate that GDF15 may be a potential therapeutic target for HF.

Association Between Upper Limb Strength Through 1-Repetition Maximum Test and V’O2peak in Heart Failure

ABSTRACT Purpose: This study aimed to evaluate whether there is a correlation between the maximum strength of upper limb when performing a multijoint exercise and peak oxygen uptake (V’O2peak) in Chronic Heart Failure (CHF) subjects. Method: This cross-sectional study involved CHF subjects with a left ventricular ejection fraction (LVEF) less than 50%, who underwent a cardiopulmonary exercise test (CPET) on a treadmill and 1-repetition maximum (1-RM) test for upper limb strength using a bench press exercise. Results: The sample consisted of 16 individuals aged 54 ± 12 years with a LVEF of 37 ± 7%. The V’O2peak was 14.98 ± 5.4 ml·min−1·kg−1 and mean maximum load in the 1-RM test was 38 ± 16 kg. There was strong correlation of V’O2peak with the load in the 1-RM test (r = 0.70; p = .037; r2 = 0.48). Conclusion: There is a strong correlation between the load in 1-RM test for upper limb with V’O2peak in CHF individuals. It is a safe, inexpensive and reproducible way to assess the muscle strength in this population.

Serum NT-Pro-BNP versus Noninvasive Bedside Inotropic Index in Paediatric Shock: A Contest of Myocardial Performance in Response to Fluid Loading

Background Mild elevation of serum amino-terminal pro-B-type natriuretic peptide (NT-pro-BNP) is associated with myocardial dysfunction. A significantly lower Smith–Madigan inotropic index (SMII) has been shown to accurately represent cardiac contractility among heart failure subjects. We aim to monitor the effect of fluid resuscitation on cardiac function among paediatric patients by measuring serum NT-pro-BNP and SMII. Methods This is an observational study on 70 paediatric shock patients. NT-pro-BNP and noninvasive bedside haemodynamic monitoring were done by using an ultrasonic cardiac output monitor (USCOM, USCOM, Sydney, Australia). The presence of cardiac diseases was excluded. SMII was obtained from the USCOM. An increase in the stroke volume index (SVI) of ≥15% indicates fluid responders. Measurements were taken before and after fluid loading. Results Preloading NT-pro-BNP and SMII category were significantly different between the fluid responsiveness group, p=0.001 and p=0.004, respectively. Higher median NT-pro-BNP (preloading NT-pro-BNP of 1175.00 (254.50–9965.00) ng/mL vs. 196.00 (65.00–509.00) ng/mL, p=0.002) was associated with fluid nonresponders (subjects >12 months old). Preloading NT-pro-BNP <242.5 ng/mL was associated with fluid responders (AUC: 0.768 (0.615–0.921), p=0.003), 82.1% sensitivity, and 68.7% specificity for subjects >12 years old. Delta NT-pro-BNP in fluid responders (15.00 (−16.00–950.00) ng/mL) did not differ from fluid nonresponders (505.00 (−797.00–1600.00) ng/mL), p=0.456. Postloading SMII >1.25 W·m−2 was associated with fluid responders (AUC: 0.683 (0.553–0.813), p = 0.011), 61.9% sensitivity, and 66.7% specificity, but not preloading SMII. Fluid responders had a higher mean postloading SMII compared to nonresponders (1.36 ± 0.38 vs. 1.10 ± 0.34, p=0.006). Conclusion Higher NT-pro-BNP and lower SMII in the absence of cardiac diseases were associated with poor response to fluid loading. The SMII is affected by low preload conditions.

Abstract 11057: Measures of Heart Rate Variability as Predictors of Clinical Outcome in Patients with Chronic Heart Failure - Results from the Myovasc Study

Introduction: Evidence supports a potential prognostic value of heart rate variability (HRV) in patients with chronic heart failure (HF). Comprehensive data comparing different domains of HRV in relation to clinical outcome in HF are scarce. Methods: Subjects with chronic HF (i.e. AHA stage C or D) from the MyoVasc study (NCT04064450; N=3,289), a prospective cohort study, were analyzed. Individuals with pacemaker or atrial fibrillation were excluded. All participants received a highly standardized medical-technical examination during a five-hour visit in a dedicated study center. Data from 24-hour Holter ECG recordings were analyzed resulting in HRV markers from the time and frequency domain, and non-linear HRV measures. Information on clinical outcome, i.e. worsening of HF (WoHF), was derived from structured follow-up with subsequent validation and independent adjudication of endpoints. Random forest models were used to identify the most predictive marker of each HRV domain, which were further analyzed with multivariable Cox regression. Results: The analysis sample comprised 554 HF subjects (mean age: 66.4±9.9 years, 34.3% female sex) with HRV data. During a median observational period of 4.08 years (interquartile range 2.22; 5.22), 153 participants experienced WoHF. In random forest analyses, the rMSSD (time domain), high frequency power in normalized units (HF nu ; frequency domain), and SD1/SD2 (non-linear measure) were ranked as most predictive HRV markers for WoHF in each HRV domain. Subsequent Cox regression analysis demonstrated that log(SD1/SD2) (hazard ratio (HR) per standard deviation 1.50, 95%CI 1.29;1.75; P&lt;0.0001), HF nu (HR SD 1.47, 95%CI 1.23;1.77; P&lt;0.0001) and log(rMSSD) (HR SD 1.36, 95%CI 1.17;1.57; P&lt;0.0001) were strong predictors of HF outcome independent of age, sex, clinical profile, and medication. In Cox regression analysis with adjustment for NT-proBNP and the established HF risk score MAGGIC, HF nu (HR SD 1.25, 95%CI 1.05;1.48; P=0.012) and log(SD1/SD2) (HR SD 1.24, 95%CI 1.07;1.43; P=0.005) remained independent predictors of WoHF. Conclusions: Markers of HRV were identified as strong predictors for HF outcome independent of established risk markers, suggesting a potential to advance risk stratification.

Clinical characteristics and correlates of patients with heart failure with mid-range ejection fraction in southwest Nigeria

A new class of Heart Failure (HF) phenotypes, HF with midrange Ejection Fraction (HFmrEF), was recently introduced, but its clinical characteristics and therapeutic distinctiveness are not yet well understood. This study aimed to describe the clinical characteristics, echocardiographic features, and other correlates of HFmrEF in southwest Nigeria. Two hundred and sixty-nine consecutive HF subjects who had echocardiography done in the cardiology clinics of two teaching hospitals were recruited for this study. Clinical parameters such as age, body mass index, waist-hip ratio, and gender were determined. The presence of comorbidities, such as hypertension and diabetes, was also assessed. Statistical analysis was done, and p &lt;0.05 was taken as statistically significant. HFmrEF subjects constituted 27.5% of total cohort, while subjects with HF with preserved Ejection Fraction (HFpEF) and HF with reduced Ejection Fraction (HFrEF) were 29.0% and 43.5% respectively. HFmrEF was more likely to be associated with high systolic blood pressure and obesity. The clinical characteristics of HFmrEF were intermediate between those of the other two HF phenotypes. Prevalence of comorbidities, such as anaemia, iron deficiency, pulmonary hypertension, and left ventricular hypertrophy were also intermediate between HFpEF and HFrEF. Atrial fibrillation was commonest among HFmrEF subjects. There was no significant age or gender variation between the three phenotypes. Patients with HFmrEF have clinical and demographic distinctiveness that are often intermediate between HFpEF and HFrEF phenotypes. Further studies of this HF phenotype will help in understanding its therapeutic identity and its prognosis among Africans.

Atrial fibrillation associated with heart failure treated by a 2-lead CRT-DX system (BIO-AffectDX): Study design and clinical protocol.

BackgroundEvidence to support use of cardiac resynchronization therapy (CRT) among patients with both heart failure (HF) and atrial fibrillation (AF) is largely limited to retrospective or post hoc subanalyses. Data from a prospectively enrolled and contemporary cohort are needed.ObjectiveWe aim to better characterize the changes from baseline in HF patients with concomitant AF subsequently implanted with a 2-lead CRT-DX system capable of sensing in the atrium, aggregating diagnostics, and delivering CRT therapy. The primary objective of this study is to evaluate the percentage of all HF subjects with an improvement in a clinical composite score from pre-CRT implant to 12 months.MethodsThe study is a US-based, prospective, observational multicenter clinical trial conducted at up to 50 sites and enrolling approximately 400 subjects with a follow-up period of 1 year. Multiple subject assessments, atrial rhythm status, and device interrogation will be collected at follow-up visits occurring at 3, 6, and 12 months postimplant.ResultsA Clinical Events Committee will adjudicate subject HF events, arrhythmia events, death events, and all device-classified ventricular tachycardia and ventricular fibrillation episodes with treatment that are collected throughout the follow-up period. Their decisions are based on independent physician review of the data from sites and device interrogation.ConclusionThe BIO-AffectDX study aims to provide further insight into the expected outcomes from CRT treatment in patients with HF and AF.

Effects of Cardiac Resynchronization Therapy on Cardio-Respiratory Coupling.

In this study, the effect of cardiac resynchronization therapy (CRT) on the relationship between the cardiovascular and respiratory systems in heart failure subjects was examined for the first time. We hypothesized that alterations in cardio-respiratory interactions, after CRT implantation, quantified by signal complexity, could be a marker of a favorable CRT response. Sample entropy and scaling exponents were calculated from synchronously recorded cardiac and respiratory signals 20 min in duration, collected in 47 heart failure patients at rest, before and 9 months after CRT implantation. Further, cross-sample entropy between these signals was calculated. After CRT, all patients had lower heart rate and CRT responders had reduced breathing frequency. Results revealed that higher cardiac rhythm complexity in CRT non-responders was associated with weak correlations of cardiac rhythm at baseline measurement over long scales and over short scales at follow-up recording. Unlike CRT responders, in non-responders, a significant difference in respiratory rhythm complexity between measurements could be consequence of divergent changes in correlation properties of the respiratory signal over short and long scales. Asynchrony between cardiac and respiratory rhythm increased significantly in CRT non-responders during follow-up. Quantification of complexity and synchrony between cardiac and respiratory signals shows significant associations between CRT success and stability of cardio-respiratory coupling.

A simplified wall-based model for regional innervation/perfusion mismatch assessed by cardiac 123I-mIBG and rest 99mTc-tetrofosmin SPECT to predict arrhythmic events in ischaemic heart failure

AimsCardiac 123iodine-meta-iodobenzylguanidine (123I-mIBG) single-photon emission computed tomography (SPECT) imaging provides information on regional myocardial innervation. However, the value of the commonly used 17-segment summed defect score (SDS) as a prognostic marker is uncertain. The present study examined whether a simpler regional scoring approach for evaluation of 123I-mIBG SPECT combined with rest 99mTc-tetrofosmin SPECT myocardial perfusion imaging could improve prediction of arrhythmic events (AEs) in patients with ischaemic heart failure (HF).Methods and ResultsFive hundred and two ischaemic HF subjects of the ADMIRE-HF study with complete cardiac 123I-mIBG and rest 99mTc-tetrofosmin SPECT studies were included. Both SPECT image sets were read together by two experienced nuclear imagers and scored by consensus. In addition to standard 17-segment scoring, the readers classified walls (i.e. anterior, lateral, inferior, septum and apex) as normal, matched defect, mismatched (innervation defect > perfusion defect), or reverse mismatched (perfusion defect > innervation defect). Cox proportional hazards ratios (HRs) were used to determine if age, body mass index, functional class, left ventricular ejection fraction (LVEF), B-type natriuretic peptide (BNP), norepinephrine, 123I-mIBG SDS, 99mTc-tetrofosmin SDS, innervation/perfusion mismatch SDS, and our simplified visual innervation/perfusion wall classification were associated with occurrence of AEs (i.e. sudden cardiac death, sustained ventricular tachycardia, resuscitated cardiac arrest, appropriate implantable cardioverter-defibrillator therapy). At 2-year median follow-up, 52 subjects (10.4%) had AEs. Subjects with 1 or 2 mismatched walls were twice as likely to have AEs compared with subjects with either 0 or 3–5 mismatched walls (16.3% vs. 8.3%, P = 0.010). Cox regression analyses showed that patients with a visual mismatch in 1-2 walls had an almost two times higher risk of AEs [HR 2.084 (1.109–3.914), P = 0.001]. None of the other innervation, perfusion and mismatch scores using standard 17 segments were associated with AEs. BNP (ng/L) was the only non-imaging parameter associated with AEs.ConclusionA visual left ventricular wall-level based scoring method identified highest AE risk in ischaemic HF subjects with intermediate levels of innervation/perfusion mismatches. This simple technique for the evaluation of SPECT studies, which are often challenging in HF subjects, seems to be superior to the 17-segment scoring method.

Analysis of Differences in Assessment of Left Ventricular Function on Echocardiography and Nuclear Perfusion Imaging

Two widely used methods for left ventricular (LV) ejection fraction (EF) determination, echocardiography (echo) and gated single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI), often have wide limits of agreement. Factors influencing discrepancies between core laboratory echo and MPI LVEF determinations were examined in a large series of heart failure (HF) subjects and normal controls. 879 HF and 101 control subjects had core lab analyses of echo and MPI (mean time between procedures 7-8 days). LVEF differences were analyzed using one-way analysis of variance and Bland-Altman plots. Relationships between LVEF differences and patient characteristics and outcome endpoints (mortality and arrhythmias) were explored with logistic regression, Cox proportional hazards models, and Kaplan-Meier survival analyses. There was a systematic difference between the 2 modalities; echo LVEF was higher with more severe LV dysfunction, MPI LVEF higher when systolic function was normal. LVEF results were within ±5% in only 37% of HF and 23% of control subjects. Considering discordance around the LVEF threshold 35%, there was disagreement between the 2 methods in 305 HF subjects (35%). Male gender (odds ratio (OR)=0.200), atrial fibrillation (OR=2.314), higher body mass index (OR=1.051) and lower LV end-diastolic volume (OR=0.985) were the strongest predictors of methodologic discordance. Cardiac event rates were highest if both LVEF values were ≤35% and lowest when both LVEF values were >35%. In conclusion, substantial disagreements between LVEF results by echo and MPI are common. HF patients with LVEF ≤35% by both techniques have the highest 2-year event risk.

Contemporary ICD Use in Patients with Heart Failure.

Despite constant breakthroughs in heart failure (HF) therapy, the population of HF patients resume to grow and is linked to increased mortality and morbidity. Ventricular arrhythmias (VA) are one of the leading causes of mortality in HF subjects. Implantable cardioverter-defibrillators (ICDs) are currently the gold standard in treatment, preventing arrhythmic sudden cardiac death (SCD) episodes. However, the death rates related to HF remain elevated, as not all HF subjects benefit equally. Cardiac resynchronization therapy (CRT) has emerged as a novel approach for HF patients. These devices have been thoroughly investigated in major randomized controlled studies but continue to be underutilized in various countries. This review discusses the use of ICD in HF populations on top of treatments.

Regulation of Mitochondrial Function by Noncoding RNAs in Heart Failure and Its Application in Diagnosis and Treatment.

Heart failure (HF) is the terminal stage of multiple cardiovascular diseases. However, the pathogenesis of HF remains unclear and prompt; appropriate diagnosis and treatment of HF are crucial. Cardiomyocytes isolated from HF subjects frequently present mitochondrial impairment and dysfunction. Many studies have suggested that the regulation by noncoding RNAs (ncRNAs) of mitochondria can affect the occurrence and progression of HF. The regulation by ncRNAs of myocardial mitochondria during HF and the recent applications of ncRNAs in the diagnosis and treatment of HF are summarized in this review that is intended to gain keen insights into the mechanisms of HF and more effective treatments.

Quality and utility of [123I]I-metaiodobenzylguanidine cardiac SPECT imaging in nondiabetic postinfarction heart failure patients qualified for implantable cardioverter defibrillator

ObjectiveImpaired cardiac adrenergic activity has been demonstrated in heart failure (HF) and in diabetes mellitus (DM). [123I]I-metaiodobenzylguanidine (MIBG) enables assessment of the cardiac adrenergic nervous system. Tomographic imaging of the heart is expected to be superior to planar imaging. This study aimed to determine the quality and utility of MIBG SPECT in the assessment of cardiac innervation in postinfarction HF patients without DM, qualified for implantable cardioverter defibrillator (ICD) in primary prevention of sudden cardiac death.MethodsConsecutive patients receiving an ICD on the basis of contemporary guidelines were prospectively included. Planar MIBG studies were followed by SPECT. The essential analysis was based on visual assessment of the quality of SPECT images (“high”, “low” or “unacceptable”). The variables used in the further analysis were late summed defect score for SPECT images and heart-to-mediastinum rate for planar images. MIBG images were assessed independently by two experienced readers.ResultsFifty postinfarction nondiabetic HF subjects were enrolled. In 13 patients (26%), the assessment of SPECT studies was impossible. In addition, in 13 of 37 patients who underwent semiquantitative SPECT evaluation, the assessment was equivocal. Altogether, in 26/50 patients (52%, 95% confidence interval 38–65%), the quality of SPECT images was unacceptable or low and was limited by low MIBG cardiac uptake and by comparatively high, interfering MIBG uptake in the neighboring structures (primarily, in the lungs).ConclusionsThe utility of MIBG SPECT imaging, at least with conventional imaging protocols, in the qualification of postinfarction HF patients for ICD, is limited. In approximately half of the postinfarction HF patients, SPECT assessment of cardiac innervation can be impossible or equivocal, even without additional damage from diabetic cardiac neuropathy. The criteria predisposing the patient to good-quality MIBG SPECT are: high values of LVEF from the range characterizing the patients qualified to ICD (i.e., close to 35%) and left lung uptake intensity in planar images comparable to or lower than heart uptake.

Is circulating Gla-rich protein linked with coronary calcium and cardiovascular pathology in patients with atrial fibrillation or heart failure? A pilot study

Introduction: Nowadays Gla-rich protein (GRP) is recognized as a novel biomarker playing a pivotal role in the crosstalk between chronic inflammation and vascular calcification. Aim: The aim of this article is to study the link between circulating GRP, cardiovascular pathology, and the degree of arterial calcification evaluated by the coronary arterial calcium score (CACS) in a Bulgarian population sample. Materials and Methods: Adult participants (n = 81) of both genders were divided into: controls (n = 41)—subjects with estimated moderate-to-high risk without known cardiovascular diseases (CVDs) and a combined CVD group (n = 40)—patients with paroxysmal or persistent atrial fibrillation in sinus rhythm, and heart failure subjects with preserved ejection fraction. A structured interview was carried out for evaluation of the classical CVD risk factors. CACS was determined by multislice computed tomography. Routine laboratory parameters were extracted from medical records. Serum levels of total GRP, matrix Gla protein, and osteocalcin were estimated by commercial ELISA kits. Standard statistical methods (descriptive statistics, Student’s t-test and Spearman’s correlation) were applied. Statistical significance was considered at p&lt;0.05. Results: Significantly lower GRP levels were established in patients with coronary calcium compared to those without calcium deposits. Clear tendency for decreased levels of GRP was observed in the combined CVD group vs controls. Circulating GRP significantly correlates with uncarboxylated matrix Gla protein. An association between serum GRP, CRP, and low-density lipoproteins (LDLs) was demonstrated. Conclusion: This study adds new information regarding the role of circulating GRP as a new player in calcification inhibition. Our findings illuminate the link between total circulating GRP, CVD pathology, and the degree of coronary calcification.

Assessing post-exercise respiratory gas kinetics in clinical sample - a pilot study

Abstract Funding Acknowledgements Type of funding sources: None. Background Cardiopulmonary exercise testing (CPX) is established in the evaluation of patients with cardiac and pulmonary diseases, and its clinical utility seems to be expanding. Currently the most important diagnostic and prognostic ventilatory metrics of CPX rely on the exercise phase. Nevertheless, a consistent body of evidence suggests that important information can be derived from the recovery phase, especially in the first few minutes after exercise. In this context, patients with heart failure (HF) demonstrate a slower recovery of the oxygen consumption (VO2) compared with healthy individuals. Purpose: To comprehensively investigate the behavior of respiratory gases during recovery from CPX in a diverse cohort of HF patients. Methods: All individuals who performed CPX at the department of cardiology of Stanford University Hospital were eligible for the study. Patients were included in the experimental group if they (i) were recorded for five minutes after the exercise phase of CPX and (ii) had documented heart failure. They were excluded if they had other clinical diagnoses which may be responsible for exercise intolerance or symptoms or were unable to give informed consent. Healthy controls were recruited from the local community and were included if they did not have documented or suspected disease. Respiratory gases were collected on a breath-by-breath basis and analysed after applying a 30 second rolling average filter. Metrics were analyzed as absolute values, percentage change from peak and the half-time of recovery (T ½; i.e. the duration until a metric had returned to ½ of its value at peak). Data was analyzed over time within patients and averages between groups using parametric statistical methods. In accordance with previous studies, the amount of change in a metric after exercise is presented as the "magnitude" of overshoot. Results: 32 patients with HF (11 Female, 47 ± 13 yrs) and 30 healthy subjects (14 Female, 43 ± 12 yrs) were included. A comparison of ventilatory metrics during recovery between HF and controls is depicted in Figure 1. Peak VO2 was 1135 ± 419 mL/min (13.5 ± 3.8 mL/Kg/min) vs 2408 ± 787 mL/min (32.5 ± 9.0 mL/Kg/min); P &amp;lt;0.01. A significant difference between patients with HF and healthy subjects was found in T ½ of VO2 (111.3 ± 51.0s vs 58.0 ± 13.2s, p &amp;lt; 0.01) and VCO2 (132.0 ± 38.8s vs 74.3 ± 21.1s, p &amp;lt; 0.01). The magnitude of the overshoot was also found to be significantly reduced in patients with HF for VE/VO2 (41.9 ± 29.1% vs 62.1 ± 17.7%, P &amp;lt; 0.01), RQ (25.0 ± 13.6% vs 38.7 ± 15.1%, p &amp;lt; 0.01) and PETO2 (7.2 ± 3.3% vs 10.1 ± 4.6%, p &amp;lt; 0.01). Finally, the magnitude of the RQ overshoot showed a moderate correlation with peak VO2 (ϱ=0.58, p &amp;lt; 0.01). Conclusions: We observed that ventilatory kinetics measured in early recovery after CPX differ significantly between healthy subjects and patients with HF. The assessment of post exercise respiratory gases in a clinical setting may add to the prognostic and diagnostic value of CPX in heart failure. Abstract Figure.

Dietary Inflammatory Index Is Related to Heart Failure Risk and Cardiac Function: A Case-Control Study in Heart Failure Patients.

Aims: Previous studies suggest that diet and inflammation are important risk factors for heart failure (HF); however, the associations remain unclear. The Dietary Inflammatory Index (DII®) was established to measure the inflammatory capacity of individuals' diet. This study aimed to explore the DII in HF subjects compared with controls.Methods and Results: We conducted a case–control (116 cases and 113 controls) study that recruited in the similar clinics. DII scores were calculated based on dietary intakes. N-Terminal pro-brain natriuretic peptide (NT-proBNP) levels and ejection fraction (EF) were assessed in both groups. In order to analyze DII scores with HF as the outcome, we used conditional logistic regression. A linear regression was applied to explore the associations between the DII and left ventricular EF (LVEF).There was statistically significant difference in DII scores in cases vs. controls (−0.16 ± 1.37 vs. −0.33 ± 1.67; p = 0.040). Conditional logistic regression has shown that subjects with higher DII scores had higher risk of HF. For every one-point rise in DII score, the odds of having HF increased by 30% (OR: 1.30; CI: 1.03, 1.69; p = 0.047). The EF was inversely associated with saturated fatty acid (β = −0.34, 95% CI: −0.61, −0.07; p = 0.012). Subjects with higher DII scores had higher NT-proBNP levels and had lower EF.Conclusion: The DII score was associated with high probability of HF. It appears that consumption of anti-inflammatory diet may lead to the prevention of HF and therefore suggests that dietary modification with the goal of reducing DII scores could be a valuable strategy for improving clinical outcomes in these patients.

Evaluation of phosphodiesterase 9A as a novel biomarker in heart failure with preserved ejection fraction.

AimsMurine models implicate phosphodiesterase 9A (PDE9A) as a nitric oxide‐independent regulator of cyclic guanosine monophosphate and promising novel therapeutic target in heart failure (HF) with preserved ejection fraction (HFpEF). This study describes PDE9A expression in endomyocardial biopsies (EMBs) and peripheral blood mononuclear cells (PBMNCs) from patients with different HF phenotypes.Methods and resultsEndomyocardial biopsies and PBMNCs were obtained from patients with HFpEF (n = 24), HF with reduced ejection fraction (n = 22), and inflammatory cardiomyopathy (n = 24) and patients without HF (n = 7). PDE9A expression was increased in EMBs and PBMNCs from patients with HFpEF as compared with other HF phenotypes or subjects without HF. Endomyocardial PDE9A expression in HFpEF correlated with the inflammatory cell count in EMBs, but not with cardiac fibrosis or left ventricular diastolic wall stress. PDE9A expression in PBMNCs was increased in HFpEF patients with higher high‐sensitivity C‐reactive protein levels and in response to pro‐inflammatory stimulation. As a validation cohort, 719 patients with HFpEF and 1106 subjects without HF were identified from the LIFE‐Heart study. PDE9A expression in PBMNCs was obtained from array data and displayed an age‐dependent distribution. PDE9A levels were elevated and conferred increased risk for HFpEF in middle‐aged subjects, but not in elderly HFpEF patients. Following age adjustment, lower PDE9A expression in PBMNCs was associated with worse survival in patients with HFpEF (log‐rank test P‐value <0.001).ConclusionExpression profiling indicates an up‐regulation of endomyocardial PDE9A in different HF phenotypes with the most robust increase in EMBs and PBMNCs from patients with HFpEF. An exclusive risk effect of PDE9A expression on HFpEF in middle‐aged patients and an unexpected association with survival calls for further studies to better characterize the role of PDE9A as a treatment target.

ASYMPTOMATIC HYPERURICEMIA AS A POTENTIAL METABOLIC RISK FACTOR FOR CORONARY ARTERY CALCIFICATION IN PATIENTS WITH ATRIAL FIBRILLATION OR HEART FAILURE

Purpose: To assess the role of asymptomatic hyperuricemia for the presence and severity of coronary arterial calcium (CAC) in adults with different cardiovascular (CV) pathology and its association with conventional CV risk factors. Material/Methods: Adults (n=81) of both genders were divided into controls: with moderate- to high risk without known CVD; AF-group: CVD-patients with paroxysmal or persistent atrial fibrillation in sinus rhythm, HF–group: heart failure subjects with preserved ejection fraction. A structured interview was performed at admittance for evaluation of the classical CVD risk factors. CAC score (CACS) was determined by multislice computed tomography. Routine laboratory parameters, including uric acid (UA), were extracted from medical documentation. Descriptive statistics, Mann-Whitney U-test, one-way ANOVA, chi-square test, Spearman's correlation, and multiple linear regression analysis were applied. The predictive power of serum UA was evaluated using receiver operating characteristic (ROC) analysis. Statistical significance was considered at p&lt;0.05. Results: Serum UA was significantly higher in subjects with CACS=1-99AU (p=0.030), and with CACS≥100AU (p=0.067) vs. patients without CACS. Within the UA tertiles, highest CACS was found in the tertile with highest serum UA. UA revealed positive relation with CACS (r=0.35, p=0.002), age (r=0.25, p=0.027), body mass index (0.27, p=0.017), waist circumference (r=0.44, p&lt;0.0001), triglycerides (r=0.29, p=0.001), and creatinine (r=0.54, p&lt;0.0001). Multiple linear regression analysis revealed significant association between UA as dependent variable and waist circumference (β=0.63, p=0.061), serum triglycerides (β=0.37, p=0.028), creatinine levels (β=0.45, p&lt;0.0001). Conclusions: Asymptomatic hyperuricaemia could be an important metabolic factor negatively affecting the chronic cardio-vascular pathology besides the conventional risk factors.

Right Ventricular Response to Exercise in LVAD-Supported Patients vs. Heart Failure and Normal Subjects

<h3>Purpose</h3> Knowledge of right ventricular (RV) responses to exercise in LVAD-supported patients is limited. RV reserve might be impaired in LVAD patients. We sought to determine RV reserve during exercise in LVAD patients vs. HF and control subjects. <h3>Methods</h3> In 2016-20, 25 LVAD patients underwent upright ergometer CPET with first-pass radionuclide imaging (n=20), with (n=13) or without (n=12) invasive hemodynamic monitoring. LVAD patients were compared to HFrEF (EF < 40%, n=31), HFpEF (EF ≥ 50%, rest mean PAP ≥ 25, PAWP ≥ 15 mmHg, n=54) and normal subjects (EF ≥ 50%, rest mean PAP ≤ 20, PAWP < 15 mmHg, n=41). Values are expressed as median (25^th-75^th interquartile range). P < 0.05 was considered significant comparison across all groups. <h3>Results</h3> Median RVEF was 41% (LVAD), 40% (HFrEF), 47% (HFpEF), 51% (normal) (p<0.01). On exercise, normal subjects augmented RVEF but LVAD and HF groups did not. Peak VO₂ was 11 (LVAD), 11.9 (HFrEF), 14.2 (HFpEF), 22.7 mL/kg/min (normal) (p<0.01). Peak filling pressures were similar in LVAD and normal subjects. Peak cardiac output (CO) was 9.9 (LVAD), 7.1 (HFrEF), 9.9 (HFpEF), 13.9 L/min (normal) (p<0.01). MeanPAP/CO slope was highest in HFrEF (5.8 mmHg/L/min [3.2-7]), intermediate in LVAD (2.6 [2-4.9]) and HFpEF (3.7 [2.7-4.8]), and lowest in normal (1.8 [1.4-2.1]) (p<0.01). Peak PVR was highest in HFrEF (2.1 Wood units [1.7-3.2], intermediate in LVAD (1.4 [1-1.8]) and HFpEF (1.5 [1.1-2]), and lowest in normal (1 [0.7-1.3]) (p<0.01). Peak RV stroke work index (RVSWI) was lowest in LVAD (0.7 mmHg.L/m² [0.5-0.9]) vs. normal (1.1 [1-1.3]), HFrEF (1.2 [1.1-1.4]) and HFpEF (1.2 [1-1.6]) (p<0.01). Peak RAP/PAWP ratio was highest in LVAD (0.6 [0.5-0.9]) vs. normal (0.5 [0.4-0.6]), HFrEF (0.4 [0.3-0.5]) and HFpEF (0.4 [0.3-0.6]) (p=0.02) (Fig. 1). <h3>Conclusion</h3> At peak upright exercise, LVAD patients had poorer RV reserve than HF and normal subjects (lower RVSWI, higher RAP/PAWP ratio). Research aimed at RV optimization is needed to improve exercise tolerance in LVAD patients.