Cardiac Wall Stress Research Articles

Sacubitril/valsartan and cardiovascular biomarkers among patients with recent COVID-19 infection: The PARACOR-19 randomized clinical trial.

The PARACOR-19 randomized controlled trial (RCT) was designed to examine the effects of sacubitril/valsartan on markers of cardiac injury, inflammation, structure, and function among patients who have recovered from acute coronavirus disease 2019 (COVID-19) infection. PARACOR-19 was a single-centre, double-blind RCT of patients with cardiovascular risk factors and a history of COVID-19 infection 4-16 weeks prior to enrolment. Patients were randomized to sacubitril/valsartan (titrated to the maximum dose of 97/103 mg twice daily) versus matching placebo. Co-primary endpoints were change from baseline to 12 weeks in high-sensitivity cardiac troponin T (hs-cTnT) and soluble ST2 (sST2). Exploratory endpoints included change from baseline to 12 weeks in additional circulating biomarkers. Overall, 42 patients were randomized between August 2021 and March 2023 (n = 20 sacubitril/valsartan, n = 22 placebo). Median (25th-75th) time from COVID-19 diagnosis to enrolment was 67 (48-80) days. Median age was 67 (62-71) years, 48% were female, and 91% were White. Compared with placebo, sacubitril/valsartan did not have a significant effect on the co-primary endpoints of change from baseline in hs-TnT and sST2 (all p ≥ 0.29). In exploratory analyses, sacubitril/valsartan led to a 46% greater reduction in N-terminal pro-B-type natriuretic peptide (NT-proBNP) and 51% greater reduction in C-terminal telopeptide of collagen type I (CITP). Permanent drug discontinuation occurred in four patients in the sacubitril/valsartan group and three patients in the placebo group. There were no deaths and one patient was hospitalized in each group. In this pilot RCT of patients who recovered from acute COVID-19, sacubitril/valsartan did not lower hs-cTnT or sST2 compared with placebo. Exploratory analyses suggested potential benefits of sacubitril/valsartan on cardiac wall stress and collagen turnover as measured by NT-proBNP and CITP. Sacubitril/valsartan was well tolerated. ClinicalTrials.gov NCT04883528.

Progresses and perspectives on natural polysaccharide based hydrogels for repair of infarcted myocardium

Myocardial infarction (MI) is serious health threat and impairs the quality of life. It is a major causative factor of morbidity and mortality. MI leads to the necrosis of cardio-myocytes, cardiac remodelling and dysfunction, eventually leading to heart failure. The limitations of conventional therapeutic and surgical interventions and lack of heart donors have necessitated the evolution of alternate treatment approaches for MI. Polysaccharide hydrogel based repair of infarcted myocardium have surfaced as viable option for MI treatment. Polysaccharide hydrogels may be injectable hydrogels or cardiac patches. Injectable hydrogels can in situ deliver cells and bio-actives, facilitating in situ cardiac regeneration and repair. Polysaccharide hydrogel cardiac patches reduce cardiac wall stress, and inhibit ventricular expansion and promote angiogenesis. Herein, we discuss about MI pathophysiology and myocardial microenvironment and how polysaccharide hydrogels are designed to mimic and support the microenvironment for cardiac repair. We also put forward the versatility of the different polysaccharide hydrogels in mimicking diverse cardiac properties, and acting as a medium for delivery of cells, and therapeutics for promoting angiogenesis and cardiac repair. The objectives of this review is to summarize the factors leading to MI and to put forward how polysaccharide based hydrogels promote cardiac repair. This review is written to enable researchers understand the factors promoting MI so that they can undertake and design novel hydrogels for cardiac regeneration.

Quantification of ventricular stress in univentricular hearts during early childhood using age-independent zlog-NT-proBNP

BackgroundChildren with univentricular hearts (UVH) undergo up to three palliative surgical procedures to achieve complete circulatory separation (Fontan circulation). As a marker of cardiac wall stress, NT-proBNP is a promising tool to assess systemic ventricular load in these patients. However, different reference intervals (RI) apply to each stage, as NT-proBNP is highly age-dependent. MethodsChildren undergoing systemic-to-pulmonary (SP) shunt placement (stage 1), bidirectional cavopulmonary shunt (BCPS, stage 2) or total cavopulmonary connection (TCPC, stage 3) between 2011 and 2021 with NT-proBNP measurement within 7 days before surgery were included. Furthermore, outpatients after TCPC with NT-proBNP measurement were enrolled. Biomarker levels were evaluated using its age-adjusted z-score (“zlog-NT-proBNP”; age-independent RI, −1.96 to +1.96), allowing comparison between different stages and revealing changes in systemic ventricular load independent of the marked physiological decline in RI with age. ResultsOverall, 289 children (227 before, 62 after TCPC) met the eligibility criteria. Median time between blood sampling and surgery (SP shunt/BCPS/TCPC) was 2 [1–3] days and 3.2 [2.0–4.5] years after TCPC. Age-adjusted zlog-NT-proBNP levels were 3.47 [2.79–3.93] in children with native UVH (before SP shunt), 3.10 [1.89–3.58] at stage 1 (before BCPS), 1.08 [0.51–1.88] at stage 2 (before TCPC), and 1.09 [0.72–1.75] at stage 3 (after TCPC/Fontan completion). Consequently, BCPS revealed the strongest decrease (median − 2.02 logarithmized standard deviations, p < 0.001). ConclusionsIn children with UVH undergoing staged Fontan palliation, zlog-NT-proBNP is a highly promising tool for course assessment of systemic ventricular load, independent of the age-related decline in physiological NT-proBNP concentration.

Sendaway capillary NT-proBNP in pulmonary hypertension

BackgroundN-terminal pro-B-type natriuretic peptide (NT-proBNP) is a biomarker of cardiac ventricular wall stress that is incorporated into pulmonary hypertension (PH) risk stratification models. Sendaway sampling may enable patients to perform...

Biomechanical response of ultrathin slices of hypertrophic cardiomyopathy tissue to myosin modulator mavacamten

Hypertrophic cardiomyopathy (HCM) is the most common inherited myocardial disorder of the heart, but effective treatment options remain limited. Mavacamten, a direct myosin modulator, has been presented as novel pharmacological therapy for HCM. The aim of this study was to analyze the biomechanical response of HCM tissue to Mavacamten using living myocardial slices (LMS). LMS (n = 58) from patients with HCM (n = 10) were cultured under electromechanical stimulation, and Verapamil and Mavacamten were administered on consecutive days to evaluate their effects on cardiac biomechanics. Mavacamten and Verapamil reduced contractile force and dF/dt and increased time-to-relaxation in a similar manner. Yet, the time-to-peak of the cardiac contraction was prolonged after administration of Mavacamten (221.0 ms (208.8 – 236.3) vs. 237.7 (221.0 – 254.7), p = 0.004). In addition, Mavacamten prolonged the functional refractory period (FRP) (330 ms (304 − 351) vs. 355 ms (313 − 370), p = 0.023) and better preserved twitch force with increasing stimulation frequencies, compared to Verapamil. As such, Mavacamten reduced (hyper-)contractility and prolonged contraction duration of HCM LMS, suggesting a reduction in cardiac wall stress. Also, Mavacamten might protect against the development of ventricular tachyarrhythmias due to prolongation of the FRP, and improve toleration of tachycardia due to better preservation of twitch force at tachycardiac stimulation frequencies.

Is COPD the Determinant Factor for Myocardial Injury and Cardiac Wall Stress in OSA Patients?

Background and Objectives: Evidence shows that COPD-OSA overlap syndrome (OS) is more frequently accompanied by cardiovascular disease (CVD) in comparison to either disease alone. The aim of the study was to explore whether patients with OS have a higher burden of subclinical myocardial injury and wall stress compared with OSA patients. Materials and Methods: Consecutive patients, without established CVD, underwent polysomnography and pulmonary function testing, due to suspected sleep-disordered breathing. An equal number of patients with OS (n = 53, with an apnea hypopnea index (AHI) > 5/h and FEV1/FVC < 0.7) and patients with OSA (n = 53, AHI > 5/h and FEV1/FVC > 0.7) were included in the study. The detection of asymptomatic myocardial injury and wall stress was performed via the assessment of serum high-sensitivity cardiac troponin T (hs-cTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP), respectively. Results: OS patients were older (p < 0.001) and had worse hypoxemic parameters, namely average oxyhemoglobin saturation (SpO2) (p = 0.002) and time spent with SpO2 < 90% (p = 0.003) during sleep as well as daytime pO2 (p < 0.001), than patients with OSA. No difference was observed between groups in terms of Epworth Sleepiness Scale (p = 0.432) and AHI (p = 0.587). Both levels of hs-cTnT (14.2 (9.1-20.2) vs. 6.5 (5.6-8.7) pg/mL, p < 0.001) and NT-proBNP (93.1 (37.9-182.5) vs. 19.2 (8.3-35.4) pg/mL, p < 0.001) were increased in OS compared to OSA patients. Upon multivariate linear regression analysis, levels of NT-proBNP and hs-cTnT correlated with age and average SpO2 during sleep. Conclusions: Our study demonstrated higher levels of hs-cTnT and NT-proBNP in OS patients, indicating an increased probability of subclinical myocardial injury and wall stress, compared with OSA individuals.

A remote monitoring-enabled home exercise prescription for patients with interstitial lung disease at risk for exercise-induced desaturation

RationaleAlternatives to center-based pulmonary rehabilitation are needed to improve patient access to this important therapy. A critical challenge to overcome is how to maximize safety of unsupervised exercise for at-risk patients. We investigated if a novel remote monitoring-enabled mobile health (mHealth) program is safe, feasible, and effective for patients who experience exercise-induced hemoglobin desaturation. MethodsAn interstitial lung disease (ILD) commonly associated with pronounced exercise desaturation was investigated - the rare, female-predominant ILD lymphangioleiomyomatosis (LAM). Over a 12-week program, hemoglobin saturation (SpO2) was continuously recorded during all home exercise sessions. Intervention effects were assessed with 6-min walk test (6MWT), maximal cardiopulmonary exercise test (CPET), lower extremity computerized dynamometry, pulmonary function tests, and health-related quality of life (QoL) surveys. Safety was assessed by blood biomarkers of systemic inflammation and cardiac wall stress, and incidence of adverse events. ResultsFifteen LAM patients enrolled and 14 completed the intervention, with high adherence to aerobic (87 ± 15%) and strength (87 ± 12%) training components. An innovative characterization of exercise training SpO2 revealed that while mild-to-moderate desaturation was common during home workouts, participants were able to self-adjust exercise intensity and supplemental oxygen levels to maintain recommended exercise parameters. Significant improvements included 6MWT distance (+36 ± 34 m, p = 0.003), CPET time (p = 0.04), muscular endurance (p = 0.008), QoL (p = 0.009 to 0.03), and fatigue (p = 0.001 to 0.03). Patient acceptability and satisfaction indicators were high, blood biomarkers remained stable (p > 0.05), and no study-related adverse events occurred. ConclusionA remote monitoring-enabled home exercise program is a safe, feasible, and effective approach even for patients who experience exercise desaturation.

Circulating Gal-3 and sST2 are associated with acute exercise-induced sustained endothelial activation: Possible relevance for fibrosis development?

Long-term, intense endurance exercise training can occasionally induce endothelial micro-damage and cardiac fibrosis. The underlying mechanisms are incompletely understood. Twenty healthy, well-trained male participants (10runners and 10cyclists) performed a strenuous high-intensity interval training (HIIT) session matched by age, height, weight and maximal oxygen consumption. We assessed the acute exercise response of novel cardiac biomarkers of fibrosis [e.g., galectin-3 (Gal-3) and soluble suppression of tumorigenicity 2 (sST2)] per exercise modality and their relationship with haemodynamic contributors, such as preload, afterload and cardiac contractility index (CTi), in addition to endothelial damage by sustained activation and shedding of endothelial cells (ECs). Serum Gal-3 and sST2 concentrations were investigated by enzyme-linked immunosorbent assays; haemodynamics were analysed via impedance plethysmography and circulating ECs by flow cytometry. The Gal-3 and sST2 concentrations and ECs were elevated after exercise (P<0.001), without interaction between exercise modalities. Circulating Gal-3 and sST2 concentrations both showed a positive relationship with ECs (rrm =0.68, P=0.001 and rrm =0.57, P=0.010, respectively, both n=18). The EC association with Gal-3 was significant only in cyclists, but equally strong for both modalities. Gal-3 was also related to exercise-induced CTi (rrm =0.57, P=0.011, n=18). Cardiac wall stress is increased after an acute HIIT session but does not differ between exercise modalities. Exercise-released Gal-3 from cardiac macrophages could very probably drive systemic endothelial damage, based on an enhanced CTi. The importance of acute exercise-induced vascular resistances and cardiac contractility for the release of fibrotic biomarkers and any long-term pathological endothelial adaptation should be investigated further, also relative to the exercise modality. NEW FINDINGS: What is the central question of this study? Circulating biomarkers of cardiac wall stress and fibrosis are influenced by physical exercise. The underlying mechanisms per exercise modality are still unclear. What is the main finding and its importance? We show that galectin-3 (Gal-3) and soluble suppression of tumorigenicity 2 (sST2) are increased after acute exercise but do not differ between running and cycling. One haemodynamic contributor to the secretion of Gal-3 is an enhanced cardiac contractility. Acute exercise-released Gal-3 and sST2 are linked to sustained endothelial activation and cell shedding. This could be relevant in the context of fibrosis development and could identify athletes at risk for pathological endothelial adaptations.

Associations between diet quality and NT-proBNP in U.S. adults, NHANES 1999-2004

ObjectiveN-terminal pro-brain-type natriuretic peptide (NT-proBNP) is a marker of cardiac wall stress and is a predictor of cardiovascular disease. Higher diet quality is associated with lower risk of cardiovascular disease. The association between diet quality and subclinical cardiovascular disease assessed by NT-proBNP is uncharacterized. We investigated the associations between diet quality, using Healthy Eating Index-2015 (HEI-2015), and NT-proBNP from the National Health and Nutrition Examination Survey (NHANES) 1999-2004. MethodsWe included 9,782 adults from NHANES 1999-2004 without self-reported cardiovascular disease. The HEI-2015 ranges from 0 to 100, with higher scores indicating better diet quality. The HEI-2015 was categorized into sex-specific quintiles. Regression models were used to quantify associations between the overall HEI-2015 score and its 13 components with log-transformed NT-proBNP. The beta coefficients were converted to percent differences. ResultsAmong 9,782 participants, mean age was 45 years, 48% were men, and 72% were non-Hispanic White adults. After adjusting for sociodemographic characteristics, lifestyle factors, and medical history, those in the highest vs. lowest HEI-2015 quintile had an 8.5% (95% CI: -14.6% to -2.0%) lower NT-proBNP level. There was a dose-response association between HEI-2015 and NT-proBNP (P value for trend = 0.01). Each 1-unit higher in sodium and added sugars score indicating lower intake was associated with lower NT-proBNP by 7.7% (95% CI: -12.8% to -2.2%) and 6.5% (95% CI: -12.0% to -0.7%), respectively. ConclusionHigher diet quality, especially lower intakes of sodium and added sugars, was associated with lower serum levels of NT-proBNP.

Abstract MP29: High-Sensitivity Troponin-T is Associated With Incident Diabetic Foot Infections in the Atherosclerosis Risk in Communities Study

Background: Diabetic foot infections (DFI) are associated with substantial morbidity and mortality. Glycemic control and prevalent cardiovascular disease have been associated with DFI risk, but the association of subclinical cardiovascular disease with incident DFI has not been explored. Hypothesis: We hypothesized that high-sensitivity troponin-T (hs-cTnT, a marker of microvascular disease) and N-terminal-pro hormone BNP (NT-proBNP, a marker of cardiac wall stress) would be associated with incident DFI in adults without prevalent cardiovascular disease. Methods: We conducted a prospective cohort analysis of 1733 Black and White participants in the Atherosclerosis Risk in Communities (ARIC) study who had diabetes without prevalent cardiovascular disease at visit 2 (1990-1992, mean age 57.7 yrs). We estimated the cumulative incidence of incident DFI through 2019 using hospitalization discharge codes. We used Cox models to assess the associations of categories of cardiac biomarkers (using clinical cut-points) with DFI after adjusting for traditional risk factors. Results: During a median follow-up of 25 years, there were 417 incident DFI events. The 25-year cumulative incidence of DFI was higher among participants with elevated hs-cTnT (≥14 ng/L) vs not elevated (35% vs. 21%; P&lt;0.001), but not among participants with elevated NT-proBNP (≥125 pg/mL) (23% vs. 23%; P=0.73). In adjusted models, elevated hs-cTnT was associated with incident DFI (HR 1.98, 95%CI 1.46, 2.68). Elevated NT-proBNP was not significantly associated with incident DFI (HR 1.04, 95%CI 0.78, 1.41). Our results were similar when the biomarkers were modeled more flexibly using splines: we observed a robust association of hs-cTnT, but not NT-proBNP, with incident DFI ( Figure ). Conclusions: Elevated hs-cTnT was associated with incident DFI among middle-aged adults without prevalent cardiovascular disease. This suggests subclinical cardiovascular disease, possibly in the form of microvascular ischemia, may play a role in the etiology of DFI.

A honeybee stinger-inspired self-interlocking microneedle patch and its application in myocardial infarction treatment

Weak tissue adhesion remains a major challenge in clinical translation of microneedle patches. Mimicking the structural features of honeybee stingers, stiff polymeric microneedles with unidirectionally backward-facing barbs were fabricated and embedded into various elastomer films to produce self-interlocking microneedle patches. The spirality of the barbing pattern was adjusted to increase interlocking efficiency. In addition, the micro-bleeding caused by microneedle puncturing adhered the porous surface of the patch substrate to the target tissue via coagulation. In the demonstrative application of myocardial infarction treatment, the bioinspired microneedle patches firmly fixed on challenging beating hearts, significantly reduced cardiac wall stress and strain in the infarct, and maintained left ventricular function and morphology. In addition, the microneedle patch was minimally invasively implanted onto beating porcine heart in 10 minutes, free of sutures and adhesives. Therefore, the honeybee stinger-inspired microneedles could provide an adaptive and convenient means to implant patches for various medical applications. Statement of significanceAdhesion between tissue and microneedle patches with smooth microneedles is usually weak. We introduce a novel barbing method of fabricating unidirectionally backward facing barbs with controllable spirality on the microneedles on microneedle patches. The microneedle patches self-interlock on mechanically dynamic beating hearts, similar to honeybee stingers. The micro-bleeding and coagulation on the porous surface provide additional adhesion force. The microneedle patches attenuate left ventricular remodeling via mechanical support and are compatible with minimally invasive implantation.

Uncoupling between intravascular and distending pressures leads to underestimation of circulatory congestion in obesity.

Patients with obesity frequently present with dyspnoea. Biomarkers that reflect wall stress are often used to evaluate circulatory congestion and help determine whether dyspnoea is of cardiac causes. Patients with obesity display greater external restraint on the heart, which may alter relationships between intravascular pressures and stress markers. Subjects with unexplained dyspnoea (n= 212) underwent cardiac catheterization with simultaneous echocardiography. Blood sampling was performed in a subset (n= 58). Relationships between echocardiographic and blood biomarkers of circulatory congestion and directly-measured haemodynamics were compared between participants with severe obesity [body mass index (BMI) ≥35 kg/m2 , Group B) and those without (BMI <35 kg/m2 , Group A). Circulatory congestion was assessed by pulmonary capillary wedge pressure (PCWP), and vascular distending pressure was assessed by left ventricular transmural pressure (LVTMP). As compared to Group A, participants in Group B displayed higher PCWP relative to N-terminal pro-B-type natriuretic peptide, mid-regional pro-atrial natriuretic peptide, troponin T, and growth differentiation factor-15 (all p< 0.01). In contrast, the relationships between LVTMP and the biomarkers were superimposable. Echocardiographic biomarkers revealed the same pattern: PCWP was higher for any E/e' ratio in Group B compared to Group A, but the relationship between LVTMP and E/e' was similar. In contrast, levels of C-terminal pro-endothelin-1 and mid-regional pro-adrenomedullin were more robustly correlated with PCWP (r=0.67 and r=0.62, both p< 0.0001), with no differential relationship based upon BMI. Non-invasive haemodynamic markers underestimate circulatory congestion in patients with obesity, an effect that appears related to uncoupling between cardiac wall stress and intravascular pressures. This may lead to systematic under-recognition of congestion in patients with obesity.

Cardiac Biomarkers Following Marathon Running: Is Running Time a Factor for Biomarker Change?

Plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) and cardiac troponin T levels show a transient increase after marathon running. The aim of this study was to investigate whether running duration influences the patterns of changes in cardiac biomarkers. Twenty participants with fast and slow finishing times were included in the study. Blood samples were taken before the marathon race, immediately after, and 24 hours after the race. Samples were analyzed for NT-proBNP and cardiac troponin T concentration. Furthermore, a complete blood cell count was performed. After the marathon race, the fast and slow runners showed similar changes of NT-proBNP and cardiac troponin T (ie,a transient increase). Curve estimation regression analysis showed a curvilinear relationship (quadratic model) between running times and NT-proBNP increments immediately after the race, with less of an increase in the very fast and the very slow runners (r2 = .359, P = .023). NT-proBNP increments immediately after the race were correlated to the decline 24hours after the marathon (r = -.612, P = .004). This study indicates that NT-proBNP release immediately after marathon running varies in a curvilinear fashion with running time. It is speculated that low NT-proBNP release is associated with training adaptation in most elite runners and the relatively low cardiac stress in the slowest (but experienced) runners. The combination of less adaptation and relatively large cardiac wall and metabolic stress may explain the highest NT-proBNP values in runners with average running times. In addition, NT-proBNP decrements 24 hours after the race depend primarily on the values reached after the marathon and not on running time.

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.

4-Methylumbelliferone Attenuates Macrophage Invasion and Myocardial Remodeling in Pressure-Overloaded Mouse Hearts.

[Figure: see text].

Unexpectedly Low Natriuretic Peptide Levels in Patients With Heart Failure

ObjectivesThe purpose of this study was to determine the frequency of unexpectedly low natriuretic peptide (NP) levels in a clinical population. BackgroundHigher NP concentrations are typically observed as a compensatory response to elevated cardiac wall stress. Under these conditions, low NP levels may be indicative of a “NP deficiency.” MethodsWe identified 3 clinical scenarios in which high B-type natriuretic peptide (BNP) levels would be expected: 1) hospitalization for heart failure (HF); 2) abnormal cardiac structure or function; or 3) abnormal hemodynamics. In Vanderbilt’s electronic health record, 47,970 adult patients had BNP measurements. A total of 13,613 patients had at least 1 of the 3 conditions (hospitalized HF, n = 9,153; abnormal cardiac structure/function, n = 7,041; abnormal hemodynamics, n = 363). We quantified the frequency of low BNP levels. We performed whole exome sequencing of the NPPB gene in a subset of 9 patients. ResultsVery low BNP levels (<50 pg/ml) were observed in 4.9%, 14.0%, and 16.3% of patients with hospitalized HF, abnormal cardiac structure/function, or abnormal hemodynamics, respectively. A small proportion (0.1% to 1.1%) in each group had BNP levels below detection limits. Higher body mass index was the strongest predictor of unexpectedly low BNP. Exome sequencing did not reveal coding variation predicted to alter detection of BNP by clinical assays. ConclusionsA subset of patients with confirmed HF or cardiac dysfunction have unexpectedly low BNP levels. Obesity is the strongest correlate of unexpectedly low BNP levels. Our findings support the possible existence of NP deficiency, which may render some individuals more susceptible to volume or pressure overload.

Mechanical difference of left ventricle between rabbits of myocardial infarction and hypertrophy

The analysis of cardiac wall stress is of importance to understand the development of heart failure (HF). The aim of the study is to carry out the cardiac mechanics analysis to show the changes of left ventricular (LV) wall stresses after LV hypertrophy (LVH) and myocardial infarction (MI). Here, LVH and MI were generated in rabbit hearts through the transverse aortic constriction (TAC) and the distal left circumflex (LCx) artery ligation operations, respectively. Physiological and CT measurements were carried out at postoperative 2 and 4 weeks, based on which a finite element (FE) model was developed to perform the mechanics computation. We found a gradual increase of end-diastolic myofiber stress in free wall and interventricular septum of LVH and MI (higher stress in the free wall than the septum). In the interventricular septum, the 4-weeks LVH group has the highest ED myofiber stresses (11.378 ± 3.022 kPa), while the 4-weeks MI group has the highest ED myofiber stresses (13.494 ± 2.835 kPa) in the free wall. LVH increased myocardial volume (3.49 ± 0.07 and 4.52 ± 0.26 ml at postoperative 2 and 4 weeks) while MI increased LV volume (from 2.75 ± 0.29 to 4.19 ± 0.27 ml). LVH and MI had different distributions of local myofiber stress.

NT-proBNP Response to Sacubitril/Valsartan in Hospitalized Heart Failure Patients With Reduced Ejection Fraction: TRANSITION Study

ObjectivesThis study examined the effects of sacubitril/valsartan on N-terminal pro–B-type natriuretic peptide (NT-proBNP) levels and determined patient characteristics associated with favorable NT-proBNP reduction response. BackgroundNT-proBNP levels reflect cardiac wall stress and predict event risk in patients with acute decompensated heart failure (ADHF). MethodsPost-hoc analysis of the TRANSITION (Comparison of Pre- and Post-discharge Initiation of Sacubitril/Valsartan Therapy in HFrEF Patients After an Acute Decompensation Event) study, including stabilized ADHF patients with reduced ejection fraction, randomized to open-label sacubitril/valsartan initiation in-hospital (pre-discharge) versus post-discharge. NT-proBNP was measured at randomization (baseline), discharge, and 4 and 10 weeks post-randomization. A favorable NT-proBNP response was defined as reduction to ≤1,000 pg/ml or >30% from baseline. ResultsIn patients receiving sacubitril/valsartan in-hospital, NT-proBNP was reduced by 28% at discharge, with 46% of patients obtaining favorable NT-proBNP reduction response compared with a 4% reduction and 18% favorable response rate in patients initiated post-discharge (p < 0.001). NT-proBNP was reduced similarly in patients initiating sacubitril/valsartan pre- and post-discharge (reduction at 4 weeks: 25%/22%; 10 weeks: 38%/34%) with comparable favorable response rates (46%/42% and 51%/48% at 4 and 10 weeks, respectively). NT-proBNP favorable response at 4 weeks was associated with lower risk of first heart failure (HF) rehospitalization or cardiovascular death through 26 weeks (hazard ratio: 0.57; 95% confidence interval [CI]: 0.38 to 0.86; p = 0.007). Predictors of a favorable response at 4 weeks were starting dose ≥49/51 mg twice daily, higher baseline NT-proBNP, lower baseline serum creatinine, de novo HF, no atrial fibrillation, angiotensin-converting enzyme inhibitor–naive or angiotensin receptor blocker–naive, and no prior myocardial infarction. ConclusionsIn-hospital initiation of sacubitril/valsartan produced rapid reductions in NT-proBNP, statistically significant at discharge. A favorable NT-proBNP response over time was associated with a better prognosis and predicted by higher starting dose and predisposing clinical profile. (Comparison of Pre- and Post-discharge Initiation of LCZ696 Therapy in HFrEF Patients After an Acute Decompensation Event [TRANSITION]; NCT02661217)

P1263ASSOCIATION OF LEFT VENTRICULAR HYPERTROPHY AND ADIPOCYTOKINES IN PATIENTS ON DIALYSIS

Abstract Background and Aims Cardiovascular (CV) disease events are the major cause of death in end-stage renal disease (ESRD) patients on dialysis. Left ventricular hypertrophy, myocardial stress and disturbances in nutritional status are common findings in ESRD patients on dialysis. The adipokines, adiponectin and leptin, are known as important mediators of cardiometabolic risk in obesity, although their role in ESRD patients is poorly clarified. N-terminal pro B-type natriuretic peptide (NT-proBNP) is synthesized within cardiac myocytes, in response to cardiac wall stress. Our aim was to study the association of left ventricular hypertrophy with adipokines (adiponectin and leptin), myocardial stress (ProBNP) and nutritional status (BMI and albumin) in ESRD patients on dialysis. Method This study included 196 ESRD patients on dialysis (hemodiafiltration and high-flux hemodialysis). LVH was defined by a value of LVMI &amp;gt; 115 g/m2 in men and 95 g/m2 in women. Patients were divided into two groups - LVH (n=131) and non-LVH (n=65). Left ventricular mass (LVM) was evaluated through echocardiographic studies, corrected for body surface area and the values are presented as LVM index (LVMI). LVMI, clinical and analytical variables (age, body mass index, dialysis vintage, dialysis adequacy, albumin, adiponectin, leptin, NT-proBNP and hemoglobin concentration) were evaluated. Results The prevalence of LVH was 66.8%; LVH patients presented significantly higher levels for NT-proBNP, and significantly lower levels for hemoglobin, when compared with non-LVH patients; a trend towards (P=0.052) lower leptin values were observed. No differences were observed between groups, for age, BMI, dialysis vintage, URR, Kt/V, eKt/V, ultrafiltration volume, albumin and adiponectin. In LVH patients, we found that LVMI presented significant positive correlations with NT-proBNP and with adiponectin; and, significant negative correlations with markers of dialysis adequacy (URR and eKt/V) and leptin. Conclusion Our data suggest that a higher LVMI in ESRD patients is associated with higher myocardial stress, with lower leptin and higher adiponectin levels, showing no association of these adipokines with increased cardiovascular risk and with worsening of left ventricular hypertrophy. Further studies are needed to understand the roles of these adipokines, considering the controversial association with left ventricular hypertrophy, a cardiovascular risk condition. Acknowledgments: The work was supported by UIDB/04378/2020 with funding from FCT/MCTES through national funds, by North Portugal Regional Coordination and Development Commission (CCDR-N)/NORTE2020/Portugal 2020 (Norte-01-0145-FEDER-000024) and by REQUIMTE-Rede de Química e Tecnologia-Associação in the form of a researcher (S. Rocha) – project Dial4Life co-financed by FCT/MCTES (PTDC/MEC-CAR/31322/2017) and FEDER/COMPETE 2020 (POCI-01-0145-FEDER-031322).

Intraventricular 4D blood flow: adding a fourth dimension to cardiovascular functional analysis by magnetic resonance imaging

Introduction Echocardiography is a standard tool for evaluating the cardiac chambers, valves and great vessels. Recent data shows techniques such as strain analysis display subtle contractile deficits long before ejection fraction (EF) drops, and this has already been linked to poor outcome. 4D colour doppler is a recent technical advancement, however its temporal resolution remains limited so far. Cardiovascular magnetic resonance (CMR) offers similar assessment of myocardial function, vessels and valves, but beyond that also offers unmatched tissue characterization (fibrosis, scar, edema, oxygenation, metabolics). A novel development in this field is 4D flow CMR, which allows for visualization and quantification of multiple parameters like blood flow velocity, direction, pattern, wall shear stress and kinetic energy deposition. Cardiac diseases in early stages may not yet feature a reduced EF but may already display abnormal 4D flow patterns, which may reduce cardiac index and increase ventricular wall stress. In this study we applied CMR-based 4D intraventricular blood flow assessment in participants with normal left ventricular (LV) systolic function. Methods Using a 3T clinical MRI, seven participants underwent a non-contrast exam (one healthy control under 35 years, five controls older than 50 years, one patient with heart failure and preserved EF (HFpEF)). A 4D block of the thoracic cavity was acquired and blood flow patterns in the left ventricle were assessed for direct flow (blood that enters and leaves the ventricle during one heartbeat), residual volume (blood that remains in the LV cavity for at least 2 heartbeats), along with delayed ejection and retained flow (figure). Furthermore, ventricular function and strain by feature tracking were measured. Results While participants had an LVEF of 65±3% and a cardiac index of greater than 3.1±0.4 L/min/m2, there was marked variation in intraventricular 4D blood flow patterns (figure). The patient with heart failure had the largest residual volume and lowest direct flow, whereas the young healthy control had the highest direct flow and lowest residual volume. Residual volume in the older controls ranged in between these two points. Furthermore, a larger direct flow was correlated with greater longitudinal strain (r = -0.886, p = 0.033), while there was a trend of larger residual volume to be associated with poorer global longitudinal strain (r = 0.829, p = 0.058). Discussion In a small cohort, CMR-derived patterns of intraventricular 4D blood flow and ventricular wall strain are associated despite quantitatively normal LVEF. Although acquisition, processing and quantification in 4D flow CMR are still time-consuming, the quantification of 4D blood flow in cardiac chambers and great vessels has the potential to offer a comprehensive evaluation of cardiovascular haemodynamics under normal and pathological conditions. Larger studies are required.