Increased Wall Stress Research Articles

Oxidative stress initiates hemodynamic change in CKD-induced heart disease.

Chronic kidney disease (CKD) predisposes to cardiac remodeling and coronary microvascular dysfunction. Studies in swine identified changes in microvascular structure and function, as well as changes in mitochondrial structure and oxidative stress. However, CKD was combined with metabolic derangement, thereby obscuring the contribution of CKD alone. Therefore, we studied the impact of CKD on the heart and combined proteome studies with measurement of cardiac function and perfusion to identify processes involved in cardiac remodeling in CKD. CKD was induced in swine at 10-12weeks of age while sham-operated swine served as controls. 5-6months later, left ventricular (LV) function and coronary flow reserve were measured. LC-MS-MS-based proteomic analysis of LV tissue was performed. LV myocardium and kidneys were histologically examined for interstitial fibrosis and oxidative stress. Renal embolization resulted in mild chronic kidney injury (increased fibrosis and urinary NGAL). PV loops showed LV dilation and increased wall stress, while preload recruitable stroke work was impaired in CKD. Quantitative proteomic analysis of LV myocardium and STRING pre-ranked functional analysis showed enrichments in pathways related to contractile function, reactive oxygen species, and extracellular matrix (ECM) remodeling, which were confirmed histologically and associated with impaired total anti-oxidant capacity. H2O2 exposure of myocardial slices from CKD, but not normal swine, impaired contractile function. Furthermore, in CKD, mitochondrial proteins were downregulated suggesting mitochondrial dysfunction which was associated with higher basal coronary blood flow. Thus, mild CKD induces alterations in mitochondrial proteins along with contractile proteins, oxidative stress and ECM remodeling, that were associated with changes in cardiac function and perfusion.

Critical diameter for a single-tank molten salt storage – Parametric study on structural tank design

Molten salt thermal energy storage (TES) is a cost-effective option for grid-connected storage in both concentrating solar power (CSP) plants and retrofitted thermal power plants in a multimegawatt scale. Current systems use two tanks (hot and cold), but future systems may use a single tank with a transient temperature profile (hot in the top and cold in the bottom) to reduce costs and space. However, the structural and mechanical design of large-scale molten salt single-tank storages at 560 °C has not been fully explored, and the impact of increasing the operating temperature to 620 °C is still uncertain. The challenge presented by a single tank is the existence of a temperature profile that results in a varying thermal expansion of the tank shell along its height. In the case of larger tanks, this discrepancy can reach a magnitude of centimeters, which in turn gives rise to bending moments. To the best of our knowledge, this study addresses the issue of bending stresses in large-sized high-temperature tanks with thermal stratification for the first time. The modelling approach is applied to single-tank CSP TES systems as a case study to evaluate the constraints imposed by tank size and wall thickness.With the help of experimentally validated numerical methods, it is revealed that a low thermocline thickness can be a limiting factor for large tank diameters. It is shown that the temperature has a major influence on maximum possible tank size: if the operating temperature is raised from 560 °C to 620 °C, the permitted tank diameter is significantly reduced when using the same tank wall material. A possible approach is to use a more heat resistant steel for 620 °C. Results of the parametric study show that designing a single tank below a critical diameter only requires a moderate increase of the wall thickness compared to the two-tank system with constant temperature profiles. Based on this parametric study a formula for the critical tank diameter is developed and presented in this work. The paper concludes with recommendations on how increased wall stresses can be addressed by an appropriate design.

Less-deformable erythrocyte subpopulations biomechanically induce endothelial inflammation in sickle cell disease

AbstractSickle cell disease (SCD) is canonically characterized by reduced red blood cell (RBC) deformability, leading to microvascular obstruction and inflammation. Although the biophysical properties of sickle RBCs are known to influence SCD vasculopathy, the contribution of poor RBC deformability to endothelial dysfunction has yet to be fully explored. Leveraging interrelated in vitro and in silico approaches, we introduce a new paradigm of SCD vasculopathy in which poorly deformable sickle RBCs directly cause endothelial dysfunction via mechanotransduction, during which endothelial cells sense and pathophysiologically respond to aberrant physical forces independently of microvascular obstruction, adhesion, or hemolysis. We demonstrate that perfusion of sickle RBCs or pharmacologically-dehydrated healthy RBCs into small venule-sized “endothelialized” microfluidics leads to pathologic physical interactions with endothelial cells that directly induce inflammatory pathways. Using a combination of computational simulations and large venule-sized endothelialized microfluidics, we observed that perfusion of heterogeneous sickle RBC subpopulations with varying deformability, as well as suspensions of dehydrated normal RBCs admixed with normal RBCs, leads to aberrant margination of the less-deformable RBC subpopulations toward the vessel walls, causing localized, increased shear stress. Increased wall stress is dependent on the degree of subpopulation heterogeneity and oxygen tension and leads to inflammatory endothelial gene expression via mechanotransductive pathways. Our multifaceted approach demonstrates that the presence of sickle RBCs with reduced deformability leads directly to pathological physical (ie, direct collisions and/or compressive forces) and shear-mediated interactions with endothelial cells and induces an inflammatory response, thereby elucidating the ubiquity of vascular dysfunction in SCD.

Impact of modulating pulmonary artery pressure on resting right ventricular function in endurance-trained and untrained individuals

Prolonged endurance training is associated with critical adaptations to right ventricular (RV) structure and function that facilitate the achievement of higher exercise capacity, peak cardiac output, and RV stroke volume in the face of large increases in pulmonary artery pressures (afterload) and RV wall stress. Compared to the left ventricle, the RV is more sensitive to increases in afterload during exercise. However, the independent effect of increased afterload on RV function in endurance trained (Trained) vs untrained individuals remain unknown. Trained were considered those with a maximal oxygen consumption ( V̇O2max) >60ml/kg/min (male) or >55ml/kg/min (female) while untrained were defined as V̇O2max <45ml/kg/min. Using echocardiography, this retrospective study sought to evaluate RV systolic function (RV global longitudinal strain [GLS]) and ventriculo-arterial coupling (ratio of RV GLS to pulmonary artery systolic pressure [PASP]) in Trained and untrained individuals while manipulating PASP. Ten participants (5 Trained and 5 Untrained) underwent resting echocardiography while breathing moderate (pressure of inspired oxygen; PiO2=89 mmHg) and severe hypoxia (PiO2=79 mmHg; order randomized) to increase PASP. Separately, eight participants (4 Trained and 4 untrained) inhaled nitric oxide (iNO; 40ppm) during echocardiography to lower PASP. Moderate and severe hypoxia increased PASP by 2.3 ± 1.3mmHg and 3.5 ± 1.8mmHg, respectively, while iNO decreased PASP by 2.6 ± 2.4mmHg, with no between group differences observed. Cardiac output was not different between any condition. A fitness-by-hypoxia interaction was observed in RV GLS in moderate hypoxia suggesting Trained had lower RV function during moderate hypoxia as compared to untrained (Untrained: -23.1 ± 4.4% vs. Trained: -20.2 ± 2.7%; p<0.01). No differences in RV GLS were observed with iNO (p=0.98). The ratio of RV GLS to PASP was significantly different between groups at moderate hypoxia (Untrained: -1.06 ± 0.09%/mmHg vs. Trained: -0.85 ± 0.12%/mmHg; p=0.04) but not severe hypoxia (p=0.78). These findings suggest reducing PASP did not alter RV function or ventriculo-arterial coupling, however, Trained individuals experienced differential RV function responses when PASP is experimentally increased with hypoxia. Natural Sciences and Engineering Research Council of Canada. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Oxidative stress: A driving force in CKD induced heart failure

Background: Several clinical investigations have shown that individuals with renal impairment are more likely to experience heart failure. Cardiac remodeling happens relatively early in the course of kidney injury, yet research into identification of common markers of cardiorenal signaling remains insuffcient. This may be because studies conducted in small animal models do not accurately reflect the complexity of the disease. To bridge the translational gap, we developed a swine model for chronic kidney disease (CKD) Aim: We employed proteome studies to clarify the pathophysiological impact of chronic kidney disease (CKD) on the heart and correlate to cardiac function and perfusion in order to offer mechanistic insights. Methods: We used microspheres to embolise both kidneys of swine at 10-12 weeks of age while sham operated swine served as controls. Post 6 months, we performed pressure volume loops to assess cardiac function, while coronary flow reserve (CFR) was measured by intracoronary infusion of adenosine in control and CKD. (LC-MS-MS based proteomic analyses of left ventricular tissue was performed. Paraffn embedded myocardium and kidney tissues were histologically examined for interstitial fibrosis and oxidative stress. Results: Renal embolization resulted in mild chronic kidney injury as evidenced by increased fibrosis staining and urinary NGAL (24±4 vs 48±9 pg/ml). Hemodynamic parameters showed increased wall stress (20±3 vs 40±7 ml*mmHg/g) as well as increase of end diastolic volume (1.5±0.1 vs 1.9±0.1 ml/kg) indicating dilation of the left ventricle in CKD. Quantitative proteomic analysis detected significant differences in the left ventricle of the controls when compared to those with CKD and STRING pre-ranked functional analysis showed enrichments in pathways related to reactive oxygen species. Furthermore, we detected alterations of pathways associated with remodeling of the extracellular matrix (ECM), Oxidative stress and ECM remodeling were confirmed histologically. Interestingly, in CKD we found that mitochondrial proteins like cytochrome oxidase (MT-CO2) and ATP5 synthase subunit were downregulated suggesting mitochondrial dysfunction which was associated with higher basal coronary blood flow (0.48±0.05 vs 0.87±0.11 ml/min/g). Conclusions: Our proteomic data in swine model provides strong evidence that mild CKD can induce early alterations in mitochondrial function along with oxidative stress and ECM remodeling. Thus, we aim to further our understanding by applying our proteomic findings in conjunction with functional hemodynamic data in this swine model of cardiorenal disease. German Center for Cardiovascular Research (DZHK81Z0600207 to D.M. and P.S.). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

A computational study of right ventricular mechanics in a rat model of pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) presents a significant challenge to right ventricular (RV) function due to progressive pressure overload, necessitating adaptive remodeling in the form of increased wall thickness, enhanced myocardial contractility and stiffness to maintain cardiac performance. However, the impact of these remodeling mechanisms on RV mechanics in not clearly understood. In addition, there is a lack of quantitative understanding of how each mechanism individually influences RV mechanics. Utilizing experimental data from a rat model of PAH at three distinct time points, we developed biventricular finite element models to investigate how RV stress and strain evolved with PAH progression. The finite element models were fitted to hemodynamic and morphological data to represent different disease stages and used to analyze the impact of RV remodeling as well as the altered RV pressure. Furthermore, we performed a number of theoretical simulation studies with different combinations of morphological and physiological remodeling, to assess and quantify their individual impact on overall RV load and function. Our findings revealed a substantial 4-fold increase in RV stiffness and a transient 2-fold rise in contractility, which returned to baseline by week 12. These changes in RV material properties in addition to the 2-fold increase in wall thickness significantly mitigated the increase in wall stress and strain caused by the progressive increase in RV afterload. Despite the PAH-induced cases showing increased wall stress and strain at end-diastole and end-systole compared to the control, our simulations suggest that without the observed remodeling mechanisms, the increase in stress and strain would have been much more pronounced. Our model analysis also indicated that while changes in the RV's material properties-particularly increased RV stiffness - have a notable effect on its mechanics, the primary compensatory factor limiting the stress and strain increase in the early stages of PAH was the significant increase in wall thickness. These findings underscore the importance of RV remodeling in managing the mechanical burden on the right ventricle due to pressure overload.

Early deterioration of right ventricular strain in patients undergoing transcatheter tricuspid valve intervention

Abstract Background Severe tricuspid regurgitation (TR) leads to volume overload and increased wall stress causing detrimental right ventricular (RV) remodelling and dysfunction and is associated with excess mortality. Transcatheter tricuspid valve interventions (TTVI) emerged to treat patients with severe TR and high surgical risk, but predictors of outcome remain largely unknown. RV free wall longitudinal strain (RVFWLS) is a sensitive parameter for RV dysfunction and has shown prognostic value in patients with functional TR treated conservatively. Periinterventional changes in RVFWLS and right atrial (RA) strain have not been evaluated in patients undergoing TTVI. Purpose To analyse the effect of transcatheter tricuspid valve annuloplasty (TTVA) and transcatheter edge-to-edge repair (TEER) on RVFWLS and RA strain, assessed by speckle tracking echocardiography, and their association with outcome. Methods We retrospectively analysed consecutive patients with severe TR that underwent TTVI at our centre between 2020 and 2022. 126 patients were included (n=48 underwent TTVA with the Cardioband system, n=78 underwent TEER with the PASCAL system). Established parameters for RV function (TAPSE, FAC) as well as RVFWLS and RA reservoir strain (RASR) were analysed at baseline and one month after TTVI. Results All patients (median age 80 years, 69% female, 79% in NYHA III/IV functional class) were at prohibitive surgical risk. RV function at baseline was slightly reduced according to FAC (34% [29-39]) and preserved according to TAPSE (18mm [15-20]), whereas RVFWLS (-18.6±5.7%) and RASR (10.0% [7.0-14.0]) were severely reduced in markedly dilated right heart chambers (RV basal 45mm [41-49], RA area 34 cm2 [28-41]). TR reduction following TTVI to TR grade ≤ 2 was achieved in 77%. Right heart chamber size significantly decreased after one month (RV basal 41mm [38-45], RA area 29cm2 [25-38], P<0.001), with no improvement of FAC (37% [30-40], P=0.668) or RASR (10% [7-13], P=0.143) but deterioration of RV longitudinal function (TAPSE 17mm [13-20], P=0.002; RFWLS -16.1±5.7%, P=0.001) compared to baseline. RVFWLS reduction occurred irrespective of the procedure performed (TEER [-9.2±41.4] vs. TTVA [-7.0±31.3], P=0.783). RVFWLS deterioration occurred in 63%, whereas it improved in 37% of patients. Symptomatic and clinical outcome did not differ in patients with deteriorated vs. improved RVFWLS (improvement of at least one NYHA class 61.9% vs. 58.3%, P=0.569, one-year mortality 13.7% vs. 12.3%, P=0.940, one-year heart failure rehospitalization 10.8% vs. 17.1%, P=0.701). Conclusion Deterioration of RVFWLS after TTVI possibly reflects the decreased wall stress due to TR and consecutive preload reduction. However, symptomatic and clinical outcomes did not differ in patients with deteriorated RVFWLS vs. patients with improved RVFWLS. Reduction of RA size after TTVI did not translate into improvement of RASR, indicating an already advanced pre-existing RA dysfunction.

Serial RV wall stress measurements: association with right ventricular function in repaired Tetralogy of Fallot patients

BackgroundOptimal timing of pulmonary valve replacement (PVR) in Tetralogy of Fallot (TOF) patients remains challenging. Ventricular wall stress is considered to be an early marker of right ventricular (RV) dysfunction.ObjectivesTo investigate the association of RV wall stresses and their change over time with functional parameters in TOF patients.MethodsTen TOF patients after surgical repair with moderate/severe pulmonary regurgitation were included. At two timepoints (median follow-up time 7.2 years), patient-specific computational biventricular models for wall stress assessment were created using CMR short-axis cine images and echocardiography-based RV pressures. RV ejection fraction (RVEF), NT-proBNP and cardiopulmonary exercise tests were used as outcome measures reflecting RV function. Associations between regional RV diastolic wall stress and RV function were investigated using linear mixed models.ResultsIncreased wall stress correlated with lower RV mass (rrm = −0.70, p = 0.017) and lower RV mass-to-volume (rrm = −0.80, p = 0.003) using repeated measures. Wall stress decreased significantly over time, especially in patients with a stable RVEF (p < 0.001). Higher wall stress was independently associated with lower RVEF, adjusted for left ventricular ejection fraction, RV end-diastolic volume and time since initial surgery (decrease of 1.27% RVEF per kPa increase in wall stress, p = 0.029) using repeated measurements. No association was found between wall stress, NT-proBNP, and exercise capacity.ConclusionsUsing a computational method to calculate wall stress locally in geometrically complex ventricles, we demonstrated that lower wall stress might be important to maintain ventricular function. RV wall stress assessment can be used in serial follow-up, and is potentially an early marker of impending RV dysfunction.

Left ventricular remodelling in rheumatic heart disease – trends over time and implications for follow-up in childhood

BackgroundRheumatic heart disease (RHD) is the most common form of acquired heart disease worldwide. In RHD, volume loading from mitral regurgitation leads to left ventricular (LV) dilatation, increased wall stress, and ultimately LV dysfunction. Improved understanding of LV dynamics may contribute to refined timing of intervention. We aimed to characterize and compare left ventricular remodelling between rheumatic heart disease (RHD) severity groups by way of serial echocardiographic assessment of volumes and function in children.MethodsChildren with RHD referred to Perth Children’s Hospital (formally Princess Margaret Hospital) (1987–2020) were reviewed. Patients with longitudinal pre-operative echocardiograms at diagnosis, approximately 12 months and at most recent follow-up, were included and stratified into RHD severity groups. Left ventricular (LV) echocardiographic parameters were assessed. Adjusted linear mixed effect models were used to compare interval changes.Results146 patients (median age 10 years, IQR 6–14 years) with available longitudinal echocardiograms were analysed. Eighty-five (58.2%) patients had mild, 33 (22.6%) moderate and 28 (19.2%) severe RHD at diagnosis. Mean duration of follow-up was 4.6 years from the initial diagnosis. Severe RHD patients had significantly increased end-systolic volumes (ESV) and end-diastolic volumes (EDV) compared to mild/moderate groups at diagnosis (severe versus mild EDV mean difference 27.05 ml/m2, p < 0.001, severe versus moderate EDV mean difference 14.95 ml/m2, p = 0.006). Mild and moderate groups experienced no significant progression of changes in volume measures. In severe RHD, LV dilatation worsened over time. All groups had preserved cardiac function.ConclusionsIn mild and moderate RHD, the lack of progression of valvular regurgitation and ventricular dimensions suggest a stable longer-term course. Significant LV remodelling occurred at baseline in severe RHD with progression of LV dilatation over time. LV function was preserved across all groups. Our findings may guide clinicians in deciding the frequency and timing of follow-up and may be of clinical utility during further reiterations of the Australia and New Zealand RHD Guidelines.

Thoracic Aorta: Anatomy and Pathology

The aorta is the largest elastic artery in the human body and is classically divided into two anatomical segments, the thoracic and the abdominal aorta, separated by the diaphragm. The thoracic aorta includes the aortic root, the ascending aorta, the arch, and the descending aorta. The aorta’s elastic properties depend on its wall structure, composed of three distinct histologic layers: intima, media, and adventitia. The different aortic segments show different embryological and anatomical features, which account for their different physiological properties and impact the occurrence and natural history of congenital and acquired diseases that develop herein. Diseases of the thoracic aorta may present either as a chronic, often asymptomatic disorder or as acute life-threatening conditions, i.e., acute aortic syndromes, and are usually associated with states that increase wall stress and alter the structure of the aortic wall. This review aims to provide an update on the disease of the thoracic aorta, focusing on the morphological substrates and clinicopathological correlations. Information on anatomy and embryology will also be provided.

Angiotensin Receptor-Neprilysin Inhibitor Therapy and Cardiac Remodeling in Heart Failure: Consensus Statement from India

Adverse cardiac remodeling refers to progressive structural and functional modifications in the heart because of increased wall stress in the myocardium, loss of viable myocardium, and neurohormonal stimulation. The guideline-directed medical therapy for Heart failure (HF) includes Angiotensin receptor-neprilysin inhibitor (ARNI) (sacubitril/valsartan), β-blockers, sodium-glucose co-transporter 2 (SGLT2) inhibitors, and mineralocorticoid receptor antagonists (MRA). ARNI is under-prescribed in India despite its attractive safety and efficacy profile. Therefore, the consensus discusses objectives and topics related to ARNI in the management of cardiac remodeling, and experts shared their views on the early timely intervention of effective dosage of ARNI to improve the diagnosis and enhance mortality and morbidity benefits in cardiac reverse remodeling (CRR).

Effects of switching from sacubitril/valsartan to valsartan alone on plasma levels of natriuretic peptides and myocardial remodeling in heart failure with reduced ejection fraction

BackgroundWe examined the effect of switching from angiotensin receptor-neprilysin inhibitor (ARNI) to angiotensin-receptor blocker (ARB) on plasma levels of natriuretic peptides and myocardial remodeling.MethodsThis is a prospective study that included 11 patients with heart failure (HF) treated with ARNI. The patients were divided into two groups: 5 patients who continued treatment with sacubitril/valsartan 194/206 mg/day (ARNI-continue group) and 6 patients who were switched to valsartan 160 mg/day (ARB-switch group). The primary endpoint was percent change (%Change) in plasma A-, B-, and N-terminal pro-B-type natriuretic peptide (ANP, BNP, and NT-proBNP) levels from the baseline to week 24. The secondary endpoint was the change in echocardiographic parameters related to myocardial remodeling from the baseline to week 24.ResultsANP levels in the ARB-switch group significantly decreased (from 1155.7 ± 592.6 pg/mL to 231.6 ± 233.8 pg/mL, p = 0.035), whereas those in the ARNI-continue group were not significant (p = 0.180). The %Change of decrease in ANP levels was significantly greater in the ARB-switch group than the ARNI-continue group (− 76.9% vs. −9.1%, p = 0.009). BNP levels were not significantly different between the baseline and week 24 in both groups. NT-proBNP levels in the ARB-switch group increased from 1185.3 ± 835.6 pg/mL to 1515.2 ± 1213.5 pg/mL, although the changes were not statistically significant (p = 0.345). The %Change of increase in NT-proBNP levels was significantly greater in the ARB-switch group than the ARNI-continue group (57.9% vs. 17.3%, p = 0.016). In the ARB-switch group, there was a significant increase in left ventricular (LV) end-systolic volume (from 41.3 ± 24.1 mL/m2 to 71.4 ± 8.8 mL/m2, p = 0.043) and LV peak-systolic wall stress (from 187.0 ± 42.7 × 103 dynes/cm2 to 279.7 ± 34.1 × 103 dynes/cm2, p = 0.012) from the baseline to week 24 and a trend toward a decrease in LV ejection fraction (p = 0.080). In the ARNI-continue group, no differences in echocardiographic parameters were observed from the baseline to week 24.ConclusionSwitching from ARNI to ARB may worsen HF due to returning to myocardial remodeling induced by a sustained decline in ANP levels.

NT-pro-BNP as a Predictor for Recurrence of Atrial Fibrillation after Primary Cryoballoon Pulmonary Vein Isolation.

NT-pro-BNP is produced in the cardiac atria and ventricles in response to increased wall stress. It may be a marker of both AF disease progression and co-morbidities that affect success after pulmonary vein isolation (PVI). This single-center retrospective study analyzed the association between pre-procedural NT-pro-BNP serum levels and the long-term outcome after a first-ever PVI in cryo-technique. Patients were followed by searching the hospital information system and conducting structured telephone interviews. Treatment failure was defined as any relapse of atrial fibrillation (AF) occurring 90 days after the index PVI at the earliest. Kaplan-Meier survival curves and Cox proportional hazards models were computed to assess the impact of NT-pro-BNP on AF recurrence. Following 374 patients over a median of 3.8 years (range: 0.25-9.4 years), baseline NT-pro-BNP was associated with the combined endpoint in univariate analysis (HR 1.04 per 100 pg/mL increase, 95% CI: 1.02-1.07, p &lt; 0.001). Results were virtually unchanged in the multivariate model or if the data were log-transformed. Intraprocedural left atrial pressure correlated positively with log NT-pro-BNP. NT-pro-BNP was associated with AF relapse during a long-term follow-up after first-ever cryo-PVI in our cohort of patients with predominantly normal left ventricular function. This lab parameter is easy to obtain and has significant potential to guide treatment decisions.

Influence of verapamil on pressure overload-induced ventricular arrhythmias by regulating gene-expression profiles.

Life-threatening ventricular arrhythmias can lead to sudden cardiac death in patients. This study aimed to investigate the changes in gene profiles involved when verapamil (VRP) affects increased wall stress (pressure overload)-induced ventricular arrhythmias, thus revealing the potential causative molecular mechanisms and therapeutic targets through gene-expression identification and functional analysis. Animal models with wall stress-induced ventricular arrhythmias were established. Low (0.5 mg/kg) and high (1 mg/kg) doses of VRP were administered intravenously 10 minutes before transverse aortic constriction, and average ventricular arrhythmia scores were calculated. Next, we evaluated the molecular role of VRP by characterising differential gene-expression profiles between VRP-pretreated (1 mg/kg) and control groups using RNA-sequencing technology. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were used to reveal molecular function. A protein-protein interaction (PPI) network was then developed. VRP exerted its anti-arrhythmic effects in response to increases in left ventricular (LV) afterload. We detected differentially expressed genes (DEGs), of which 36 were upregulated and 1 397 downregulated, between the VRP-pretreated and model groups during acute increases in LV wall stress. GO analysis demonstrated that the DEGs were associated with cytoskeletal protein binding. KEGG analysis showed that enriched pathways were mainly distributed in adherens junctions, actin cytoskeleton regulation and the MAPK signalling pathway. Centralities analysis of the PPI identified Rac1, Grb2, Rbm8a and Mapk1 as hub genes. VRP prevented acute pressure overload-induced ventricular arrhythmias, possibly through the hub genes Rac1, Grb2, Rbm8a and Mapk1 as potential targets of VRP.

Diastolic dysfunction in late postmenopausal patients with undifferentiated connective tissue disease and hypertension

Aim. To assess myocardial diastolic function (DF) in late postmenopausal women with undifferentiated connective tissue disease (UCTD) and hypertension (HTN).Material and methods. This cross-sectional study included 135 postmenopausal women, the median age of which was 68 years (65÷70,5 years). The anamnesis was collected using a standardized questionnaire. Verification of UCTD was carried out according to clinical guidelines. All patients underwent standard transthoracic echocardiography. The assessment of left ventricular (LV) DF was carried out according to the transmitral flow. LV diastolic dysfunction (DD) was classified into three types: rigid, pseudonormal, and restrictive. Statistical processing was carried out in the STATISTICA 13.0 environment. The measure of data averaging is the median, the measure of dispersion is 25%÷75%. The significance of differences was assessed using the Mann-Whitney test. Differences were considered significant at p˂0,05.Results. Group 1 — 20 (14,8%) patients with verified UCTD and HTN, group 2 — 88 (65,2%) patients with HTN without UCTD, control group — 23 (30%) patients without HTN and UCTD. There were no differences in age, duration of postmenopause and body mass index between the groups. In the first group, a significant decrease in the ratio of peak early to late diastolic LV filling velocity was revealed (p˂0,01). A significant increase in left ventricular end-systolic wall stress revealed in group 1. In 108 (100%) patients, LVDD was detected; among the patients of the control group, DD was not detected. In 8 (40%) patients in group 1, a pseudo-normal type of DD was detected, while in 12 out of 20 patients (60%) — rigid type of DD. When assessing DF in patients of group 2, a significant decrease was found in the ratio of peak early to late diastolic LV filling velocity, a significant increase in LV end-diastolic wall stress and end-diastolic pressure. In 2 out of 3 (57,80%) patients of group 2, DD of the rigid type was detected, while pseudonormal type — in 32,2% of patients in this group. Group 2 patients had a significant decrease in the early diastolic mitral annular velocity (p˂0,01).Conclusion. The analysis of myocardial echocardiographic characteristics indicates a significant contribution of HTN-associated UCTD to the development of LVDD in postmenopausal women.

Matrix Metalloproteinase-Targeted SPECT/CT Imaging for Evaluation of Therapeutic Hydrogels for the Early Modulation of Post-Infarct Myocardial Remodeling.

Following myocardial infarction (MI), maladaptive upregulation of matrix metalloproteinase (MMP) alters extracellular matrix leading to cardiac remodeling. Intramyocardial hydrogel delivery provides a vehicle for local delivery of MMP tissue inhibitors (rTIMP-3) for MMP activity modulation. We evaluated swine 10-14days following MI randomized to intramyocardial delivery of saline, degradable hyaluronic acid (HA) hydrogel, or rTIMP-3 releasing hydrogel with an MMP-targeted radiotracer (99mTc-RP805), 201Tl, and CT. Significant left ventricle (LV) wall thinning, increased wall stress, reduced circumferential wall strain occurred in the MI region of MI-Saline group along with left atrial (LA) dilation, while these changes were modulated in both hydrogel groups. 99mTc-RP805 activity increased twofold in MI-Saline group and attenuated in hydrogel animals. Infarct size significantly reduced only in rTIMP-3 hydrogel group. Hybrid SPECT/CT imaging demonstrated a therapeutic benefit of intramyocardial delivery of hydrogels post-MI and reduced remodeling of LA and LV in association with a reduction in MMP activation.

N- terminal pro brain natriuratic peptide (nt-probnp) in apparently healthy subjects compared to metabolic syndrome subjects

Background and objectives: B –type natriuretic peptide is synthesized in myocardial cells to respond to increased wall stress in association with heart failure or acute myocardial ischemia. High B –type natriuretic peptide and high Nt-pro B –type natriuretic peptide levels are candidates for cardiovascular risk markers and hypertension, left ventricular hypertrophy, and albuminuria. The level and relation of Nt-pro B –type natriuretic peptide with metabolic syndrome was examined in this study. Methods: In this case-control investigation, level of Nt-pro B –type natriuretic peptide of 80 metabolic syndrome patients diagnosed based on the International Diabetes Federation guidelines was compared to its level in 40 healthy controls. The subjects who accompanied the diabetic patients at Duhok Diabetes Center were screened for inclusion and exclusion criteria between the first March and May 2019. Results: The concentrations of triglyceride (215.09 vs. 104.02 mg/dL), total cholesterol (179.68 vs. 162.75mg/dL), and fasting blood glucose (188.71 vs. 88.08 mg/dL) were significantly higher in metabolic syndrome patients compared to the healthy controls, respectively. Nt-pro B –type natriuretic peptide was significantly lower in patients in contrast with healthy individuals (35.00 vs. 46.00 pg/mL), respectively. However, the proBNP level was not significantly different in metabolic syndrome patients with normal and abnormal biochemical parameters. Conclusions: This study showed a significantly lower concentration of Nt-proBNP in metabolic syndrome compared to healthy controls. However, the study did not find a significant correlation with content of metabolic syndrome.

TAKOTSUBO SYNDROME REVEALING PHEOCHROMOCYTOMA

Objective: We report the case of 57-year old woman with no previously known cardiovascular disease. Design and method: Her conventional cardiovascular risk factors were type 2 diabetes (HbA1c&lt; 6.5%), hypertension and active smoking. She presented to the ER for thoracic pain, headache, sweating and tachycardia (150 bpm). Results: Blood analysis showed an elevation of cardiac biomarkers (Troponin 2035ng/l; BNP 541ng/l, Ddimers 19500ug/l), and acute renal impairment (creatinin 158umol/l) while EKG showed inferior NSTEMI. Echocardiography visualized typical takotsubo aspect with apical hypokinesia. Thoraco-abdominal CT-scan showed an important left adrenal tumor. Plasmatic and urinary metanephrine and normetanephrine were high. The patient benefited from adrenal surgery with an optimal result on blood pressure control. Conclusions: Although the association TTS-pheochromocytoma has already been described, it remains uncommon. Catecholamine excessive secretion mediates TTS cardiomyopathy having a negative impact essentially on apical segments increasing wall stress and pressure, but different ventricular segments may be concerned as individual adrenoreceptors distribution patterns vary. TTS diagnosis should legitimate pheochromocytoma screening when associated with labile hypertension.

European Neuroendocrine Tumor Society (ENETS) 2022 Guidance Paper for Carcinoid Syndrome and Carcinoid Heart Disease

European Neuroendocrine Tumor Society (<scp>ENETS</scp>) 2022 Guidance Paper for Carcinoid Syndrome and Carcinoid Heart Disease

Understanding the Pathobiology of Pulmonary Hypertension Due to Left Heart Disease.

The development of pulmonary hypertension (PH) is common and has adverse prognostic implications in patients with heart failure due to left heart disease (LHD), and thus far, there are no known treatments specifically for PH-LHD, also known as group 2 PH. Diagnostic thresholds for PH-LHD, and clinical classification of PH-LHD phenotypes, continue to evolve and, therefore, present a challenge for basic and translational scientists actively investigating PH-LHD in the preclinical setting. Furthermore, the pathobiology of PH-LHD is not well understood, although pulmonary vascular remodeling is thought to result from (1) increased wall stress due to increased left atrial pressures; (2) hemodynamic congestion-induced decreased shear stress in the pulmonary vascular bed; (3) comorbidity-induced endothelial dysfunction with direct injury to the pulmonary microvasculature; and (4) superimposed pulmonary arterial hypertension risk factors. To ultimately be able to modify disease, either by prevention or treatment, a better understanding of the various drivers of PH-LHD, including endothelial dysfunction, abnormalities in vascular tone, platelet aggregation, inflammation, adipocytokines, and systemic complications (including splanchnic congestion and lymphatic dysfunction) must be further investigated. Here, we review the diagnostic criteria and various hemodynamic phenotypes of PH-LHD, the potential biological mechanisms underlying this disorder, and pressing questions yet to be answered about the pathobiology of PH-LHD.