Increased Wall Stress Research Articles

Arterial Wall Stress Induces Phenotypic Switching of Arterial Smooth Muscle Cells in Vascular Remodeling by Activating the YAP/TAZ Signaling Pathway

Background/Aims: Increasing wall stress or biomechanical stretch experienced by arteries influences the initiation of atherosclerotic lesions. This initiation is mediated by Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ), which are both effectors of the Hippo pathway. In this study, the functional roles of YAP/TAZ proteins in the regulation of the stretch-mediated programing of human umbilical arterial smooth muscle cells (HUASMCs) to a proliferative phenotype were examined. Methods: HUASMCs were seeded on a Matrigel-coated silicone chamber and subjected to biomechanical stretch for 24 h after 48 h of growth. YAP/TAZ small interfering RNA was used to specifically knockdown YAP/ TAZ expression in HUASMCs. Results: We observed that YAP/TAZ activation via biomechanical stretching is involved in the regulation of critical aspects of the HUASMC phenotypic switch. YAP/TAZ knockdown significantly attenuated the stretch-induced proliferative and pro-inflammatory phenotypes in HUASMCs. Furthermore, treatment with atorvastatin, an anti-atherosclerotic drug, attenuated the stretch-induced phenotypic switch of HUASMCs from the contractile to synthetic state by suppressing YAP/TAZ expression. Additional investigations demonstrated the role of stretch in inhibiting the Hippo pathway, leading to the activation of PI3-kinase (PI3K) and phosphoinositide dependent kinase (PDK1); the key molecule for the regulation of the PDK1 and Hippo complex interaction was Sav1. These results showed the importance of YAP/TAZ activation, induced by biomechanical stretch, in promoting atheroprone phenotypes in HUASMCs. Conclusion: Taken together, our findings revealed a mechanism by which YAP/TAZ activation contributes to the pathogenesis of atherosclerosis.

Effects of Transcatheter Mitral Valve Repair With MitraClip on Left Ventricular and Atrial Hemodynamic Load and Myocardial Wall Stress

AimsTo evaluate the effects of MitraClip on left ventricular (LV) and left atrial (LA) myocardial wall stress as assessed with the use of N-terminal pro–B-type natriuretic peptide (NT-proBNP) and strain imaging. Methods and resultsSixty-five patients with symptomatic moderate and severe mitral regurgitation (MR; age 75 ± 9 y, 57% male, 89% functional MR) treated with the use of MitraClip were evaluated. Patients were divided according to 6-month NT-proBNP tertiles. Changes in echocardiographic parameters over 6 months were assessed. Reductions in LV end-diastolic volumes (178 ± 77 mL to 170 ± 79 mL; P = .045) and LV end-systolic volumes (120 ± 70 mL to 111 ± 69 mL; P = .040) were observed in the overall population. Interestingly, low–NT-proBNP–tertile patients showed slight improvements in LV and LA longitudinal strain, whereas high–NT-proBNP–tertile patients showed impairment. ConclusionsAlthough MitraClip induces hemodynamic unloading in patients with predominantly functional MR, myocardial wall stress is not consistently improved. In patients with reduced NT-proBNP, improvements in LA volume index and LV and LA strains were observed. Patients who showed an increase in NT-proBNP exhibited impairment in LV and LA strain, suggesting an increase of myocardial wall stress.

Innovative approach to determine the minimum wall thickness of flexible buried pipes

This paper uses a finite element based approach to provide a comprehensive understanding to the behaviour and the design performance of buried uPVC pipes with different diameters. It also investigates pipes with good and poor haunch support and proposes minimum safe wall thicknesses for these pipes. The results for pipes with good haunch support showed that the maximum pipe wall stress and deformation increase as the diameter increased. The results for pipes with poor haunch support showed an increase in the dependency of the developed vertical displacement on the haunch support as the diameter or the backfill height increased. Additionally, poor haunch support was found to increase the soil pressure, with the effect increasing as the diameter increased. The design of uPVC pipes for both poor and good haunch support was found to be governed by critical buckling. A key outcome is a new design chart for the minimum wall thickness, which enables the robust and economic design of buried uPVC pipes. Importantly, the methodology adopted in this study can also be applied to the design of flexible pipes manufactured from other materials, buried under different conditions and subjected to different loading arrangements.

Biomechanical Stretch Induces Inflammation, Proliferation, and Migration by Activating NFAT5 in Arterial Smooth Muscle Cells.

The increasing wall stress as is elicited by arterial hypertension promotes their reorganization in the vessel wall which may lead to arterial stiffening and contractile dysfunction. The nuclear factor of activated T cells 5 (NFAT5) pathway plays a role in regulating growth and differentiation in various cell types. We investigated whether the NFAT5 pathway was involved in the regulation of biomechanical stretch-induced human arterial smooth muscle cell (HUASMC) proliferation, inflammation, and migration. Herein, we showed that stretch promoted the expression of NFAT5 in human arterial smooth muscle cells and regulated through activation of c-Jun N-terminal kinase under these conditions. This may contribute to an improved activity of HUASMCs and thus promote reorganization in vascular remodeling processes such as hypertension-induced arterial stiffening and contractile dysfunction.

Exercise and the right ventricle: a potential Achilles' heel.

Exercise is associated with unequivocal health benefits and results in many structural and functional changes of the myocardium that enhance performance and prevent heart failure. However, intense exercise also presents a significant hemodynamic challenge in which the right-sided heart chambers are exposed to a disproportionate increase in afterload and wall stress that can manifest as myocardial fatigue or even damage if intense exercise is sustained for prolonged periods. This review focuses on the physiological factors that result in a disproportionate load on the right ventricle during exercise and the long-term consequences. The changes in cardiac structure and function that define 'athlete's heart' disproportionately affect the right-sided heart chambers and this can raise important diagnostic overlap with some cardiac pathologies, particularly some inherited cardiomyopathies. The interaction between exercise and arrhythmogenic right ventricular cardiomyopathy (ARVC) will be highlighted as an important example of how hemodynamic stressors can combine with deficiencies in cardiac structural elements to cause cardiac dysfunction predisposing to arrhythmias. The extent to which extreme exercise can cause adverse remodelling in the absence of a genetic predisposition remains controversial. In the athlete with profound changes in heart structure, it can be extremely challenging to determine whether common symptoms such as palpitations may be a marker of more sinister arrhythmias. This review discusses some of the techniques that have recently been proposed to identify pathology in these circumstances. Finally, we will discuss recent evidence defining the role of exercise restriction as a therapeutic intervention in individuals predisposed to arrhythmogenic cardiomyopathy.

Percutaneous Ventricular Restoration Using the Parachute Device: The Parachute III Pressure-Volume Loop Sub-study

ABSTRACTBackground: Left ventricular (LV) dilatation and remodeling following acute myocardial infarction increases wall stress, ventricular volumes and leads to heart failure (HF), which is associated with a high mortality. Percutaneous ventricular restoration (pVR) therapy reduces LV volumes leading to a more effective ejection. This study investigated the hemodynamic effects of LV volume reduction from pVR on LV performance and its interaction with the arterial system.Methods: Ten patients with symptomatic ischemic HF of New York Heart Association (NYHA) classes II to IV with LV antero-apical wall motion abnormalities underwent Parachute implantation. Pressure-volume loops were recorded immediately pre- and post-pVR implantation and at 6-month follow up.Results: Parachute implantation significantly reduced end-diastolic volume index (from 112 ± 39 mL to 100 ± 41 mL; p < 0.05), with a greater relative reduction in end-systolic volume index (from 66 ± 33 mL to 56 ± 32 mL; p < 0.05) with an overall 7% increase in ejection fraction (from 38 ± 11 to 46 ± 14%; p < 0.05). Furthermore, there was an observed reduction in dyssynchrony index (from 20 ± 4 to 14 ± 6%; p < 0.05) and enhanced contractile function (Ees) immediately post-procedure, sustained at 6-months (from 0.92 ± 0.27 mmHg/mL to 1.37 ± 0.52 mmHg/mL, p < 0.05).Conclusion: This present study confirms positive hemodynamic effects of LV volume reduction using the Parachute percutaneous ventricular restoration device. The Parachute device improved synchronous contraction and enhanced ventricular-arterial interaction likely due to LV reverse remodeling.

EFFECTS OF HYPERTENSION AND PRESSURE GRADIENT IN A HUMAN CEREBRAL ANEURYSM USING FLUID STRUCTURE INTERACTION SIMULATIONS

Fluid–structure interaction (FSI) simulations were carried out in a human cerebral aneurysm model with the objective of quantifying the effects of hypertension and pressure gradient on the behavior of fluid and solid mechanics. Six FSI simulations were conducted using a hyperelastic Mooney–Rivlin model. Important differences in wall shear stress (WSS), wall displacements, and effective von Mises stress are reported. The hypertension increases wall stress and displacements in the aneurysm region; however, the effects of hypertension on the hemodynamics in the aneurysm region were small. The pressure gradient affects the WSS in the aneurysm and also the displacement and wall stress on the aneurysm. Maximum wall stress with hypertension in the range of rupture strength was found.

Are There Clinical Cardiac Complications From Too Much Exercise?

The dose-response association between physical activity and cardiovascular outcomes is well described (10). As little as 15 min·d−1 of moderate-intensity exercise significantly lowers the risk for cardiovascular morbidity and mortality. Greater volumes yield greater cardiovascular benefit. However, the impact of extreme volumes of exercise on cardiovascular health is under debate (9), because some studies present evidence of adverse clinical outcomes in endurance athletes who perform exercise volumes at the extreme upper end of the physical activity continuum. These observations raise the possibility that high doses of exercise have deleterious cardiac effects.

Sudden death due to aortic pathology.

Sudden death from aortic dissection of an ascending aortic aneurysm is an uncommon but important finding in all series of sudden death in young, apparently healthy athletes. Individuals at risk include those having any of a variety of conditions in which structural weakness of the ascending aorta predisposes to pathological dilation under prolonged periods of increased wall stress. These conditions include Marfan syndrome, Loeys-Dietz syndrome, bicuspid aortic valve, and the vascular form of Ehlers-Danlos syndrome. Diagnostic criteria, surveillance strategies, medical management, and surgical indications are discussed. Finally, the current recommendations for sports participation are provided.

Institution of Veno-arterial Extracorporeal Membrane Oxygenation Does Not Lead to Increased Wall Stress in Patients with Impaired Myocardial Function.

The effect of veno-arterial extracorporeal membrane oxygenation (VA ECMO) on wall stress in patients with cardiomyopathy, myocarditis, or other cardiac conditions is unknown. We set out to determine the circumferential and meridional wall stress (WS) in patients with systemic left ventricles before and during VA ECMO. We established a cohort of patients with impaired myocardial function who underwent VA ECMO therapy from January 2000 to November 2013. Demographic and clinical data were collected and inotropic score calculated. Measurements were taken on echocardiograms prior to the initiation of VA ECMO and while on full-flow VA ECMO, in order to derive wall stress (circumferential and meridional), VCFc, ejection fraction, and fractional shortening. A post hoc sub-analysis was conducted, separating those with pulmonary hypertension (PH) and those with impaired systemic output. Thirty-three patients met inclusion criteria. The patients' median age was 0.06years (range 0-18.7). Eleven (33%) patients constituted the organ failure group (Gr2), while the remaining 22 (66%) patients survived to discharge (Gr1). WS and all other echocardiographic measures were not different when comparing patients before and during VA ECMO. Ejection and shortening fraction, WS, and VCFc were not statistically different comparing the survival and organ failure groups. The patients' position on the VCFc-WS curve did not change after the initiation of VA ECMO. Those with PH had decreased WS as well as increased EF after ECMO initiation, while those with impaired systemic output showed no difference in those parameters with initiation of ECMO. The external workload on the myocardium as indicated by WS is unchanged by the institution of VA ECMO support. Furthermore, echocardiographic measures of cardiac function do not reflect the changes in ventricular performance inherent to VA ECMO support. These findings are informative for the interpretation of echocardiograms in the setting of VA ECMO. ECMO may improve ventricular mechanics in those with PH as the primary diagnosis.

Changes in overall ventricular myocardial architecture in the setting of a porcine animal model of right ventricular dilation

BackgroundChronic pulmonary regurgitation often leads to myocardial dysfunction and heart failure. It is not fully known why secondary hypertrophy cannot fully protect against the increase in wall stress brought about by the increased end-diastolic volume in ventricular dilation. It has been assumed that mural architecture is not deranged in this situation, but we hypothesised that there might be a change in the pattern of orientation of the aggregations of cardiomyocytes, which would contribute to contractile impairment.MethodsWe created pulmonary valvular regurgitation by open chest, surgical suturing of its leaflets in seven piglets, performing sham operations in seven control animals. Using cardiovascular magnetic resonance imaging after 12 weeks of recovery, we demonstrated significantly increased right ventricular volumes in the test group. After sacrifice, diffusion tensor imaging of their hearts permitted measurement of the orientation of the cardiomyocytes.ResultsThe helical angles in the right ventricle approached a more circumferential orientation in the setting of right ventricular RV dilation (p = 0.007), with an increased proportion of surface-parallel cardiomyocytes. In contrast, this proportion decreased in the left ventricle. Also in the left ventricle a higher proportion of E3 angles with a value around zero was found, and conversely a lower proportion of angles was found with a numerical higher value. In the dilated right ventricle the proportion of E3 angles around −90° is increased, while the proportion around 90° is decreased.ConclusionContrary to traditional views, there is a change in the orientation of both the left ventricular and right ventricular cardiomyocytes subsequent to right ventricular dilation. This will change their direction of contraction and hinder the achievement of normalisation of cardiomyocytic strain, affecting overall contractility. We suggest that the aetiology of the cardiac failure induced by right vetricular dilation may be partly explained by morphological changes in the myocardium itself.

Abstract 12524: Changes in Pulmonary Autograft Wall Stresses Immediately After the Ross Operation: First Steps Towards Understanding Aneurysmal Remodeling

Introduction: Pulmonary autograft dilatation is the Achilles heel of the Ross operation, often necessitating reoperation. To understand normal and abnormal autograft remodeling, first biomechanical understanding of human autografts after exposure to systemic pressure is required. Our aim was to quantify biomechanical wall stresses on normal autografts after Ross operation prior to remodeling and dilatation. Hypothesis: Elevated pressure of systemic circulation results in increased autograft wall stress to drive biomechanical remodeling. Methods: We previously developed a normal human autograft model using micro-computed tomography to obtain zero-pressure luminal geometry. Material properties of normal human autografts (n=9) was obtained by bi-axial stretching. Patient-specific zero-pressure wall thickness was incorporated. Autograft diameter and wall stress were determined at pulmonic and systemic pressures using finite element analyses. Results: At systemic systole, mean autograft diameter was 35.0±1.7mm at sinuses and 33.4±1.3mm at sinotubular junction (STJ); while at pulmonary systole, they were 32.5±1.9mm and 30.5±1.4mm, respectively. Distensibility, percent change in diameter from diastole to systole, was 1.4% at systemic pressures versus 3.0% at pulmonary pressures. Peak von Mises wall stress was 581±449kPa at systemic systole compared to 89.7±65.3kPa at pulmonic systole. Average wall stress at systemic systole was 223±88.3kPa and at pulmonic systole was 37.4±16.8kPa (Fig 1). Conclusions: Normal human pulmonary autograft biomechanical responses to systemic pressure were quantified. Nearly 6 fold increase in peak and average wall stress was observed at systemic pressures. Regions of peak stresses were observed in the sinuses. This data will serve as a necessary control for future comparison to aneurysmal pulmonary autografts, and will enable better understanding of patient-specific risk for autograft dilatation.

Estrogen receptor antagonism exacerbates cardiac structural and functional remodeling in female rats.

We assessed the estrogen receptor (ER) dependence of female-specific cardioprotection using a rat model of chronic volume-overload stress. ER antagonism worsened ventricular wall stress, ventricular dilation, and cardiac dysfunction induced by volume overload. Further, blocking ERs resulted in cardiac remodeling and functional changes similar to that previously found in ovariectomized rats.

Supervised exercise training in peripheral arterial disease increases vascular shear stress and profunda femoral artery diameter.

Background Arteriogenesis is promoted by flow- and pressure-related forces such as tangential wall stress and laminar shear stress. Exercise training (ET) is known to promote arteriogenesis in peripheral arterial disease (PAD) patients. It remains unclear whether supervised ET (SET) promotes arteriogenesis more efficiently than non-SET (nSET). Methods and results Forty PAD patients participated in a SET or nSET training programme ( n = 20 each) and were compared to 20 healthy individuals without any history of cardiovascular events. Femoral artery diameter, flow and velocity were measured by ultrasound. Tangential wall stress and laminar shear stress were calculated for femoral arteries. Follow-up was performed after a mean of 7.65 ± 1.62 months. At follow-up, only the SET group showed a significant increase in lumen diameter of the profunda femoral artery ( p = 0.03), accompanied by an increase of tangential wall stress ( p = 0.002). Laminar shear stress decreased, but remained higher for the SET group compared to controls ( p < 0.01). Individual changes in walking distance were higher for SET patients ( p = 0.01) than nSET patients ( p = 0.07). Profunda femoral lumen diameter and tangential wall stress correlated directly with walking distance ( r = 0.446; p < 0.001), as well as with each other ( r = 0.743; p < 0.0001). Conclusions Our results indicate that SET promotes arteriogenesis more efficiently than nSET. Femoral lumen diameter and flow might help with the monitoring of ET efficiency and potential arteriogenesis.

PS 02-41 HYPERPULSATILE PRESSURE, SYSTEMIC INFLAMMATION AND CARDIAC STRESS ARE ASSOCIATED WITH CARDIAC WALL REMODELLING IN AN AFRICAN MALE COHORT

Objective: Inflammation may contribute to an increase in cardiac wall stress through multiple pathways related to cardiac remodeling. Cardiac remodeling is a compensatory mechanism characterised by myocyte hypertrophy, myocyte death and modifications of the extra-cellular matrix. We aimed to explore associations of inflammation and myocardial injury with cardiac remodeling in a bi-ethnic sex cohort of South Africa. Design and Method: We included 165 men (76 African and 89 Caucasian) and 174 women (80 African and 94 Caucasian) participants between 20 and 65 years of age. Inflammatory markers that were employed were C-reactive protein (CRP), interleukin-6 and tumor necrosis factor-alpha (TNF-α), while troponin T (Trop T) and the N-terminal of pro B-type natriuretic peptide (NT-proBNP) were employed as cardiac markers. Frequency of ischemic events (ST segment depression) and left ventricular strain (left ventricular hypertrophy: LVH) were monitored by recording ambulatory 24-h blood pressure (BP), -ECG and 12 lead standard ECG. Results: Hypertension diagnosed with ambulatory monitoring was more evident in Africans (53.85% vs. 24.59%; p < 0.001) as was the number of ischemic events (6 vs 3; p = 0.006) irrespective of sex. Inflammatory markers (CRP, IL-6 and TNF-α) were significantly higher in Africans, as were Trop T concentrations and degree of LVH (p < 0.05). BP was associated (p < 0.05) with Trop T in all men. In African men, associations were evident between cardiac stress (NT-proBNP), TNF alpha (p < 0.001), Trop T (p < 0.001) and pulse pressure (p = 0.048), adjusted R2 = 0.45. Conclusions: A risk profile of overload to the heart will increase the susceptibility for cardiac wall remodeling, characterised by hyper- pulsatile pressure, low-grade systemic inflammation and ventricular stress, which may lead to the development of future cardiovascular events in African men.

Abstract 79: Sarcospan Has a Protective Effect During Development of Cardiac Disease

Sarcospan (SSPN) has an important role in stabilizing sarcolemmal dystrophin- and utrophin-glycoprotein adhesion complexes at the cell membrane. Loss of cell adhesion leads to contraction-induced muscle damage, causing muscle dysfunction and cell death. Recently we have shown a specific role for SSPN in modulating cardiac cell adhesion and physiological function. After transthoracic aortic constriction (TAC), SSPN-null mice transitioned toward failure faster than wild-type (WT) mice. Muscle histology revealed large focal areas of collagen deposition in SSPN-null hearts after TAC compared to WT hearts, suggesting that increased membrane fragility affected cardiomyocyte survival. Our laboratory has shown that SSPN loss reduces sarcolemmal dystrophin levels and associated adhesion complexes in the heart. Whereas, the complete loss of dystrophin leads to development of Duchenne muscular dystrophy (DMD), causing cardiac dysfunction and early mortality. Overexpression of SSPN in DMD mice increased cell adhesion and laminin binding in hearts, leading to improvements in tissue histopathology and increased expression of utrophin, a functional homologue of dystrophin. Examining the restorative potential of SSPN in dystrophic cardiac tissue, led us to query whether compensatory upregulation of SSPN occurs in failing hearts of TAC-treated WT mice. In failing non-DMD hearts, we found that SSPN expression is increased. We have evidence of a chaperone role for SSPN, and its increased expression in the failing heart may contribute to the increased localization of dystrophin and associated glycoprotein complexes at the sarcolemma, which we observed in failing WT hearts compared to untreated controls. The upregulation of cell-stabilizing cell adhesion complexes may compensate for increased wall stress and counter pathological processes that culminate in cardiomyocyte demise, and we are exploring whether naturally increased expression or transgenic overexpression of SSPN in the heart may protect against damage. In summary, we have found that SSPN promotes cardiac function by maintaining cell adhesion and promoting cell survival during disease conditions.

Arterial Stiffening in Western Diet-Fed Mice Is Associated with Increased Vascular Elastin, Transforming Growth Factor-β, and Plasma Neuraminidase.

Consumption of excess fat and carbohydrate (Western diet, WD) is associated with alterations in the structural characteristics of blood vessels. This vascular remodeling contributes to the development of cardiovascular disease, particularly as it affects conduit and resistance arteries. Vascular remodeling is often associated with changes in the elastin-rich internal elastic lamina (IEL) and the activation of transforming growth factor (TGF)-β. In addition, obesity and type II diabetes have been associated with increased serum neuraminidase, an enzyme known to increase TGF-β cellular output. Therefore, we hypothesized that WD-feeding would induce structural modifications to the IEL of mesenteric resistance arteries in mice, and that these changes would be associated with increased levels of circulating neuraminidase and the up-regulation of elastin and TGF-β in the arterial wall. To test this hypothesis, a WD, high in fat and sugar, was used to induce obesity in mice, and the effect of this diet on the structure of mesenteric resistance arteries was investigated. 4-week old, Post-weaning mice were fed either a normal diet (ND) or WD for 16 weeks. Mechanically, arteries from WD-fed mice were stiffer and less distensible, with marginally increased wall stress for a given strain, and a significantly increased Young's modulus of elasticity. Structurally, the wall cross-sectional area and the number of fenestrae found in the internal elastic lamina (IEL) of mesenteric arteries from mice fed a WD were significantly smaller than those of arteries from the ND-fed mice. There was also a significant increase in the volume of elastin, but not collagen in arteries from the WD cohort. Plasma levels of neuraminidase and the amount of TGF-β in mesenteric arteries were elevated in mice fed a WD, while ex vivo, cultured vascular smooth muscle cells exposed to neuraminidase secreted greater amounts of tropoelastin and TGF-β than those exposed to vehicle. These data suggest that consumption of a diet high in fat and sugar causes stiffening of the vascular wall in resistance arteries through a process that may involve increased neuraminidase and TGF-β activity, elevated production of elastin, and a reduction in the size and number of fenestrae in the arterial IEL.

Elevated ventricular wall stress disrupts cardiomyocyte t-tubule structure and calcium homeostasis.

AimsInvaginations of the cellular membrane called t-tubules are essential for maintaining efficient excitation–contraction coupling in ventricular cardiomyocytes. Disruption of t-tubule structure during heart failure has been linked to dyssynchronous, slowed Ca2+ release and reduced power of the heartbeat. The underlying mechanism is, however, unknown. We presently investigated whether elevated ventricular wall stress triggers remodelling of t-tubule structure and function.Methods and resultsMRI and blood pressure measurements were employed to examine regional wall stress across the left ventricle of sham-operated and failing, post-infarction rat hearts. In failing hearts, elevated left ventricular diastolic pressure and ventricular dilation resulted in markedly increased wall stress, particularly in the thin-walled region proximal to the infarct. High wall stress in this proximal zone was associated with reduced expression of the dyadic anchor junctophilin-2 and disrupted cardiomyocyte t-tubular structure. Indeed, local wall stress measurements predicted t-tubule density across sham and failing hearts. Elevated wall stress and disrupted cardiomyocyte structure in the proximal zone were also associated with desynchronized Ca2+ release in cardiomyocytes and markedly reduced local contractility in vivo. A causative role of wall stress in promoting t-tubule remodelling was established by applying stretch to papillary muscles ex vivo under culture conditions. Loads comparable to wall stress levels observed in vivo in the proximal zone reduced expression of junctophilin-2 and promoted t-tubule loss.ConclusionElevated wall stress reduces junctophilin-2 expression and disrupts t-tubule integrity, Ca2+ release, and contractile function. These findings provide new insight into the role of wall stress in promoting heart failure progression.

Hyperpulsatile pressure, systemic inflammation and cardiac stress are associated with cardiac wall remodeling in an African male cohort: the SABPA study.

Inflammation may contribute to an increase in cardiac wall stress through pathways related to cardiac remodeling. Cardiac remodeling is characterized by myocyte hypertrophy, myocyte death and modifications of the extracellular matrix. We sought to explore associations among cardiac remodeling, inflammation and myocardial cell injury in a bi-ethnic cohort of South African men and women. We included 165 men (76 African and 89 Caucasian) and 174 women (80 African and 94 Caucasian) between 20 and 65 years of age. Inflammatory markers used were C-reactive protein (CRP), interleukin-6 and tumor necrosis factor-alpha (TNF-α), whereas troponin T (Trop T) and the N-terminal of pro B-type natriuretic peptide (NT-proBNP) were used as cardiac markers. The frequency of ischemic events (ST segment depression) and left ventricular strain (left ventricular hypertrophy: LVH) were monitored by a 24-h recording of ambulatory blood pressure (BP), ECG and 12-lead standard ECG. Hypertension diagnosed with ambulatory monitoring was more frequent in Africans (53.85 vs. 24.59%; P<0.001), as was the number of ischemic events (6±15 (1; 5) vs. 3±6 (0; 3)). Inflammatory markers (CRP, IL-6 and TNF-α) and the degree of LVH were all significantly higher in Africans (P<0.05). BP was associated (P<0.05) with Trop T in men across ethnic groups. In African men, cardiac stress (NT-proBNP) was associated with TNF-alpha (P<0.001), Trop T (P<0.001) and pulse pressure (P=0.048; adjusted R(2)=0.45). The susceptibility for cardiac wall remodeling appears to increase with hyperpulsatile pressure, low-grade systemic inflammation and ventricular stress, and may lead to the development of future cardiovascular events in African men.

Lysyl Oxidase Inhibition Alleviates Fibrosis and Dysfunction in Rodents with Established Cardiac Disease

Heart failure is the end result of many cardiovascular disorders, including myocardial infarction, hypertension, and diabetes. Regardless of etiology, a key mechanism of heart failure is adverse extracellular matrix (ECM) remodeling. Lysyl oxidase (LOX) is a collagen cross‐linking enzyme that is elevated in failing human hearts, and is associated with cardiac fibrosis. Our goal for this study was to determine if inhibition of LOX in rodents with established cardiac disease would provide protection against further adverse cardiac remodeling and dysfunction. The aortocaval fistula rat surgical model of volume overload (VO) was used. Eight weeks after surgery, both sham‐operated and VO rats were treated with a LOX inhibitor, beta‐aminopropionitrile (BAPN; 100 mg/kg/d). Treatment was administered for six weeks using an osmotic minipump inserted into the peritoneal cavity.Echocardiography was used to assess progressive alterations in cardiac remodeling and function. At 14 weeks, left ventricular (LV) catheterization was used to assess alterations in contractility, stiffness, and other indices of cardiac function. Using LV homogenates and fixed sections, interstitial myocardial collagen (immunohistochemistry), and protein expression of collagens I and III (Western Blot) were measured. Collagen cross‐linking was assessed using pyridinoline (Pyd) assay.VO induced significant LV hypertrophy (116% increase vs sham), diastolic LV wall stress (363% increase vs sham), fibrosis (172%, 77% and 22% increase in interstitial myocardial collagen, collagen I and collagen III, respectively, vs sham; p&lt;0.05), and cardiac dysfunction (17% decrease in ejection fraction vs sham). LOX inhibition partially attenuated VO‐induced increases in LV hypertrophy (23% decrease vs VO; p&lt;0.05). Inhibiting LOX also completely attenuated VO‐induced increases in interstitial myocardial collagen, and protein expression of collagens I and III (180%, 76% and 22% decrease, respectively, vs VO; p&lt;0.05). LOX inhibition significantly attenuated increases in cardiac wall stress (33.5% decrease vs VO) and conferred cardioprotective effects as indicated by improved fractional shortening (19% increase vs untreated VO; p&lt;0.05). LOX inhibition also significantly attenuated VO‐induced decreases in contractility, assessed using end systolic pressure‐volume catheterization and preload recruited stroke work (70% and 30% increase, respectively, vs VO; p&lt;0.05). Overall, our data demonstrate the cardioprotective effects of LOX inhibition on the volume overload stressed heart, and its potential to slow or even prevent the transition to heart failure.Support or Funding InformationSupported by the NIH/NCRR #P20RR016456 and the American Heart Association Greater Southeast Affiliate #11GRNT7700002 (jdg).