Cardiovascular Stiffening Research Articles

Mineralocorticoid Receptor Activation in Vascular Insulin Resistance and Dysfunction.

Systemic insulin resistance is characterized by reduced insulin metabolic signaling and glucose intolerance. Mineralocorticoid receptors (MRs), the principal receptors for the hormone aldosterone, play an important role in regulating renal sodium handling and blood pressure. Recent studies suggest that MRs also exist in tissues outside the kidney, including vascular endothelial cells, smooth muscle cells, fibroblasts, perivascular adipose tissue, and immune cells. Risk factors, including excessive salt intake/salt sensitivity, hypertension, and obesity, can lead to the activation of vascular MRs to promote inflammation, oxidative stress, remodeling, and fibrosis, as well as cardiovascular stiffening and microcirculatory impairment. These pathophysiological changes are associated with a diminished ability of insulin to initiate appropriate intracellular signaling events, resulting in a reduced glucose uptake within the microcirculation and related vascular insulin resistance. Therefore, the pharmacological inhibition of MR activation provides a potential therapeutic option for improving vascular function, glucose uptake, and vascular insulin sensitivity. This review highlights recent experimental and clinical data that support the contribution of abnormal MR activation to the development of vascular insulin resistance and dysfunction.

Abstract P272: Mechanisms By Which Aldosterone And Insulin Stimulate Endothelial Cell Sodium Currents.

Aldosterone and insulin are known to increase the activity of the epithelial Na + channel (ENaC) in tubular epithelial cells through multiple mechanisms involving both transcriptional and post-transcriptional events. Such studies have implicated a key role for serum and glucocorticoid-stimulated kinase 1 (SGK-1) in determining ENaC activity. Comparatively less information is available regarding such regulation of the endothelial cell (EC) Na+ channel (EnNaC). The importance of such knowledge relates to prior studies having shown that EnNaC contributes to cardiovascular stiffening in states of hyperaldosteronism and hyperinsulinemia/insulin resistance. We hypothesized that aldosterone and insulin converge on SGK-1 to increase EnNaC activity. To determine how EnNaC is affected by insulin and aldosterone pulmonary ECs were isolated from wild-type mice and global SGK-1 deficient mice and held under conditions of short-term tissue culture. ECs were subsequently exposed to aldosterone (10 nM), insulin (100 nM) or DMSO control for 24 hr and whole cell EnNaC currents measured by patch clamp. Both chronic aldosterone and insulin increased Na + currents in ECs from wild-type mice, while in cells from SGK-1-/- mice the response to aldosterone was significantly blunted. However, insulin continued to increase EnNaC activity in SGK-1-/- mice. Acute insulin treatment (10 mins) showed a concentration-dependent (10 – 100 nM) increase in EC Na + currents in both SGK+/+ and SGK-/- mice which was prevented by PI3 kinase inhibition with LY294002 (30 uM). Thus, in ECs aldosterone-mediated activation of EnNaC is dependent on SGK-1 while insulin exerts a stimulatory effect via PI3 kinase, even in the absence of SGK-1.

Insulin- and Aldosterone-Mediated Signaling in Endothelial Cells Converge on SGK1 to Promote Endothelial Sodium Channel Activation

Background: Abnormal cardiovascular (CV) stiffening precedes overt tissue fibrosis and dysfunction. Although CV stiffening normally occurs with ageing it is accelerated in states of hyperinsulinemia/insulin (INS) resistance including obesity and Type 2 diabetes. While questions remain regarding the underlying cellular mechanisms, heightened activation of endothelial cell (EC) mineralocorticoid receptors (MRs) and INS receptors occur in hyperinsulinemic/INS resistance states. Further, EC sodium (Na+) channel (EnNaC) activation has recently been identified as a key determinant of endothelial dysfunction, CV fibrosis and stiffening in diet-induced obesity and associated INS resistance . As renal epithelial Na+ channels are known to be regulated via sodium glucocorticoid kinase (SGK-1) through INS and MR-dependent mechanisms this study aimed to determine whether vascular EnNaC is similarly regulated. Methods: Lung ECs were isolated from SGK-1 -/- mice and littermate control and maintained under short-term tissue culture conditions. EnNaC activity was determined as Na+ current measured by whole cell patch clamp. Results: The SGK-1 inhibitor, GSK 650394 suppressed amiloride-sensitive Na+ currents in isolated ECs, consistent with an effect on EnNaC activity. Under similar conditions INS caused concentration (0 – 100nM)-dependent stimulation of EnNaC currents. MR activation with aldosterone (24 hrs) caused an increase in EnNaC current which was absent in cells from the SGK-1 -/- mice. INS stimulated EnNaC currents were decreased in cells from SGK-1 -/- mice compared to littermate control.

Exercise intolerance in heart failure with preserved ejection fraction: time to scrutinize diuretic therapy?

Exercise intolerance in heart failure with preserved ejection fraction: time to scrutinize diuretic therapy?

Effects of sex and hypertension subtype on haemodynamics and left ventricular diastolic function in older patients with stage 1 hypertension

Hypertension is associated with cardiovascular stiffening and left ventricular diastolic dysfunction, leading to comorbidities such as heart failure with preserved ejection fraction (HFpEF). It is unknown whether sex and hypertension subtype affect haemodynamics and left ventricular function in older individuals. Ninety-five older patients with Stage 1 hypertension (ambulatory awake SBP135-159 mmHg) and 56 normotensive controls were enrolled. Patients were stratified prospectively into isolated systolic hypertension (ISH, DBP <85 mmHg) or systolic-diastolic hypertension (SDH, DBP ≥85 mmHg). Haemodynamics and Doppler variables including early filling (E) and averaged mitral annular (E'mean) velocities were measured during supine rest. Ambulatory awake blood pressures (BPs) were the highest in SDH, whereas supine SBP was similar in both hypertensive groups. No sex difference was observed in supine or ambulatory awake BPs in all groups. Stroke volume was similar among groups within the same sex, but smaller in women. Women exhibited faster E, slower E'mean and greater E/E'mean, whereas no group difference was observed in E within the same sex. In women, E'mean was significantly slower in SDH (5.9 ± 1.6 vs. 7.4 ± 1.1 cm/s, P < 0.01) and ISH (6.6 ± 1.6 cm/s, P = 0.07) than controls, resulting in the highest E/E'mean in SDH. In men, E'mean and E/E'mean were similar among the three groups. These results suggest that elderly hypertensive women may have left ventricular early diastolic dysfunction and higher estimated filling pressure, consistent with their susceptibility to HFpEF. Women with SDH seemed to have more left ventricular diastolic dysfunction, which might be explained by the greater cumulative afterload when ambulatory.

Hemodynamic and pathophysiological characteristics of intradialytic blood pressure elevation in patients with end-stage renal disease

An increase in systolic blood pressure (SBP) after hemodialysis (intradialytic-HTN) is associated with adverse outcomes in patients on regular hemodialysis. However, the hemodynamic and Doppler echocardiographic characteristics of intradialytic-HTN and its impact on clinical outcomes are unclear. A retrospective analysis of 84 patients (45 men, 70±9 years) stratified into three groups on the basis of SBP response from pre- to post-hemodialysis: GHTN (intradialytic-HTN, SBP increase 10 mm Hg), GDROP<15 mm Hg (SBP drop <15 mm Hg), and GDROP15 mm Hg (SBP drop 15 mm Hg). Hemodynamic and echocardiographic assessments were performed pre- and post-hemodialysis, and patients were followed for 41±17 months. GHTN had higher blood glucose and lower baseline SBP, serum potassium and total cholesterol. Cardiothoracic ratio was smaller, and peak early diastolic mitral annular velocity (E') was lower in GHTN. During hemodialysis, SBP and diastolic blood pressure increased only in GHTN. After hemodialysis, left ventricular (LV) filling pressure (E/E' ratio) decreased only in GDROP15 mm Hg, resulting in a higher E/E' ratio in GHTN than GDROP15 mm Hg. Multivariate logistic regression analysis revealed a positive correlation between blood glucose and intradialytic-HTN, whereas cardiothoracic ratio, pre-hemodialysis SBP and the change in E/E' ratio with hemodialysis were negatively related to intradialytic-HTN. During follow-up, GHTN had more cardiovascular deaths than GDROP15 mm Hg (P=0.03). Multivariate Cox regression analysis showed that lower serum potassium and previous coronary artery disease, but not intradialytic-HTN, were associated with cardiovascular deaths. A higher LV afterload and elevated filling pressures after hemodialysis, indicative of increased cardiovascular stiffening and impaired diastolic filling, may contribute in part to an increased cardiovascular burden in patients with intradialytic-HTN.

Cardiovascular effects of 1 year of progressive endurance exercise training in patients with heart failure with preserved ejection fraction

Heart failure with preserved ejection fraction (HFpEF) is a disease of the elderly with cardiovascular stiffening and reduced exercise capacity. Exercise training appears to improve exercise capacity and cardiovascular function in heart failure with reduced ejection fraction. However, it is unclear whether exercise training could improve cardiovascular stiffness, exercise capacity, and ventricular-arterial coupling in HFpEF. Eleven HFpEF patients and 13 healthy controls underwent invasive measurements with right heart catheterization to define Starling and left ventricular (LV) pressure-volume curves; secondary functional outcomes included Doppler echocardiography, arterial stiffness, cardiopulmonary exercise testing with cardiac output measurement, and ventricular-arterial coupling assessed by the dynamic Starling mechanism. Seven of 11 HFpEF patients (74.9 ± 6 years; 3 men/4 women) completed 1 year of endurance training followed by repeat measurements. Pulmonary capillary wedge pressures and LV end-diastolic volumes were measured at baseline during decreased and increased cardiac filling. LV compliance was assessed by the slope of the pressure-volume curve. Beat-to-beat LV end-diastolic pressure (estimated from pulmonary arterial diastolic pressure) and stroke volume index were obtained, and spectral transfer function analysis was used to assess the dynamic Starling mechanism. Before training, HFpEF patients had reduced exercise capacity, distensibility and dynamic Starling mechanism but similar LV compliance and end-diastolic volumes compared to controls albeit with elevated filling pressure and increased wall stress. One year of training had little effect on LV compliance and volumes, arterial stiffness, exercise capacity or ventricular-arterial coupling. Contrary to our hypothesis, 1 year of endurance training failed to impart favorable effects on cardiovascular stiffness or function in HFpEF.

Congestive heart failure with preserved ejection fraction is associated with severely impaired dynamic Starling mechanism

Sedentary aging leads to increased cardiovascular stiffening, which can be ameliorated by sufficient amounts of lifelong exercise training. An even more extreme form of cardiovascular stiffening can be seen in heart failure with preserved ejection fraction (HFpEF), which comprises ~40~50% of elderly patients diagnosed with congestive heart failure. There are two major interrelated hypotheses proposed to explain heart failure in these patients: 1) increased left ventricular (LV) diastolic stiffness and 2) increased arterial stiffening. The beat-to-beat dynamic Starling mechanism, which is impaired with healthy human aging, reflects the interaction between ventricular and arterial stiffness and thus may provide a link between these two mechanisms underlying HFpEF. Spectral transfer function analysis was applied between beat-to-beat changes in LV end-diastolic pressure (LVEDP; estimated from pulmonary artery diastolic pressure with a right heart catheter) and stroke volume (SV) index. The dynamic Starling mechanism (transfer function gain between LVEDP and the SV index) was impaired in HFpEF patients (n = 10) compared with healthy age-matched controls (n = 12) (HFpEF: 0.23 ± 0.10 ml·m⁻²·mmHg⁻¹ and control: 0.37 ± 0.11 ml·m⁻²·mmHg⁻¹, means ± SD, P = 0.008). There was also a markedly increased (3-fold) fluctuation of LV filling pressures (power spectral density of LVEDP) in HFpEF patients, which may predispose to pulmonary edema due to intermittent exposure to higher pulmonary capillary pressure (HFpEF: 12.2 ± 10.4 mmHg² and control: 3.8 ± 2.9 mmHg², P = 0.014). An impaired dynamic Starling mechanism, even more extreme than that observed with healthy aging, is associated with marked breath-by-breath LVEDP variability and may reflect advanced ventricular and arterial stiffness in HFpEF, possibly contributing to reduced forward output and pulmonary congestion.

Cardiovascular Effects of 1 Year of Progressive and Vigorous Exercise Training in Previously Sedentary Individuals Older Than 65 Years of Age

Healthy but sedentary aging leads to cardiovascular stiffening, whereas life-long endurance training preserves left ventricular (LV) compliance. However, it is unknown whether exercise training started later in life can reverse the effects of sedentary behavior on the heart. Twelve sedentary seniors and 12 Masters athletes were thoroughly screened for comorbidities. Subjects underwent invasive hemodynamic measurements with pulmonary artery catheterization to define Starling and LV pressure-volume curves; secondary functional outcomes included Doppler echocardiography, magnetic resonance imaging assessment of cardiac morphology, arterial stiffness (total aortic compliance and arterial elastance), and maximal exercise testing. Nine of 12 sedentary seniors (70.6±3 years; 6 male, 3 female) completed 1 year of endurance training followed by repeat measurements. Pulmonary capillary wedge pressures and LV end-diastolic volumes were measured at baseline, during decreased cardiac filling with lower-body negative pressure, and increased filling with saline infusion. LV compliance was assessed by the slope of the pressure-volume curve. Before training, Vo(2)max, LV mass, LV end-diastolic volume, and stroke volume were significantly smaller and the LV was less compliant in sedentary seniors than Masters athletes. One year of exercise training had little effect on cardiac compliance. However, it reduced arterial elastance and improved Vo(2)max by 19% (22.8±3.4 versus 27.2±4.3 mL/kg/mL; P<0.001). LV mass increased (10%, 64.5±7.9 versus 71.2±12.3 g/m(2); P=0.037) with no change in the mass-volume ratio. Although 1 year of vigorous exercise training did not appear to favorably reverse cardiac stiffening in sedentary seniors, it nonetheless induced physiological LV remodeling and imparted favorable effects on arterial function and aerobic exercise capacity.

Relationship of ambulatory arterial stiffness index with blood pressure response to exercise in the early stages of hypertension

We sought to investigate the plausible interrelationship of exaggerated blood pressure response during exercise (EBPR) with ambulatory arterial stiffness index (AASI) in never-treated patients with uncomplicated essential hypertension. Ninety-nine never-treated hypertensive patients (aged 50.7 years, 61 male) underwent 24 h ambulatory blood pressure (BP) recording, complete echocardiographic study and treadmill exercise testing and were classified as patients with (n=36) and without EBPR (n=63) based on the systolic BP elevation at peak exercise (>or=210 mmHg for men and >or=190 mmHg for women). Arterial stiffness was evaluated by means of both AASI and pulse wave velocity (PWV). Hypertensives with EBPR, compared with those without EBPR, exhibited significantly higher 24 h systolic BP and pulse pressure (by 3.8 mmHg, P=0.041 and by 7.2 mmHg, P<0.001, respectively), and decreased peak early diastolic velocity and peak early diastolic velocity/peak atrial systolic velocity ratio (by 1.1 cm/s and by 0.11, both P<0.05, respectively). PWV and AASI values were higher in the EBPR group compared with the normal response group independently of confounders (by 0.9 m/s, P<0.001 and by 0.06, P=0.043, respectively). PWV (beta=0.308, P=0.008) and 24-h pulse pressure (beta=0.297, P=0.010), but not AASI, were independently associated with peak exercise systolic BP. EBPR constitutes a sign of premature cardiovascular stiffening in the setting of uncomplicated hypertension. The close relationship between EBPR and PWV but not AASI enhances the concept of PWV as a superior measure of arterial stiffness and constitutes an important factor in the interpretation of EBPR-linked cardiovascular risk.

Abstract 5529: Excessive Inotropic Response During Exercise Reflects Cardiovascular Stiffening in Newly Diagnosed Essential Hypertensives

Introduction: Exaggerated blood pressure response during exercise (EBPR) is associated with high risk for worsening hypertension, while arterial stiffness and left ventricular (LV) diastolic dysfunction have both been related with adverse cardiovascular outcomes. Hypothesis: EBPR may be associated with arterial stiffness and LV diastolic dysfunction in a large cohort of hypertensives. Methods: 222 untreated non-diabetics (152 males, mean age 54 years) with stage I – II EH underwent treadmill exercise testing and were classified as hypertensives with EBPR (n=75) based on the systolic BP elevation ≥210mmHg for men and ≥190mmHg for women, at peak exercise. The remaining patients were classified as normal inotropic responders (n=147). In all subjects carotid to femoral pulse wave velocity (PWV) was measured by means of Complior SP, while LV diastolic function was estimated by pulsed Tissue Doppler Imaging (TDI), averaging diastolic mitral annular velocities (Em, Am) from 4 separate sites of measurement. Results: Hypertensives with EBPR compared to normal inotropic responders had increased 24-hour systolic BP (137.4±10 vs 134±9mmHg, p=0.013) and PP (52.6±8 vs 49±7mmHg, p=0.001), while there was no difference in terms of age, sex and body mass index. Hypertensives with EBPR exhibited also greater relative wall thickness (0.47±0.06 vs 0.44±0.07, p=0.014), E/Em (9.45±3.1 vs 8.35±3.3, p=0.034) and PWV (9.1±1.6 vs 8.5±1.3m/s, p=0.007), as well as significantly lower values of Em (8.5±2.5 vs 9.4±2.9cm/s, p=0.046), while they did not differ in LV mass index and transmitral flow Doppler parameters (p=NS for all). Exercise capacity was also significantly deteriorated in hypertensives with EBPR based on the lower values of achieved METs (9.95±2.3 vs 11±2.3, p=0.003). Peak systolic BP at exercise was correlated with 24-hour systolic BP (r=0.240, p&lt;0.001), 24-hour PP (r=0.218, p=0.001), PWV (r=0.152, p=0.046) and E/Em (r=0.150, p=0.049). Multiple logistic regression analysis revealed that PWV was the only independent predictor of EBPR (OR=1.31, p=0.047). Conclusions: EBPR constitutes a sign of cardiovascular stiffening in the setting of newly diagnosed EH, further elucidating the adverse prognostic role of abnormal systolic BP elevation at peak exercise.

Brain natriuretic peptide as an integrator of cardiovascular stiffening in hypertension

Background Left ventricular (LV) diastolic dysfunction and impairment of aortic elastic properties represent common sequelae of hypertension. We investigated the relationships of these cardiovascular adaptations with brain natriuretic peptide (BNP) levels in newly-diagnosed hypertension. Methods 200 consecutive hypertensives without LV hypertrophy (aged 52 years, 134 males, office BP = 151.4/95.5 mmHg) underwent 24 hour ambulatory BP measurement as well as aortic stiffness and LV diastolic function assessment by means of carotid-femoral pulse wave velocity (c-f PWV) measurement and Tissue Doppler Imaging (TDI), respectively. Based on BNP values patients were classified into tertiles. Results Hypertensives in the highest, compared to those in the lowest BNP tertile had significantly higher 24 h pulse pressure (by 6.2 mmHg, p = 0.002), lower 24 h diastolic BP (by 5.7 mmHg, p = 0.014), decreased Em/Am ratio (by 0.09, p = 0.048) and increased c-f PWV (by 0.7 m/s, p = 0.042). Moreover, hypertensives in the highest, compared with those in the lowest and the medium tertile of BNP, exhibited significantly lower Em (by 1.2 cm/s, p = 0.001 and 1 cm/s, p = 0.004, respectively) and higher E/Em ratio (by 1.3, p = 0.018 and 1.3, p = 0.014, respectively). BNP was significantly associated with E/Em ratio, 24 h pulse pressure and c-f PWV independently from age. Conclusion In hypertensives plasma BNP levels are associated not only with LV diastolic dysfunction but also with aortic stiffening. These findings suggest that BNP even within normal range constitutes a surrogate for cardiovascular functional impairment in the setting of essential hypertension without LV hypertrophy.

Nitrite-Induced Cross-Linking Alters Remodeling and Mechanical Properties of Collagenous Engineered Tissues

Cumulative damage to long-lived connective tissue proteins play a key role in the development of age-related human diseases such as cardiovascular stiffening and age-related macular degeneration. The processes that result in the accumulation of increasingly insoluble, undigestible damaged collagen are only partially known. Nonenzymatic glycation (NEG) is one such process and has been linked to the development of diabetic-related complications and aging. An additional novel mechanism particularly relevant to smoking- and inflammation-related diseases involves the nonenzymatic nitrite (NEN) modification of connective tissue proteins. The present study was undertaken to examine the effects of NEN of fibrillar type I collagen on cell-mediated remodeling and mechanical properties of collagenous tissues. Using a modification of an in vitro fibroblast-populated collagen gel model system developed in our laboratory, we tested two hypotheses: NEN reduces the ability of primary adult cardiac fibroblasts to remodel type I collagen gels; NEN reduces the deformability of type I collagen gels subjected to mechanical testing. The results show that NEN impairs both cell-mediated remodeling and mechanical deformability in collagenous engineered tissues. Furthermore, these mechanical changes correlate with the degree of cross-linking as determined by SDS-PAGE. Thus, we concluded that NEN reactions may contribute to alterations in the biomechanical properties of collagen-containing tissues consistent with the age-related functional decline observed in human disease.