Diastolic Stiffness Research Articles

Abstract 11168: Right Atrial Adaptation in Pulmonary Hypertension: In-Depth Pressure-Volume Analysis

Introduction: Pulmonary hypertension (PH) is associated with increased right atrial (RA) pressure and volume. We hypothesized that RA stroke work and RA stiffness are higher in PH patients in comparison to healthy controls. Methods: RA PV loops were created through a novel method. RA volume was measured throughout the cardiac cycle on a magnetic resonance transverse stack of slices (typically 8-10). RA pressure was averaged over at least 10 cardiac cycles and approximately two respiratory cycles. Alignment of RA volume and pressure was done based on the v-wave (peak during ventricular contraction, see figure). RA stroke work was calculated as the area under the PV loop from the p-wave (start of atrial contraction) to the minimal RA volume. RA active emptying as the difference between p-wave and minimal volume. An exponential curve was fitted through the reservoir portion of the PV loop from the x-descent to the v-wave. The slope of this curve at the v-wave (RA end-reservoir elastance) was determined as a measure of RA stiffness. Results: RA PV loops were created for healthy controls (n=9) and PH patients (n=27). The averaged PV loops in the figure show RA dilatation in PH patients as well as elevated pressure, especially during atrial contraction. The difference between RA maximal pressure and p-wave pressure was higher in PH patients in comparison with controls (4.01 [3.12-6.75] vs 2.83 [2.54-3.06] mmHg; p=0.001). RA stroke work (493±253 vs 171±50 mmHg*ml; p=0.001) and active emptying (41±13 vs 23±5 ml; p<0.001) were also higher in PH, while RA end-reservoir elastance was not (0.26 [0.23-0.37] vs 0.33 [0.24-0.64] mmHg/ml; p=0.22). Conclusions: PH patients have increased RA stroke work and active emptying, as assessed with a novel method to derive RA PV loops. They do not show signs of RA stiffening. Future associations with right ventricular diastolic stiffness will show whether RA stroke work is able to match the increase in RA afterload.

Right atrial function is associated with right venticular diastolic stiffness: RA-RV interaction in pulmonary arterial hypertension.

BackgroundPulmonary arterial hypertension (PAH) patients have altered right atrial (RA) function and right ventricular (RV) diastolic stiffness. This study assessed the impact of RV diastolic stiffness on RA–RV interaction.MethodsPAH patients with low or high end-diastolic elastance (Eed) (n=94) were compared with controls (n=31). Treatment response was evaluated in 62 patients. RV and RA longitudinal strain, RA emptying and RV filling were determined and diastole was divided into a passive and active phase. Vena cava backflow was calculated as RA active emptying−RV active filling and RA stroke work as RA active emptying×RV end-diastolic pressure.ResultsWith increased Eed, RA and RV passive strain were reduced while active strain was preserved. In comparison to controls, patients had lower RV passive filling but higher RA active emptying and RA stroke work. RV active filling was lower in patients with high Eed, resulting in higher vena cava backflow. Upon treatment, Eed was reduced in ~50% of the patients with high Eed, which coincided with larger reductions in afterload, RV mass and vena cava backflow and greater improvements in RV active filling and stroke volume in comparison with patients in whom Eed remained high.ConclusionsIn PAH, RA function is associated with changes in RV function. Despite increased RA stroke work, severe RV diastolic stiffness is associated with reduced RV active filling and increased vena cava backflow. In 50% of patients with high baseline Eed, diastolic stiffness remained high, despite treatment. A reduction in Eed coincided with a large reduction in afterload, increased RV active filling and decreased vena cava backflow.

Diabetes and SGLT2-iss inhibitors in patients with heart failure with preserved or mid-range left ventricular ejection fractions.

Diabetic patients frequently develop heart failure with preserved (HFpEF) or mid-range (HFmEF) cardiac ejection fractions. This condition may be secondary to diabetic cardiomyopathy or one of several relevant comorbidities, mainly hypertension. Several mechanisms link diabetes to HFpEF or HFmEF. Among these, non-enzymatic glycation of interstitial proteins, lipotoxicity, and endothelial dysfunction may promote structural damage and ultimate lead to heart failure. Findings from several large-scale trials indicated that treatment with sodium/glucose cotransporter 2 inhibitors (SGLT2-iss) resulted in significant improvements in cardiovascular outcomes in diabetic patients with high cardiovascular risk. However, there is currently some evidence that suggests a clinical advantage of using SGLT2-iss specifically in cases of HFpEF or HFmEF. Preclinical and clinical studies revealed that SGLT2-iss treatment results in a reduction in left ventricular mass and improved diastolic function. While some of the beneficial effects of SGLT2-iss have already been characterized (e.g., increased natriuresis and diuresis as well as reduced blood pressure, plasma volume, and arterial stiffness, and nephron-protective activities), there is increasing evidence suggesting that SGLT2-iss may have direct actions on the heart. These findings include SGLT2-iss-mediated reductions in the expression of hypertrophic foetal genes and diastolic myofilaments stiffness, increases in global phosphorylation of myofilament regulatory proteins (in HFpEF), inhibition of cardiac late sodium channel current and Na+/H+ exchanger activity, metabolic shifts, and effects on calcium cycling. Preliminary data from previously published studies suggest that SGLT2-iss could be useful for the treatment of HFpEF and HFmEF. Several large ongoing trials, including DELIVER AND EMPEROR -preserved have been designed to evalute the efficacy of SGLT2-iss in improving clinical outcomes in patients diagnosed with HFpEF. The goal of this manuscript is to review the use of SGLT2-iss inhibitors for HFpEF or HFmEF associated with diabetes.

Coffee Pulp, a By-Product of Coffee Production, Modulates Gut Microbiota and Improves Metabolic Syndrome in High-Carbohydrate, High-Fat Diet-Fed Rats.

Waste from food production can be re-purposed as raw material for usable products to decrease industrial waste. Coffee pulp is 29% of the dry weight of coffee cherries and contains caffeine, chlorogenic acid, trigonelline, diterpenes and fibre. We investigated the attenuation of signs of metabolic syndrome induced by high-carbohydrate, high-fat diet in rats by dietary supplementation with 5% freeze-dried coffee pulp for the final 8 weeks of a 16-week protocol. Coffee pulp decreased body weight, feed efficiency and abdominal fat; normalised systolic blood pressure, left ventricular diastolic stiffness, and plasma concentrations of triglycerides and non-esterified fatty acids; and improved glucose tolerance in rats fed high-carbohydrate, high-fat diet. Further, the gut microbiota was modulated with high-carbohydrate, high-fat diet and coffee pulp supplementation and 14 physiological parameters were correlated with the changes in bacterial community structures. This study suggested that coffee pulp, as a waste from the coffee industry, is useful as a functional food for improving obesity-associated metabolic, cardiovascular and liver structure and function, and gut microbiota.

Increased Excess Pressure After Creation of an Arteriovenous Fistula in End-Stage Renal Disease.

ABSTRACTBACKGROUNDReservoir-wave analysis (RWA) separates the arterial waveform into reservoir and excess pressure (XSP) components, where XSP is analogous to flow and related to left ventricular workload. RWA provides more detailed information about the arterial tree than traditional blood pressure (BP) parameters. In end-stage renal disease (ESRD), we have previously shown that XSP is associated with increased mortality and is higher in patients with arteriovenous fistula (AVF). In this study, we examined whether XSP increases after creation of an AVF in ESRD.METHODSBefore and after a mean of 3.9 ± 1.2 months following creation of AVF, carotid pressure waves were recorded using arterial tonometry. XSP and its integral (XSPI) were derived using RWA through pressure wave analysis alone. Aortic stiffness was assessed by carotid–femoral pulse wave velocity (CF-PWV).RESURLTSIn 38 patients (63% male, age 59 ± 15 years), after AVF creation, brachial diastolic BP decreased (79 ± 10 vs. 72 ± 12 mm Hg, P = 0.002), but the reduction in systolic BP, was not statistically significant (133 ± 20 vs. 127 ± 26 mm Hg, P = 0.137). However, carotid XSP (14 [12–19] to 17 [12–22] mm Hg, P = 0.031) and XSPI increased significantly (275 [212–335] to 334 [241–439] kPa∙s, P = 0.015), despite a reduction in CF-PWV (13 ± 3.6 vs. 12 ± 3.5 m/s, P = 0.025).CONCLUSIONSCreation of an AVF resulted in increased XSP in this population, despite improvement in diastolic BP and aortic stiffness. These findings underline the complex hemodynamic impact of AVF on the cardiovascular system.

Diastolic disorder inherent to doxorubicin cardiotoxicity

Background: The doxorubicin (Dx) cardiotoxicity is manifested by a marked heart failure evolution. The impact of Dx on lusitrop functions of the heart and the inherent diastolic disorders have a theoretical and practical value for the connection cardiology-oncology. Material and methods: Dx cardiotoxicity was reproduced by its administration i/p in white rats in cumulative dose 16 mg/kg (Dx group n=9). Control group (n=9) received only physiological solution. The study was performed in vitro by using models of isolated heart perfusion in either isovolumic or exterior working regimens. The assayed indices of diastole functioning were: left ventricle (LV) end-diastolic pressure (LVEDP), diastolic stiffness, isovolumic relaxation velocity (-dP/dTmax) and protodiastolic pressure of LV (LVPDP). Results: The indices of diastolic disorders induced by Dx were elevation of LVEDP, diastolic stiffness and LVPDP in a range of 97-168% comparing to control as well as diminution of -dP/dTmax in the physiological pattern of hemodynamics. LVEDP increased more in conditions of calcium overloading or endothelin-1 (ET-1) action that are involved in pathogenesis of diastolic rigidity. Dx action led to decrease of myocardium resistance to ischemiareperfusion action resulting in the LVEDP elevation by 53% comparing to control. Conclusions: 1. Diastolic disorders inherent to Dx cardiotoxicity are manifested by the increase of LVEDP and diastolic stiffness. 2. Diastolic disorders compromised the volume-pressure relationship of LV, the adaptation of the heart to effort with volume, being more pronounced during the action of calcium excess and ET-1

Externally induced shear waves in the right ventricular free wall during the cardiac cycle

Increased right ventricular (RV) diastolic stiffness is linked to adverse prognosis in pulmonary arterial hypertension. Currently, a non-invasive method for measuring RV stiffness is lacking. In the left ventricle, shear wave (SW) speed is related to diastolic stiffness. We show for the first time that SWs in the RV free wall (RVFW) can be induced and imaged transthoracically with ultrasound. SW imaging was performed using an L7-4 array (ATL, USA) with a Vantage 256 system (Verasonics, USA) in a 5-weeks-old Yorkshire-Landrace pig (±120 beats/min). SWs were induced by a push beam (f0 = 4.5MHz, push duration = 800μs) on the RVFW and its propagation was imaged (f0 = 5.2MHz) using plane wave compounding (-12 deg, 0 deg, +12 deg) at 3 kHz framerate. Three acquisitions of 1 s were performed, where fourteen SWs were sequentially induced during each acquisition. SW propagation speeds were calculated using a semi-automatic pipeline that includes tissue velocity estimation along a manually traced spline on the RVFW, and Radon transform to estimate SW speed. At least 85% of the waves were tracked successfully for all acquisitions. The SW velocities varied during the heart cycle as expected, ranging from 0.58 ± 0.09 m/s at end-diastole to 1.8 ± 0.2 m/s during systole. Pathological increase in stiffness may be demonstrated in longitudinal case/control studies.

Distinct time courses and mechanics of right ventricular hypertrophy and diastolic stiffening in a male rat model of pulmonary arterial hypertension.

Although pulmonary arterial hypertension (PAH) leads to right ventricle (RV) hypertrophy and structural remodeling, the relative contributions of changes in myocardial geometric and mechanical properties to systolic and diastolic chamber dysfunction and their time courses remain unknown. Using measurements of RV hemodynamic and morphological changes over 10 wk in a male rat model of PAH and a mathematical model of RV mechanics, we discriminated the contributions of RV geometric remodeling and alterations of myocardial material properties to changes in systolic and diastolic chamber function. Significant and rapid RV hypertrophic wall thickening was sufficient to stabilize ejection fraction in response to increased pulmonary arterial pressure by week 4 without significant changes in systolic myofilament activation. After week 4, RV end-diastolic pressure increased significantly with no corresponding changes in end-diastolic volume. Significant RV diastolic chamber stiffening by week 5 was not explained by RV hypertrophy. Instead, model analysis showed that the increases in RV end-diastolic chamber stiffness were entirely attributable to increased resting myocardial material stiffness that was not associated with significant myocardial fibrosis or changes in myocardial collagen content or type. These findings suggest that whereas systolic volume in this model of RV pressure overload is stabilized by early RV hypertrophy, diastolic dilation is prevented by subsequent resting myocardial stiffening.NEW & NOTEWORTHY Using a novel combination of hemodynamic and morphological measurements over 10 wk in a male rat model of PAH and a mathematical model of RV mechanics, we found that compensated systolic function was almost entirely explained by RV hypertrophy, but subsequently altered RV end-diastolic mechanics were primarily explained by passive myocardial stiffening that was not associated with significant collagen extracellular matrix accumulation.

Hipertansif hastalarda presistolik A dalgası ile aort distensibilitesi arasındaki ilişki

Purpose: Arterial stiffness has been shown as an independent predictor of cardiovascular and all-cause mortality in hypertensive patients. commonly seen in pulse wave Doppler echocardiographic examination of the left ventricle outflow tract, is related to diastolic dysfunction and arterial stiffness parameters. Our study aims to investigate the relation between aortic distensibility (AD) and presystolic A wave (PSW),.
 Materials and Methods: Hypertensive patients were included in the study. Aortic stiffness was calculated by measuring aortic diameters with m-mode in echocardiography, and the presence of PSW was noted from the left ventricle outflow tract just proximal to the aortic valve in apical five-chamber view. 
 Results: A total of 149 hypertensive patients were included. Diastolic blood pressure, septum diameter, posterior wall diameter, aortic diastolic, and systolic diameter were significantly higher in the presence of PSW. Aortic distensibility (AD) was higher in patients with PSW. Multivariable logistic regression analysis showed that AD (OR: 0.812, 95% CI: 0.712 – 0.927, p = 0.002) was an independent predictor of PSW presence. 
 Conclusion: PSW presence is associated with aortic stiffness evaluated by decreased aortic distensibility and highlights that PSW presence could be an independent predictor of aortic stiffness in patients with HT.

Influence of Left Ventricular Function on the "Aortic Regurgitation Index" Proposed for the Hemodynamic Assessment of Postprocedural Aortic Regurgitation.

The aortic regurgitation (AR) index, proposed as an objective indicator of postprocedural AR, decreases in proportion to AR severity, besides reportedly providing additional prognostic information. Meanwhile, left ventricular (LV) function has also been considered an essential prognostic factor. This study aimed to clarify whether LV function affected the AR index using cardiac catheterization data.A retrospective study was performed in patients whose LV function was evaluated using a micromanometer-tipped catheter. Patients with grade 2 or higher AR were excluded to explore non-AR factors affecting the AR index value. The AR index was calculated as a ratio of the gradient between the aortic diastolic blood pressure (DBP) and the LV end-diastolic pressure (EDP) to the aortic systolic blood pressure (SBP): AR Index = [ (DBP - LVEDP) / SBP] × 100.A total of 64 patients [age, 62 (interquartile range: 48-70) years; LV ejection fraction, 19% (16%-26%) ] were examined. AR index values ranged from 18.3 to 68.6. Despite having no AR, two patients displayed an AR index < 25, indicating significant AR. Multiple-regression analysis revealed that LV diastolic stiffness (β = -0.750, P < 0.001), LV max dP/dt (β = -0.296, P = 0.006), and heart rate (β = 0.284, P = 0.011) were independent determinants of the AR index value.Patients with impaired LV diastolic function and preserved systolic function had low AR index values. The additional prognostic information of the AR index may be related to LV diastolic function.

Abstract P104: Simultaneous Treatment With Ivabradine And Spironolactone Does Not Modify Hypertension-induced Myocardial Fibrosis In Dahl Salt-sensitive Rats

Background: Hypertension (HT)-induced accumulation of myocardial collagen stiffens the left ventricular (LV) wall and, hence, promotes diastolic dysfunction. Considering that a competitive aldosterone receptor antagonist spironolactone (SL) as well as a “pure” heart rate-lowering drug ivabradine (IVA) have both been proven to exert an anti-fibrotic effect during cardiac remodeling, we hypothesized that, in combination, these drugs would complement each other in alleviating HT-induced myocardial fibrosis and, therefore, could better preserve diastolic function. Methods: Sustained HT was induced in 7-week-old male Dahl salt-sensitive rats by feeding them a high-salt (8%) diet for 7 weeks. Then, HT rats were randomly assigned in two experimental groups: 1) IVA (10 mg/kg/day) + SL (20 mg/kg/day)-treated (HT-T) and 2) vehicle only (HT-V). The drugs and the vehicle (a mixture of 50% dimethyl sulfoxide/50% propylene glycol, v/v) were delivered IP by osmotic pumps for 8 weeks. The age-matched rats were used as normotensive controls (NT). Heart rate (HR) and blood pressure (BP) were recorded every other week using a CODA tail-cuff plethysmography system. At the end of the study, the hemodynamic parameters were assessed using a Millar pressure catheter and the hearts were collected for histology and quantitative morphometry. Statistical analysis was performed using Prism 6. Results: We found that during 8-week treatment period, BP had remained comparably elevated in both HT groups by ~26% (P≤0.01) on average vs. NT rats, whereas HR had been persistently reduced in HT-T group by ~38% and ~27% (P≤0.01) on average vs. HT-V and NT rats, respectively. At the end of the study period, all groups revealed a similar level of LV end-diastolic pressure, suggesting the analogous diastolic stiffness of the myocardium. At the same time, morphological examination of the hearts has confirmed that sustained HT caused significant interstitial and perivascular fibrosis (P≤0.01) in both experimental groups compared to NT rats, and that the treatment did not change the extent of fibrillar collagen accumulation as compared to HT-V rats. Conclusions: Taken together, our findings confirmed that a combined treatment with IVA and SL could not alleviate HT-induced myocardial fibrosis.

Lower muscular strength is associated with smaller left and right chambers and lower cardiac mass in the general population – The Sedentary's Heart

BackgroundThe cardiac muscle has the ability to adapt to different loading conditions. We analyzed the associations of the age-related decreasing handgrip strength (HGS), a marker of muscular fitness, on cardiac structure and function in a community-based sample. MethodsWe performed cross-sectional analyses of 4646 subjects (2554 women; 55.0%) aged 20 to 93 years from two independent cohorts of the Study of Health in Pomerania (SHIP-2 and SHIP-TREND-0). We analyzed the associations of HGS with structural and functional left and right ventricular (LV and RV) and left atrial (LA) parameters as determined by echocardiography and magnetic resonance imaging (MRI) as well with log-transformed NT-proBNP values using multivariable-adjusted linear regression models. ResultsMRI data showed that a 1 kg lower HGS was associated with a 0.40 mL (95% confidence interval: 0.26 to 0.54; p < 0.001) lower LV end-diastolic volume, a 0.011 mm (0.005 to 0.018; p = 0.001) lower LV wall-thickness, a 0.59 g (0.43 to 0.75; p < 0.001) lower LV mass, a 0.58 mL/beat (0.43 to 0.74; p < 0.001) lower LV stroke volume, a 0.03 L/min (0.02 to 0.04; p < 0.001) lower LV cardiac output, a 0.48 mL (0.27 to 0.68; p < 0.001) lower LA end-diastolic volume, and a 1.02 mL (0.71 to 1.32) lower RV end-diastolic volume. Similar findings were observed for echocardiographic parameters. Moreover, lower HGS was associated with higher echocardiographic LV diastolic stiffness and NT-proBNP levels. ConclusionsIn this large population-based sample, lower muscular fitness as assessed by HGS was associated with lower LV wall thickness and mass as well as with smaller chamber size, stroke volume and cardiac output of the LV, LA and RV. Moreover, HGS was inversely related to LV diastolic stiffness and NT-proBNP values. These outcomes might demonstrate the effects of an aging-related decrease in physical activity and lower muscular fitness on the heart - “the sedentary's heart”.

Coarctation of aorta is associated with left ventricular stiffness, left atrial dysfunction and pulmonary hypertension

Brachial systolic blood pressure (BP) is the most commonly used metric for monitoring hypertension. However, recent studies suggest that brachial systolic BP underestimates left ventricle (LV) systolic load in patients with coarctation of aorta (COA). Since brachial systolic BP is used as a surrogate of arterial afterload in clinical practice, it is important to determine how well it correlates with LV remodeling and stiffness in patients with COA as compared to patients with idiopathic hypertension. This is cross-sectional study of COA patients with hypertension (COA group) and adults with idiopathic hypertension (control group). Both groups were matched 1:1 based on age, sex, BMI and systolic BP. We hypothesized that the COA group will have higher LV systolic and diastolic stiffness, and more advanced left atrial remodeling and pulmonary hypertension. We assessed LV systolic stiffness using end-systolic elastance, and diastolic stiffness using LV stiffness constant and chamber capacitance (LV-end-diastolic volume at an end-diastolic pressure of 20mm Hg) RESULTS: There were 112 patients in each group. Although both groups had similar systolic BP, the COA group had a higher end-systolic elastance (2.37 ± 0.74 vs 2.11 ± 0.54 mm Hg/mL, P= .008), higher LV stiffness constant (6.91 ± 0.81 vs 5.93 ± 0.79, P= .006) and lower LV-end-diastolic volume at an end-diastolic pressure of 20mm Hg (58 ± 9 vs 67 ± 11 mL/m2, P< .001). Additionally, the COA group had more advanced left atrial remodeling and higher pulmonary artery pressures which is corroborating evidence of high LV filling pressure. COA patients have more LV stiffness and abnormal hemodynamics compared to non-COA patients with similar systolic BP, suggesting that systolic BP may underestimate LV systolic load in this population. Further studies are required to determine whether the observed LV stiffness and dysfunction translates to more cardiovascular events during follow-up, and whether adopting a stricter systolic BP target in clinical practice or changing threshold for COA intervention will lead to less LV stiffness and better clinical outcomes.

RA pressure waveforms as a means for describing right ventricular diastolic stiffness

Introduction Exercise-induced changes in right atrial (RA) pressure associates with morality in patients with pulmonary hypertension (PH). Increased right ventricular (RV) diastolic stiffness impairs right ventricular filling during atrial contraction. Right atrial waveforms consist of the a-wave (atrial contraction) and v-wave (RA passive filling), as well as x and y descents representing atrial relaxation and ventricular filling, respectively. Ventricular distensibility has been associated with the difference between the x- and y-descents (x-y difference) in RA pressure. A positive x-y difference correlates with increased ventricular stiffness. The study aim was to investigate the relationship between RA pressure waveforms and RV diastolic function in patients with pulmonary arterial hypertension (PAH). We hypothesized that exercise-induced increases in RA pressure associate with increased RV diastolic stiffness and a positive x-y difference. Methods Participants (n = 52) with a right heart catheterization (RHC) and invasive cardiopulmonary exercise test were selected from the University of Arizona Pulmonary Hypertension Registry. Resting (REST) and peak exercise (EX) measurements of RA pressure (RAP), pulmonary artery pressure (PAP), cardiac output (CO), and heart rate (HR) were analyzed. Raw RA waveforms were analyzed to identify the a-wave, v-wave, and x- and y-descents using a custom MATLAB program. Single-beat methods were used to calculate end-diastolic elastance (Eed) a measure of RV stiffness. Wilcoxon signed-rank test was used test differences between rest and exercise conditions (R version 4.0.3). Data is presented as mean ± standard deviation or median [IQR]. A p< 0.05 is considered significant. Results Forty-three participants with pulmonary arterial hypertension diagnosis (age: 53 ± 13, sex: 73% female) and 9 participants without PH (age: 61 ± 13 years, sex: 100% female) were included. At rest, patients with pulmonary hypertension have increased PAP (37 ± 11 vs 16 ± 5 mmHg, p < 0.001) but no significant differences in RAP (2.7 [0.5-4.7] vs 0.1 [-0.1 – 3.0] mmHg, p = 0.4). There is a non-significant increase in Eed (0.61 [0.34-0.93] vs. 0.31 [0.26-0.53] mmHg/ml, p = 0.07) compared to controls. At peak exercise (PAH: 20 [10-50] W and controls: 30 [10-60] W), RA pressure significantly increased (Figure 1A). Participants with PAH had an exercise-induced increase in RA x-descent (Figure 1B) and y-descent (Figure 1C). There was an exercise-induced decrease in the x-y descent in participants with PAH but not Controls (Figure 1D). The x-y difference did not correlate with resting Eed at rest (p = 0.58) or peak exercise (p = 0.22). Discussion/Conclusion Exercise significantly increased average RA, x-descent, and y-descent pressure. The RA x-y difference did not correlate with end-diastolic elastance, another measure of ventricular stiffness. Overall, exercise decreased the x-y difference in participants with PAH that suggests an exercise-induced increase in ventricular distensibility. Further investigations are needed to determine if exercise-induced changes in RA pressure can unmask structural or pressure induced changes in RV diastolic function.

Repetitive Preload Elevation and Stretch‐Induced Stiffening of Non‐Ischemic Myocardium in a Porcine Model of Multi‐Vessel Coronary Artery Disease

Objective We have recently shown that a transient elevation in left ventricular (LV) preload causes stretch-induced myocyte injury, with repetitive episodes resulting in interstitial fibrosis and reduced diastolic compliance. The present study was designed to test the hypothesis that this phenomenon contributes to stiffening of remote, non-ischemic myocardium that is subjected to repetitive preload elevation secondary to demand-induced ischemia in the setting of chronic multi-vessel coronary artery disease (CAD). Methods Swine (n=12) were instrumented with fixed 1.5 mm constrictors on the proximal left anterior descending (LAD) and left circumflex (LCx) coronary arteries. One month later, continuous ECG and LV pressure monitoring was initiated via implantable telemetry (PhysioTel Digital, DSI) to assess the frequency of preload elevation (LV end-diastolic pressure (EDP) > 30 mmHg) and tachycardia (heart rate > 170 beats/min). Serial physiological studies were performed for 3 months to assess stenosis severity (angiography), coronary flow reserve (fluorescent microspheres at rest and during adenosine vasodilation), and LV function (echocardiography). Circumferential diastolic stiffness was derived from stress-strain relationships obtained via speckle tracking echocardiography and invasive measurements of LV minimum pressure and EDP. Myocardial tissue samples were subsequently collected from the LAD (ischemic) and right coronary artery (RCA; non-ischemic) perfusion territories for post-mortem quantification of collagen content (hydroxyproline assay) and comparison to normal controls (n=8). Results By the end of the 3 month study period, animals exhibited severe LAD (93 ± 2 %) and LCx (91 ± 3 %) stenoses and significant reductions in subendocardial flow reserve (LAD: 1.4 ± 0.2; LCx: 1.3 ± 0.2) relative to the RCA territory (3.8 ± 0.6). Although LV EDP was only mildly elevated at rest (18 ± 2 mmHg), transient preload elevation occurred frequently (63 ± 10 episodes/day) and resulted in a total of 199 ± 45 min/day during which LV EDP exceeded 30 mmHg. Spontaneous tachycardia was also common (26 ± 5 episodes/day) and associated with transient elevations in LV EDP (28 ± 2 mmHg; p<0.05 vs. rest). Although LV ejection fraction was preserved (58 ± 3 %), radial and circumferential strain was depressed in ischemic and non-ischemic segments of the LV compared with controls (Table). Non-ischemic segments also exhibited increased diastolic stiffness, which coincided with a significant ~40% elevation in collagen content (0.31 ± 0.03 mg/g) vs. normal controls (0.22 ± 0.03 mg/g) that was comparable to that observed in the ischemic area of the LV (0.29 ± 0.02 mg/g). Conclusions Transient elevations in preload are common in swine with multi-vessel CAD and associated with interstitial fibrosis and myocardial stiffening in normally-perfused segments of the LV. Repetitive stretch-induced stiffening of remote myocardium may contribute to diastolic dysfunction and could explain the high prevalence of angiographically-significant CAD in patients with heart failure with preserved ejection fraction (HFpEF).

Using a General Algebraic Formula to Identify the Primary Mechanical Properties Impacting Blood Loss Capacity

The physiological response to hypovolemia is conventionally characterized in terms of clinical symptoms rather than fundamental homeostatic mechanisms. It is well understood how complex changes in the mechanical properties of the ventricles and the vasculature are coordinated to regulate arterial pressure and cardiac output. However, these mechanical properties in animal models are difficult to measure and control. Although complex mathematical models of the cardiovascular system have been developed to predict how changes in mechanical properties affect hemodynamic variables, solutions require assumption of a specific set of parameter values that characterizes each subject. Unlike complex mathematical models, however, equations characterizing simple closed-loop cardiovascular models can be solved algebraically, which provides general algebraic formulas applicable to all mammals in health and disease. Therefore, the purpose of the present work is to use a simple closed-loop model to develop an algebraic formula for maximum blood loss in terms of the mechanical properties of the cardiovascular system. First, the standard minimal closed-loop model was assumed, consisting of four vascular compartments, two ventricles, and two resistances. Second, to solve the set of eight model equations algebraically, the ventricular end-diastolic pressure-volume relationships were linearized. Third, the impact of the baroreflex was assumed to be limited by a maximum heart rate and cardiac contractility, as well as a maximum change in unstressed vascular volumes. Fourth, the blood loss capacity was assumed to be exhausted when mean arterial pressure and cardiac output have reached their minimum levels following failure of homeostatic mechanisms. For healthy adults, it was found that the mechanical properties having the greatest impact on blood loss capacity are venous compliances, ventricular diastolic stiffness, and the maximum change in vascular unstressed volume. This algebraic formula is a novel tool for clinical investigators to address challenges as diverse as comparing experimental results across mammalian species, identifying risk factors for adverse outcomes, and exploring new clinical strategies to extend blood loss capacity.

Sacubitril/valsartan inhibits obesity-associated diastolic dysfunction through suppression of ventricular-vascular stiffness

ObjectiveCardiac diastolic dysfunction (DD) and arterial stiffness are early manifestations of obesity-associated prediabetes, and both serve as risk factors for the development of heart failure with preserved ejection fraction (HFpEF). Since the incidence of DD and arterial stiffness are increasing worldwide due to exponential growth in obesity, an effective treatment is urgently needed to blunt their development and progression. Here we investigated whether the combination of an inhibitor of neprilysin (sacubitril), a natriuretic peptide-degrading enzyme, and an angiotensin II type 1 receptor blocker (valsartan), suppresses DD and arterial stiffness in an animal model of prediabetes more effectively than valsartan monotherapy.MethodsSixteen-week-old male Zucker Obese rats (ZO; n = 64) were assigned randomly to 4 different groups: Group 1: saline control (ZOC); Group 2: sacubitril/valsartan (sac/val; 68 mg•kg−1•day−1; ZOSV); Group 3: valsartan (31 mg•kg−1•day−1; ZOV) and Group 4: hydralazine, an anti-hypertensive drug (30 mg•kg−1•day−1; ZOH). Six Zucker Lean (ZL) rats that received saline only (Group 5) served as lean controls (ZLC). Drugs were administered daily for 10 weeks by oral gavage.ResultsSac/val improved echocardiographic parameters of impaired left ventricular (LV) stiffness in untreated ZO rats, without altering the amount of food consumed or body weight gained. In addition to improving DD, sac/val decreased aortic stiffness and reversed impairment in nitric oxide-induced vascular relaxation in ZO rats. However, sac/val had no impact on LV hypertrophy. Notably, sac/val was more effective than val in ameliorating DD. Although, hydralazine was as effective as sac/val in improving these parameters, it adversely affected LV mass index. Further, cytokine array revealed distinct effects of sac/val, including marked suppression of Notch-1 by both valsartan and sac/val, suggesting that cardiovascular protection afforded by both share some common mechanisms; however, sac/val, but not val, increased IL-4, which is increasingly recognized for its cardiovascular protection, possibly contributing, in part, to more favorable effects of sac/val over val alone in improving obesity-associated DD.ConclusionsThese studies suggest that sac/val is superior to val in reversing obesity-associated DD. It is an effective drug combination to blunt progression of asymptomatic DD and vascular stiffness to HFpEF development in a preclinical model of obesity-associated prediabetes.

Left-ventricular hypertrophy in 18-month-old donor rat hearts was not associated with graft dysfunction in the early phase of reperfusion after cardiac transplantation\u2013gene expression profiling

The use of hearts with left-ventricular (LV) hypertrophy (LVH) could offer an opportunity to extend the donor pool for cardiac transplantation. We assessed the effects of LVH in 18-month-old spontaneously hypertensive stroke-prone (SHRSP) donor rats and following transplantation. In donors, cardiac function and structural alterations were assessed. Then, the hearts were transplanted into young normotensive-rats. We evaluated LV graft function 1 h after transplantation. The myocardial expression of 92 genes involved in apoptosis, inflammation, and oxidative-stress was profiled using PCR-array. Compared to controls, SHRSP-rats developed LVH, had increased LV systolic performance (slope of the end-diastolic pressure-volume (PV) relationship: 1.6±0.2 vs 0.8±0.1mmHg/μl, p<0.05) accompanied by diastolic dysfunction [prolonged time constant of LV pressure decay (Tau: 15.8±0.6 vs 12.3±0.5ms) and augmented diastolic stiffness (LV end-diastolic PV relationship: 0.103±0.012 vs 0.045±0.006mmHg/ml), p<0.05]. They presented ECG changes, myocardial fibrosis, and increased nitrotyrosine immunoreactivity and plasma troponin-T and creatine kinase-CM levels. After transplantation, even though the graft contractility was better in SHRSP rats compared to controls, the adverse impact of ischemia/reperfusion-injury on contractility was not altered (Ees ratio after versus before transplantation: 32% vs 29%, p>0.05). Whereas nitrotyrosine immunoreactivity was higher, myeloperoxidase-positive cell infiltration was decreased in the SHRSP+transplanted compared to control+transplanted. Among the tested genes, LVH was associated with altered expression of 38 genes in donors, while transplantation of these hearts resulted in the change of four genes. Alterations in 18-month-old donor hearts, as a consequence of hypertension and LVH, were not associated with graft dysfunction in the early phase of reperfusion after transplantation.

IS BP LOAD ON AMBULATORY MONITORING A PREDICTOR OF TARGET ORGAN DAMAGE IN YOUTH? THE SHIP AHOY STUDY

Objective: Ambulatory BP monitoring (ABPM) is increasingly utilized for the diagnosis of hypertension (HTN). Pediatric guidelines consider BP load (% of reading above the ‘normal’ threshold) in risk-stratification of the ABPM phenotype. We sought to determine if load was an independent predictor of target organ damage (TOD) in youth. Design and method: Casual BP, ABPM, anthropometrics, echo for LV mass index (LVMI), systolic strain, diastolic function (E’/e’ ratio) and pulse wave velocity (PWV) for arterial stiffness (PWV) were measured in 367 adolescents (mean 15.6 + 1.7 years, 63% white, 58% male). ABPM was performed with Ontrak device (Spacelabs Inc., Snoqualmie, WA). Subjects were stratified by load (low &lt;25% = 215, mid 25-&lt;50% = 62, high &gt;=50% =47) according to sex- and height-specific pediatric cut points. ANOVA was used to evaluate differences in CV risk factors and TOD across load groups. General linear models were used to evaluate load as an independent predictor of TOD after adjusting age, demographics, body mass index (BMI), and mean daytime SBP on ABPM. Results: There was a graded increase in most clinic and ambulatory BP means and loads across load groups (all p &lt; 0.05). There was only a trend for higher LVMI (p = 0.06) and reduced strain (p = 0.05) in low vs high load groups. Diastolic function (E/e’) was lower in high vs low and mid groups and there was a graded increase in arterial stiffness (PWV) across load groups. Daytime SBP load was an independent determinant of all forms of TOD after adjusting for age and sex but lost significance for LVMI after adjusting for BMI%. Load remained a significant determinant of PWV &amp; E/e’ after adjusting for BMI% and mean daytime ambulatory SBP. Load group was also a significant determinant of PWV and E/e’ even after adjustment for age, sex, BMI% and daytime ambulatory SBP (all p &lt; 0.0001). Conclusions: Daytime SBP load adds to prediction of diastolic dysfunction and arterial stiffness but not LVMI or systolic function. Increased load on ABPM may indicate need for advanced imaging to detect early TOD in youth with HTN.

Sacubitril/Valsartan Improves Diastolic Function But Not Skeletal Muscle Function in a Rat Model of HFpEF.

The angiotensin receptor/neprilysin inhibitor Sacubitril/Valsartan (Sac/Val) has been shown to be beneficial in patients suffering from heart failure with reduced ejection fraction (HFrEF). However, the impact of Sac/Val in patients presenting with heart failure with preserved ejection fraction (HFpEF) is not yet clearly resolved. The present study aimed to reveal the influence of the drug on the functionality of the myocardium, the skeletal muscle, and the vasculature in a rat model of HFpEF. Female obese ZSF-1 rats received Sac/Val as a daily oral gavage for 12 weeks. Left ventricle (LV) function was assessed every four weeks using echocardiography. Prior to organ removal, invasive hemodynamic measurements were performed in both ventricles. Vascular function of the carotid artery and skeletal muscle function were monitored. Sac/Val treatment reduced E/é ratios, left ventricular end diastolic pressure (LVEDP) and myocardial stiffness as well as myocardial fibrosis and heart weight compared to the obese control group. Sac/Val slightly improved endothelial function in the carotid artery but had no impact on skeletal muscle function. Our results demonstrate striking effects of Sac/Val on the myocardial structure and function in a rat model of HFpEF. While vasodilation was slightly improved, functionality of the skeletal muscle remained unaffected.