Endovascular Reversal of Renovascular Hypertension Blunts Cardiac Dysfunction and Deformation in Swine

Abstract

Objectives:

Renovascular hypertension (RVH) induces hemodynamic and humoral aberrations that may impair cardiac function, structure and mechanics, including cardiac twist and deformation. Revascularization of a stenotic renal artery can decrease blood pressure (BP), but its ability to restore cardiac mechanics in RVH remains unclear. We hypothesized that percutaneous transluminal renal angioplasty (PTRA) would improve cardiac function and left ventricular (LV) deformation in swine RVH.

Methods:

Seventeen domestic pigs were studied for 16 weeks: RVH, RVH+PTRA and normal controls (n=5–6 each). Global LV function was estimated by multidetector computed-tomography, and LV deformation by electrocardiographically-triggered magnetic resonance imaging tagging at the apical, mid, and basal LV levels. Cardiomyocyte hypertrophy, myocardial capillary density, and fibrosis were evaluated ex-vivo.

Results:

BP and wall thickness were elevated in RVH and decreased by PTRA, yet remained higher than in controls. LV myocardial muscle mass increased in RVH pigs, which also developed diastolic dysfunction, whereas cardiac output increased. Furthermore, both apical rotation and peak torsion angle increased in RVH compared with controls. Ex-vivo, RVH induced myocardial fibrosis and vascular rarefaction. PTRA restored cardiac function and alleviated hypertrophy, vascular rarefaction, and fibrosis. PTRA also normalized apical rotation and peak torsion angle, and elevated basal peak radial strain and apical peak radial strain compared to RVH.

Conclusions:

Besides cardiac LV adaptive hypertrophy and diastolic dysfunction, short-term RVH causes cardiac deformation. Despite only partial improvement in BP, PTRA effectively restored cardiac function and reversed abnormal mechanics. Hence, renal revascularization may be a useful strategy to preserve cardiac function in RVH.

INTRODUCTION

Renovascular hypertension (RVH) is a central type of secondary hypertension caused by renal hypoperfusion resulting from occlusive renovascular diseases (RVD) and activation of the renin-angiotensin-aldosterone system. In Western countries, over 85% of RVD is secondary to atherosclerotic renal artery stenosis (ARAS) which in up to 6.8% of subjects older than 65 involves more than 60% occlusion [1]. As age increased, the prevalence of ARAS in hypertensive individuals rises as well (from 3% among 50–59 to 25% above age 70) [2]. Constituting a powerful risk factor, RVH increased cardiovascular mortality and morbidity. Our previous study also confirmed RVH can result in decreasing myocardial perfusion, myocardial hypoxia, and cardiac diastolic dysfunction in swine [3].

Accumulating evidence indicates that global cardiac function alone is not sufficient for comprehensive cardiac assessment. In recent years, assessment of cardiac regional mechanics gained traction for evaluation of cardiovascular diseases, like acute myocardial infarction, left ventricular (LV) hypertrophy, aortic stenosis, and cardiomyopathy, as well as for post-operative monitoring [4]. Regional mechanical changes reflect regional myocardial function and deformation, providing added value to global cardiac function for assessment of the heart.

Evaluation of myocardial strain using either cardiovascular magnetic resonance (CMR) imaging or two-dimensional echocardiography has become the reference standard for regional cardiac morphology and mechanics [5, 6]. Given the different directions in which the myocardium deforms during the cardiac cycle, circumferential and radial strain and rotation, as well as torsion angle, can all be calculated noninvasively. LV rotation and torsion angle are considered to be associated with global LV function, and rise during physical exercise and in patients with aortic stenosis, but fall in myocardial ischemia [7]. Similarly, radial and circumferential strain changes in cardiac diseases suggest alterations in cardiac contractility. Prominently hypertensive disorders can cause LV deformation, including RVH which results in heart failure with both preserved and reduced ejection fraction [8].

Percutaneous transluminal renal angioplasty (PTRA) is the most common invasive strategy to restitute renal arterial patency. While in some clinical cases PTRA can achieve improvement of hypertension and heart failure in patients with preserved EF [9], the CORAL trial showed that the rate of the primary composite end-point showed no significant benefit for PTRA over medical therapy alone [10]

However, the ability of PTRA to reverse altered cardiac mechanics in RVH remains unclear. Therefore, the present study was designed to test the hypothesis that early stage RVH caused cardiac deformation, whereas PTRA can improve cardiac mechanics.

METHODS

Experimental Design

The present study was approved by the Institutional Animal Care and Use Committee and followed the National Institutes of Health guidelines for the care and use of laboratory animals. Seventeen 3-month-old domestic pigs were studied for 16 weeks (Figure 1A), of which 11 were fed with high-cholesterol/high-carbohydrate diet in order to mimic the clinical situation in which RVH often coexists with metabolic disorders [11]. The 6 other pigs were fed with standard pig chow during the entire study and served as normal controls. Six weeks after initiation of the diet, pigs were anesthetized with 0.25g of intramuscular tiletamine hydrochloride/zolazepam hydrochloride (Telazol, Fort Dodge Animal Health, Kansas, USA) and 0.5g of xylazine. Intravenous injection of ketamine (0.2mg/kg/min) and xylazine (0.03mg/kg/min) was used to maintain anesthesia. Renal artery stenosis (RAS) was induced in 11 high-fat dieted pigs, as previously described [11]. Six weeks later, the pigs were anesthetized again and underwent angiography to estimate the degree of RAS. All RAS pigs had comparable unilateral RAS with an average degree of 86.0±13.97%. Then 5 pigs were randomly treated with PTRA using a balloon catheter inflated at high pressure, and then deflated and removed. Repeat angiography was used to confirm renal artery patency [11, 12]. The protocol yielded in 3 experimental groups: RVH (n=6), RVH+PTRA (n=5) and Control (n=6). Four weeks after PTRA or sham angiography, all pigs were anesthetized, underwent repeat angiography, and were then scanned by electrocardiographically-triggered multidetector computed tomography (MDCT) [Somatom Sensation-128, Siemens Medical Solution, Forchheim, Germany] and magnetic resonance imaging (MRI) (Signa Echo Speed, GE Medical Systems, Milwaukee, Wisconsin, USA) to evaluate cardiac global function and deformation, respectively. Systemic blood sample were collected from a central vein for measurement of plasma renin activity (PRA, ALPCO Diagnostics). A few days after the in vivo-studies, we used a lethal intravenous dose of sodium pentobarbital (100mg/kg) to euthanize all pigs. Hearts were dissected shock-frozen in liquid nitrogen, or preserved in formalin for histology.

Figure 1.

A. Schematic of the experimental protocol. B. Changes in cardiac function determined by MDCT. Stroke volume and cardiac output increased in RVH whereas only cardiac output decreased after PTRA. E/A ratio decreased in RVH and normalized after PTRA. a. Stroke volume; b. Cardiac output; c. E/A ratio; d. Left ventricular ejection fraction.* P<0.05 vs. Control ^# P<0.05 vs. RVH. RVH: Renovascular hypertension; PTRA: percutaneous transluminal renal angioplasty.

Global Cardiac Function

Global LV cardiac function was assessed using MDCT and cine MRI, as described previously [3]. LV myocardial mass (LVMM), cavity volume, length, diameter, and wall thickness were estimated by 3.0 T cine MRI using a fast spoiled gradient echo sequence with the following parameters: short-axis slices located from base to apex with slice thickness=8 mm, slice gap =2–5 mm, field of view (FOV)=30×30 to 36×36 cm², phase FOV=0.75, matrix size=192×128 reconstructed to 256×256, TR/TE=6.7/3.74 ms, flip angle=20°, and 20 reconstructed phases per cardiac cycle. All MRI scans were performed with suspended respiration. In order to analyze LV parameters, we manually labeled the contours of end-diastolic and –systolic endocardial and epicardial borders in short axis images. Papillary muscles were excluded in the measurement of LV muscle. LV length was measure directly on the long axis of LV three times at the longest slice, and averaged. LVMM was calculated by multiplying end-diastolic LV muscle volume by the specific density of the myocardium. For diameter, we used the minimum value of average thickness of four regions of the LV in the middle slice. Data analysis was performed using MATLAB 7.10 (Math-Works, Natick, Massachusetts, USA).

Cardiac function was assessed in vivo using MDCT after a bolus injection of a contrast agent (iopamidol, 0.33ml/kg over 2s) into the right atrium. Then, the LV was scanned 20 times throughout the cardiac cycle. Cardiac output, stroke volume, and ejection fraction were acquired as previously described [11]. Early (E) and late (A) LV filling rates were obtained from the positive slopes of volume/time curves, and E/A ratio calculated using MATLAB 7.10 [11, 13]. Images were analyzed with the Analyze™ software package (Biomedical Imaging Resource, Mayo Clinic, Rochester, Minnesota, USA).

Myocardial Deformation

We used myocardial strain acquired from myocardial tagging to describe cardiac deformation. MRI tagging was performed using a fast gradient echo sequence with spatial modulation of magnetization on the same slices as in cine MRI. Slice positions were taken from the cine MR imaging dataset, and in all we obtained three short-axis planes. The first to show circumferential myocardium at both diastole and systole was defined as the basal slice. The apical slice was the last to show the intracavity blood pool in all phases over the cardiac cycle. The mid-LV slice was positioned half-way between the basal and apical slices. Myocardial deformation was quantified by semi-automated tagline tracking using harmonic phase analysis on 3 LV tomographic slices. A segmented 2-dimensional electrocardiographically-triggered fast low-angle shot-pulse sequence was used during breath-holding (tagging resolution: 6mm; FOV, 30×30 to 36×36 cm²; matrix, 256×192 reconstructed to 256×256; phase FOV: 0.75; TR/TE, 1 R-R interval/2.21 ms; flip angle, 10°). Tagged images were processed using MATLAB 7.10. In the end-diastolic frame, we defined the endocardial and epicardial contours, and the software detected the tag-grid using an affine plus anisotropic radial scaling transform algorithm. The grid was adapted to each of the acquired images from the end-diastolic to the end-systolic frame. Manual editing was made by moving, adding, or deleting tag intersections as needed. The degree of deformation of myocardial segments from end-diastole to end-systole represented myocardial strain as percentage⁷. Radial strain inferred myocardial deformation towards the center of the LV cavity, indicating thickening and thinning motion of the LV wall. Circumferential strain represented LV myocardial fiber shortening during the cardiac cycle, represented by negative value, and strain rate was the rate of shortening. The clockwise rotation of basal segments and counterclockwise rotation of apical segments relative to a stationary mid-myocardial reference point created LV torsion angle, which is related to the circumferential longitudinal shear angle directly.

Histological Assessment of Myocardial Fibrosis and Cardiomyocyte Size

Wheat germ agglutinin (Thermo Fisher, Waltham, Massachusetts, USA) staining was used to evaluate cardiomyocyte cross-sectional area in mid-LV cross sections (5μm). Digital images were taken from x40 magnification of 5 random fields of view in each heart sample. Area of cardiomyocytes were analyzed using ImageJ. For myocardial fibrosis, trichrome (Newcomer Supply, Middleton, Wisconsin, USA) stained slides (1 per animal) were examined using ZEN microscope software (Carl Zeiss Microscopy, Cambridge, United Kingdom) and quantified using MATLAB 7.10.

Capillary density

To assess capillary density, slides were fixed with 4% paraformaldehyde and blocked with 2% bovine serum albumin. The slides were then incubated with goat anti-swine CD31 (Bio-Rad, Oxford, United Kingdom) antibody overnight at 4°, and then with Alexa Fluor 488 donkey anti-goat secondary antibody, at 37° for 1hour. The nuclei were indicated by counterstaining with 4’, 6-diamidino-2-phenylindole dihydrochloride. All the slides were examined and semi-automatically quantified using Citation-5 (BioTek, Vermont, USA).

Statistical Analysis

Statistical analysis was performed using SPSS version 17.0 software (SPSS, Chicago, Illinois, USA). Results were expressed as mean±standard deviation for normally-distributed variables, or median (range) for non-Gaussian distributed data. Parametric (ANOVA followed by unpaired Student’s t-test) and non-parametric (Wilcoxon followed by Kruskal-Wallis) tests were used when appropriate. Correlations of strain and histological findings was assessed with Pearson’s correlation coefficient for normally distributed data, and otherwise using Spearman’s correlation coefficient. Statistical significance was defined using P values less than 0.05.

RESULTS

Systemic Characteristics and Cardiac Structure

Characteristics of the study groups and LV remodeling estimated by cine MRI are shown in Table 1. RVH pigs were heavier compared with controls. RAS induced elevation of systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) (all P<0.001 vs. controls) in RVH, which PTRA attenuated but failed to normalize, except for DBP. DBP in PTRA-treated RVH tended to be higher than in Controls, but this has not reached statistical significance (P=0.052). LVMM (P=0.004 vs. controls) and wall thickness (P=0.004 vs. controls) were elevated in RVH, whereas LV cavity volume was similar among the groups. PTRA reversed the increase of LVMM (P=0.049 vs. RVH), whereas wall thickness (P=0.044 vs. RVH) was decreased compared to RVH, but remained thicker than controls. LV length increased in RVH (P<0.001 vs. Control) and remained unchanged after PTRA (P=0.898 vs. RVH). PRA significantly increased in RVH compared with Controls (P<0.001 vs. Controls) and decreased after PTRA (P=0.035 vs. RVH), although not fully normalized (P<0.001 vs. Controls).

Table 1.

Characteristics of the experimental groups after 16-week observation.

Measurements	Control (n=6)	RVH(n=6)	RVH+PTRA(n=5)
Body weight (kg)	61.03±6.38	83.03±7.42*	81.40±7.33*
Heart rate (bpm)	119.00±13.45	112.17±10.68	121.60±19.73
Systolic pressure (mmHg)	119.50±13.47	158.60±7.02*	137.20±10.45*#
Diastolic pressure (mmHg)	83.83±12.00	114.20±5.76*	95.80±6.98#
MAP (mmHg)	95.7±11.99	129.00±3.60*	109.60±6.80*#
LV volume (mL)	165.57±36.09	204.30± 58.87	160.96±15.96
LVMM (g)	122.96±14.25	173.52±22.52*	142.94±19.02#
LV Length (mm)	87.11±3.65	98.06±4.29*	98.50±6.37*
LV Diameter (mm)	78.52±5.71	81.63±2.17	77.35±3.23#
Wall Thickness (mm)	8.25±0.73	10.80±1.34*	9.30±0.67*#
Wall thickness ratio to radius	0.21±0.03	0.27±0.03*	0.24±0.02

^*P<0.05 vs. Control;

^#P<0.05 vs. RVH; LVMM: Left ventricular myocardial mass;

Left Ventricular Systolic and Diastolic Function

LV global function evaluated by MDCT is shown in Figure 1B. Stroke volume and cardiac output increased in RVH, whereas EF was unchanged, indicating maintance of systolic function. E/A ratio deceased in RVH (P=0.011 vs. controls) and was restored after PTRA (P=0.007 vs. RVH).

Myocardial Strain

Parameters of cardiac deformation are shown in Table 2. Compared with the Control group, apical rotation (P=0.045) and torsion (P=0.029) angles were significantly increased in RVH, but normalized by PTRA (P=0.962 and P=0.396 vs. control; P=0.026 and P=0.015 vs. RVH). On the other hand, PTRA increased basal and apical peak strain radial compared to both RVH (P=0.031; P=0.018) and control (P=0.037; P=0.006), and basal peak systolic strain rate radial compared to RVH (P=0.012). LV wall thickness was significantly associated with torsion angle (r=0.538, P=0.031), whereas other parameters cardiac structure, function, and myocardial strain were not.

Table 2.

Left ventricular systolic rotation, torsion, peak rad strain, and peak circumferential strain and rate of pigs with RVH after revascularization in comparison with the untreated RVH.

Slice	Measurements	Control	RVH	RVH+ PTRA
Basal	PSR (%)	0.31±0.04	0.31±0.05	0.40±0.07*#
	PSSRR (1/s)	1.26±0.26	1.12±0.18	1.56±0.32#
	PSC (%)	−0.10±0.01	−0.12±0.01	−0.11±0.02
	PSSRC(1/s)	−0.40±0.09	−0.43±0.07	−0.45±0.08
	Rotation(°)	−1.78±1.55	−2.21±1.79	−2.91±2.28
Mid ventricular	PSR (%)	0.26±0.05	0.26±0.07	0.30±0.03
	PSSRR (1/s)	1.04±0.21	0.94±0.20	1.20±0.24
	PSC (%)	−0.10±0.01	−0.11±0.01	−0.12±0.01
	PSSRC(1/s)	−0.41±0.08	−0.42±0.04	−0.47±0.08
	Rotation (°)	6.15±1.59	5.56±1.64	4.75±2.77
Apex	PSR (%)	0.16±0.06	0.20±0.05	0.29±0.05*#
	PSSRR (1/s)	0.62±0.24	0.72±0.19	0.97±0.64
	PSC (%)	−0.09±0.01	−0.10±0.02	−0.10±0.01
	PSSRC(1/s)	−0.35±0.05	−0.35±0.08	−0.39±0.09
	Rotation(°)	10.70±3.20	14.38±1.96*	10.62±3.17#
Peak Torsion (°)		12.48±3.21	16.60±1.90*	13.80±1.40#
Peak Torsion (degree/cm)		2.57±0.68	3.28±0.51	2.89±0.29

^*P<0.05 vs. Control;

^#P<0.05 vs. RVH; PSR: Peak strain radial, PSC: peak strain circumference; PSSRR: peak systolic strain rate radial; PSSRC: peak systolic strain-rate circumference.

Myocardial Histology

The average size of cardiomyocytes in RVH increased dramatically compared to controls, and decreased after PTRA (Figure 2A). Fibrosis increased in RVH and improved after PTRA, but failed to normalize (Figure 2B), whereas myocardial capillary density in RVH was significantly lower than controls but improved by PTRA (Figure 2C). Cardiomyocyte cross-section area was significantly associated with apical rotation (r=0.60) and torsion angle (r=0.69), whereas myocardial fibrosis was associated with mid rotation angle (r=−0.51), and capillary density with basal PSC (r=0.52) (Figure 2D).

Figure 2.

PTRA alleviated left ventricular (LV) myocardial fibrosis and cardiomyocyte hypertrophy and normalized capillary density. A. Average size of cardiomyocytes with cell membrane labeled by FITC-conjugated WGA (red) and nuclei by DAPI (blue). Scale bar=100μm. B. LV fibrosis shown by Masson’s Trichrome staining. Scale bar=100μm. C. LV capillary indicated by anti-CD31 immunofluorescent staining (red), and nuclei indicated by counterstaining with DAPI (blue). Scale bar = 200μm. D. Correlation between myocardial strain and histological finding. * P<0.05 vs. Control; ^# P<0.05 vs. RVH. RVH: Renovascular hypertension; PTRA: percutaneous transluminal renal angioplasty.

DISCUSSION

The aim of the present study was to assess the ability of PTRA to reverse regional cardiac deformation induced by RVH and assessed using MR tagging. We observed a noteworthy increase in LVMM, wall thickness, stroke volume, and cardiac output, which PTRA successfully decreased (except for stroke volume). E/A ratio was considerably decreased in RVH, indicating diastolic dysfunction, which PTRA normalized. Apical rotation and torsion angles increased in RVH and declined after PTRA. Interestingly, basal and apical peak strain radial, and basal peak systolic strain rate radial, increased after PTRA compared to both RVH and controls. Cardiac mechanics at the mid-LV level remained relatively preserved. Cardiomyocyte hypertrophy, vascular rarefaction, and fibrosis were observed in RVH, and all improved after PTRA. Cardiomyocyte hypertrophy was significantly associated with apical rotation and torsion angle. These observations suggest that RVH impairs cardiac mechanics, and that at its early phase, a decrease in blood pressure can restore many aspects of cardiac dynamics.

In 2010, one-third of the world’s adults had hypertension, of which 5–10% were considered secondary often due to RVH [14]. The pathophysiology of RVH includes progressive RAS, causing hypoperfusion of kidney, activating the renin-angiotensin system (RAAS) with increased PRA. RVH in turn increases cardiac afterload, the duration and severity of which impact on LV hypertrophy, while activation of the RAAS may also contribute directly to development of cardiomyopathy. Furthermore, additional factors may mediate cardiomyopathy partly through downstream processes, including oxidative stress, inflammation, and dysfunctional immune modulation [16]. This in turn may decrease myocardial microvascular density, which may disrupt oxygen supply and demand and may cause myocardial hypoxia, cellular autophagy, and mitochondrial degradation [17]. All these abnormalities act in concert to promote cardiac interstitial fibrosis, stiffness, diastolic dysfunction, and ultimately systolic dysfunction [18].

Besides deterioration of global cardiac function, RVH may also affect the myocardial mechanics. Abnormal myocardial strain is an early impairment in many cardiovascular diseases, and may precede any other abnormal findings on CMR in patients with acute myocarditis [19], hypertension, or chemotherapy-induced cardiac dysfunction [20]. Among the types of myocardial strain, cardiac torsion serves as a useful integrated index of cardiac pathology, because it is sensitive to changes in several cardiovascular parameters like preload, afterload, and contractility [21]. Our pig model with early RVH showed no discernible changes in EF compared with controls, suggesting preservation of cardiac systolic function, whereas a concurrently decreased E/A ratio suggested LV diastolic dysfunction. Nonetheless, we found a meaningful increase in apical rotation and torsion angle in RVH, consistent with pressure-overload hypertrophy, which is characterized by increased ratio of LV wall thickness to radius [22, 23]. The increasing myocardium wring motion may compensate for cardiac systolic function, but might result in an increase in untwisting velocity or duration [24], which might in turn worsen LV relaxation and induce LV diastolic dysfunction [25].

Antihypertensive treatment is often effective in alleviating cardiac hypertrophy, balancing cardiac output, and reversing cardiac dysfunction by lowering oxidative stress and decreasing immune activation [25]. In some patients with RVH followed for 4 years, stenting also decreased BP, preserved renal function, and improved LV structure and function, underscoring the cardio-protective effect of preserving systemic hemodynamics and renal function [26]. Indeed, selective improvement in renal function significantly reduces renal and systemic oxidative stress and inflammation, alleviates remote myocardial microvascular dysfunction, and improves its architecture [27]. This finding underscores the feasibility of preserving cardiac function through attenuation of renal injury.

We have previously shown that PTRA performed after 6 weeks of RVH can restore renal perfusion and function, reverse early RVH, improve coronary microvascular function and architecture and decrease myocardial ischemia and inflammation [28]. Therefore, in the present study, we performed PTRA 6 weeks after RVH induction [29–31]. We found that PTRA reversed myocardial and cardiomyocyte hypertrophy, improved vascular density, ameliorated cardiac fibrosis, and restored apical rotation and torsion angle, which may have normalized diastolic function. Importantly, the levels of myocardial fibrosis observed in RVH pigs 4 weeks after PTRA were lower than those that we previously observed in RVH pigs at time points comparable to pre-PTRA in the current study [32]. Hence, PTRA likely not only prevented progression but also induced a slight regression of myocardial fibrosis.

Interestingly, after PTRA, apical and basal peak strain radial increased compared with RVH, resembling observations on cardiac mechanics from one year follow-up after valvular replacement surgery in patients with aortic stenosis, possibly due to a rebound effect [23]. In our study, we also found elevation of basal and apical PSR after PTRA compared with controls and untreated RVH. Speculatively, this may represent an alternative mechanism for development of LV hypertrophy to ensure LV performance in the face of residual hypertension after PTRA. Future studies are needed to explore this phenomenon. Importantly, in hypertensive adults with asymptomatic LV dysfunction, antihypertensive treatment alleviates altered cardiac mechanics [33], suggesting the latter as a novel target for antihypertensive treatment, possibly related to recovery of cardiac contractility and alleviation of cardiac fibrosis and hypertrophy. Alas, antihypertensive treatment did not alleviate diminished cardiac mechanics in pediatric hypertensive patients, regardless of the agent used [34]. Additional studies are needed to determine the factors that govern aberrant cardiac mechanics.

The limitations of our study included the short duration of the disease, which induce relatively milder changes in myocardial mechanics. Yet, the use of a high-fat diet mimicked the clinical scenario, in which often RVH coexists with metabolic disorders. In addition, with CMR tagging to evaluate cardiac regional deformation, tags gradually fade, limiting its use to the first two-thirds of the cardiac cycle, hampering estimation of some regional myocardial abnormalities. We used MDCT to estimate systolic and diastolic function, because we have substantial experience with this methodology [12, 28]. Furthermore, we used a single parameter (E/A ratio) to estimate diastolic function. In addition, given that PRA increased significantly in RVH and decreased in RVH+PTRA, we cannot distinguish cardiac modifications due to arterial hypertension versus RAAS activation, which might impose cardiac modifications beyond BP. Moreover, in the present study we fed pigs with high-fat diet in order to simulate more closely patients with RVH, who often present with comorbidities like dyslipidemia and obesity. Consequently, all RVH pigs gained excessive weight, and we cannot rule out some effect of obesity on cardiac mechanics. However, PTRA but not sham improved cardiac mechanics in RVH, despite a similar body weight in both groups, suggesting that any confounding effects of obesity on cardiac mechanics were likely minor in comparison to changes in BP. Similarly, we cannot exclude a contribution of high-fat diet to sustained blood pressure elevation in RVH. These confounding factors might account for the failure of PTRA to fully restore BP in the RVH+PTRA group to the same levels as in control pigs. Notably, the main goal of this study was to evaluate the effect of revascularization on reversing cardiac alterations in RVH. Our results should be interpreted with caution, because elucidation of the role of hypertension on cardiac dynamics would require studying different models of hypertension as well as different treatment modalities. Future studies should include subjects with dyslipidemia alone and renin-independent hypertension to determine the relative contributions of hemodynamic vs. metabolic factors to cardiac alterations, as well as pharmacological treatment modalities to compare to PTRA.

In summary, our study shows that, in addition to cardiac hypertrophy, fibrosis, capillary loss and LV diastolic dysfunction, short-term experimental RVH resulted in abnormal myocardial mechanics, including increases of apical rotation and torsion angle. Although PTRA did not fully normalize blood pressure, it improved cardiac structure and diastolic function, as well as apical rotation and torsion. This observation underscores the beneficial effect of PTRA on myocardial mechanics in RVH.