Thomas S. Denney

Rapid Reversal of Left Ventricular Hypertrophy and Intracardiac Volume Overload in Patients With Resistant Hypertension and Hyperaldosteronism A Prospective Clinical Study

We have shown previously that patients with resistant hypertension and hyperaldosteronism have increased brain natriuretic peptide suggestive of increased intravascular volume. In the present study, we tested the hypothesis that hyperaldosteronism contributes to cardiac volume overload. Thirty-seven resistant hypertensive patients with hyperaldosteronism (urinary aldosterone ≥12 &mgr;g/24 hours and plasma renin activity ≤1.0 ng/mL per hour) and 71 patients with normal aldosterone status were studied. Both groups had similar blood pressure and left ventricular mass, whereas left and right ventricular end-diastolic volumes measured by cardiac MRI were greater in high versus normal aldosterone subjects (P<0.05). Spironolactone treatment (19 patients in the high aldosterone group and 15 patients from the normal aldosterone group participated in the follow-up) resulted in a significant decrease in clinic systolic blood pressure, right and left ventricular end diastolic volumes, left atrial volume, left ventricular mass, and brain natriuretic peptide at 3 and 6 months of follow-up in patients with high aldosterone, whereas in those with normal aldosterone status, spironolactone decreased blood pressure and left ventricular mass without changes in ventricular or atrial volumes or plasma brain natriuretic peptide. Hyperaldosteronism causes intracardiac volume overload in patients with resistant hypertension in spite of conventional thiazide diuretic use. Mineralocorticoid receptor blockade induces rapid regression of left ventricular hypertrophy irrespective of aldosterone status. In subjects with high aldosterone, mineralocorticoid receptor blockade induces a prominent diuretic effect compared with a greater vasodilatory effect in subjects with normal aldosterone status.

Measurement of transient deformations using digital image correlation method and high-speed photography: application to dynamic fracture

The digital image correlation method is extended to the study of transient deformations such as the one associated with a rapid growth of cracks in materials. A newly introduced rotating mirror type, multichannel digital high-speed camera is used in the investigation. Details of calibrating the imaging system are first described, and the methodology to estimate and correct inherent misalignments in the optical channels are outlined. A series of benchmark experiments are used to determined the accuracy of the measured displacements. A 2%-6% pixel accuracy in displacement measurements is achieved. Subsequently, the method is used to study crack growth in edge cracked beams subjected to impact loading. Decorated speckle patterns in the crack tip vicinity at rates of 225,000 frames per second are registered. Two sets of images are recorded, one before the impact and another after the impact. Using the image correlation algorithms developed for this work, the entire crack tip deformation history, from the time of impact to complete fracture, is mapped. The crack opening displacements are then analyzed to obtain the history of failure characterization parameter, namely, the dynamic stress intensity factor. The measurements are independently verified successfully by a complementary numerical analysis of the problem.

Left ventricular motion reconstruction from planar tagged MR images: a comparison

Through recent development of MR techniques, it is now possible to assess regional myocardial wall function in a non-invasive way. Using MR tagging, space is marked with planes which deform with the tissue, providing markers for tracking the local motion of the myocardium. Numerous methods to reconstruct the three-dimensional displacement field have been developed. The aim of this article is to provide a framework to quantitatively compare the performance of four methods the authors have developed. Five sets of experiments are described, and their results are reported. Instructions are also provided to perform similar tests on any method using the same data. The experiments show that some characteristic properties of the methods, such as sensitivity to noise or spatial resolution, can be quantitatively classified. Cross-comparison of performances show what range values for these properties can be considered acceptable.

Increased oxidative stress and cardiomyocyte myofibrillar degeneration in patients with chronic isolated mitral regurgitation and ejection fraction >60%.

OBJECTIVES This study assessed myocardial damage in patients with chronic isolated mitral regurgitation (MR) and left ventricular ejection fraction (LVEF) >60%. BACKGROUND Typically, MR patients have decreased LVEF after mitral valve (MV) repair despite normal pre-operative LVEF. METHODS Twenty-seven patients with isolated MR had left ventricular (LV) biopsies taken at time of MV repair. Magnetic resonance imaging with tissue tagging was performed in 40 normal subjects and in MR patients before and 6 months after MV repair. RESULTS LVEF (66 +/- 5% to 54 +/- 9%, p < 0.0001) and LV end-diastolic volume index (108 +/- 28 ml/m(2) to 78 +/- 24 ml/m(2), p < 0.0001) decreased, whereas left ventricular end-systolic (LVES) volume index was 60% above normal pre- and post-MV repair (p < 0.05). The LV circumferential and longitudinal strain rates decreased below normal following MV repair (6.38 +/- 1.38 vs. 5.11 +/- 1.28, p = 0.0009, and 7.51 +/- 2.58 vs. 5.31 +/- 1.61, percentage of R to R interval, p < 0.0001), as LVES stress/LVES volume index ratio was depressed at baseline and following MV repair versus normal subjects (0.25 +/- 0.10 and 0.28 +/- 0.05 vs. 0.33 +/- 0.12, p < 0.01). LV biopsies demonstrated cardiomyocyte myofibrillar degeneration versus normal subjects (p = 0.035). Immunostaining and immunoblotting demonstrated increased xanthine oxidase in MR versus normal subjects (p < 0.05). Lipofuscin deposition was increased in cardiomyocytes of MR versus normal subjects (0.62 +/- 0.20 vs. 0.33 +/- 0.11, percentage of area: p < 0.01). CONCLUSIONS Decreased LV strain rates and LVES wall stress/LVES volume index following MV repair indicate contractile dysfunction, despite pre-surgical LVEF >60%. Increased oxidative stress could cause myofibrillar degeneration and lipofuscin accumulation resulting in LV contractile dysfunction in MR.

Microarray identifies extensive downregulation of noncollagen extracellular matrix and profibrotic growth factor genes in chronic isolated mitral regurgitation in the dog.

Background— The volume overload of isolated mitral regurgitation (MR) in the dog results in left ventricular (LV) dilatation and interstitial collagen loss. To better understand the mechanism of collagen loss, we performed a gene array and overlaid regulated genes into ingenuity pathway analysis. Methods and Results— Gene arrays from LV tissue were compared in 4 dogs before and 4 months after MR. Cine-magnetic resonance–derived LV end-diastolic volume increased 2-fold (P=0.005), and LV ejection fraction increased from 41% to 53% (P<0.007). LV interstitial collagen decreased 40% (P<0.05) compared with controls, and replacement collagen was in short strands and in disarray. Ingenuity pathway analysis identified Marfan syndrome, aneurysm formation, LV dilatation, and myocardial infarction, all of which have extracellular matrix protein defects and/or degradation. Matrix metalloproteinase-1 and -9 mRNA increased 5- (P=0.01) and 10-fold (P=0.003), whereas collagen I did not change and collagen III mRNA increased 1.5-fold (P=0.02). However, noncollagen genes important in extracellular matrix structure were significantly downregulated, including decorin, fibulin 1, and fibrillin 1. In addition, connective tissue growth factor and plasminogen activator inhibitor were downregulated, along with multiple genes in the transforming growth factor-β signaling pathway, resulting in decreased LV transforming growth factor-β1 activity (P=0.03). Conclusions— LV collagen loss in isolated, compensated MR is chiefly due to posttranslational processing and degradation. The downregulation of multiple noncollagen genes important in global extracellular matrix structure, coupled with decreased expression of multiple profibrotic factors, explains the failure to replace interstitial collagen in the MR heart.

Relation of torsion and myocardial strains to LV ejection fraction in hypertension.

OBJECTIVES The goal of this study was to define the mechanism of preserved ejection fraction (EF) despite depressed myocardial strains in hypertension (HTN). BACKGROUND Concentric left ventricular (LV) remodeling in HTN may have normal or supranormal EF despite depressed myocardial strains. The reason for such discordance is not clear. The aim of this study was to comprehensively evaluate the LV mechanics in a well-defined HTN population to define underlying reasons for such a paradox. METHODS Sixty-seven patients with resistant HTN and 45 healthy control subjects were studied by cardiac magnetic resonance imaging and tissue tagging with 3-dimensional analysis. Amplitude and directional vector of longitudinal (Ell), circumferential (Ecc), and principal strain for maximal shortening (E3) were computed at basal, mid, and distal LV levels, respectively. LV torsion, defined as the rotation angle of apex relative to base, and LV twist, which accounts for the effects of differential LV remodeling on torsion for comparison among the 2 groups, were also calculated. RESULTS LV mass index and LV mass/LV end-diastolic volume ratio were significantly higher in the HTN group compared with controls, consistent with concentric LV remodeling. Ell and Ecc were significantly decreased in amplitude with altered directional vector in HTN compared with controls. However, the amplitude of E3 was similar in the 2 groups. Torsion and twist were significantly higher in HTN, which was mainly due to increase in apical rotation. The HTN group demonstrated significantly increased LV wall thickening compared with controls that resulted in greater LVEF in the HTN group compared with controls (70% vs. 65%, p < 0.001, respectively). CONCLUSIONS In compensated LV remodeling secondary to HTN, there is increased LV wall thickening with preserved E3 and increased torsion compared with normal controls. This, therefore, contributes to supranormal LVEF in HTN despite depressed longitudinal and circumferential strains.

A Randomized Controlled Phase IIb Trial of Beta1-Receptor Blockade for Chronic Degenerative Mitral Regurgitation

OBJECTIVES The purpose of the study was to evaluate the effect of long-term β(1)-aderergic receptor (AR) blockade on left ventricular (LV) remodeling and function in patients with chronic, isolated, degenerative mitral regurgitation (MR). BACKGROUND Isolated MR currently has no proven therapy that attenuates LV remodeling or preserves systolic function. METHODS Thirty-eight asymptomatic subjects with moderate to severe, isolated MR were randomized either to placebo or β(1)-AR blockade (Toprol-XL, AstraZeneca, London, United Kingdom) for 2 years. Magnetic resonance imaging with tissue tagging and 3-dimensional analysis was performed at baseline and at 6-month intervals for 2 years. Rate of progression analysis was performed for endpoint variables for primary outcomes: LV end-diastolic volume/body surface area, LV ejection fraction, LV end-diastolic (ED) mass/ED volume ratio, LV ED 3-dimensional radius/wall thickness; LV end-systolic volume/body surface area, LV longitudinal strain rate, and LV early diastolic filling rate. RESULTS Baseline LV magnetic resonance imaging or demographic variables did not differ between the 2 groups. Significant treatment effects were found on LV ejection fraction (p = 0.006) and LV early diastolic filling rate (p = 0.001), which decreased over time in untreated patients on an intention-to-treat analysis and remained significant after sensitivity analysis. There were no significant treatment effects found on LV ED or LV end-systolic volumes, LV ED mass/LV ED volume or LV ED 3-dimensional radius/wall thickness, or LV longitudinal strain rate. Over 2 years, 6 patients treated in the placebo group and 2 patients in the β(1)-AR blockade group required mitral valve surgery (p = 0.23). CONCLUSIONS β(1)-AR blockade improves LV function over a 2-year follow-up in isolated MR and provides the impetus for a large-scale clinical trial with clinical outcomes. (Molecular Mechanisms of Volume Overload-Aim 1 [SCCOR in Cardiac Dysfunction and Disease]; NCT01052428).

A dual propagation contours technique for semi-automated assessment of systolic and diastolic cardiac function by CMR

BackgroundAlthough cardiovascular magnetic resonance (CMR) is frequently performed to measure accurate LV volumes and ejection fractions, LV volume-time curves (VTC) derived ejection and filling rates are not routinely calculated due to lack of robust LV segmentation techniques. VTC derived peak filling rates can be used to accurately assess LV diastolic function, an important clinical parameter. We developed a novel geometry-independent dual-contour propagation technique, making use of LV endocardial contours manually drawn at end systole and end diastole, to compute VTC and measured LV ejection and filling rates in hypertensive patients and normal volunteers.Methods39 normal volunteers and 49 hypertensive patients underwent CMR. LV contours were manually drawn on all time frames in 18 normal volunteers. The dual-contour propagation algorithm was used to propagate contours throughout the cardiac cycle. The results were compared to those obtained with single-contour propagation (using either end-diastolic or end-systolic contours) and commercially available software. We then used the dual-contour propagation technique to measure peak ejection rate (PER) and peak early diastolic and late diastolic filling rates (ePFR and aPFR) in all normal volunteers and hypertensive patients.ResultsCompared to single-contour propagation methods and the commercial method, VTC by dual-contour propagation showed significantly better agreement with manually-derived VTC. Ejection and filling rates by dual-contour propagation agreed with manual (dual-contour – manual PER: -0.12 ± 0.08; ePFR: -0.07 ± 0.07; aPFR: 0.06 ± 0.03 EDV/s, all P = NS). However, the time for the manual method was ~4 hours per study versus ~7 minutes for dual-contour propagation. LV systolic function measured by LVEF and PER did not differ between normal volunteers and hypertensive patients. However, ePFR was lower in hypertensive patients vs. normal volunteers, while aPFR was higher, indicative of altered diastolic filling rates in hypertensive patients.ConclusionDual-propagated contours can accurately measure both systolic and diastolic volumetric indices that can be applied in a routine clinical CMR environment. With dual-contour propagation, the user interaction that is routinely performed to measure LVEF is leveraged to obtain additional clinically relevant parameters.

Left ventricular motion reconstruction with a prolate spheroidal B-spline model

Tagged cardiac magnetic resonance (MR) imaging can non-invasively image deformation of the left ventricular (LV) wall. Three-dimensional (3D) analysis of tag data requires fitting a deformation model to tag lines in the image data. In this paper, we present a 3D myocardial displacement and strain reconstruction method based on a B-spline deformation model defined in prolate spheroidal coordinates, which more closely matches the shape of the LV wall than existing Cartesian or cylindrical coordinate models. The prolate spheroidal B-spline (PSB) deformation model also enforces smoothness across and can compute strain at the apex. The PSB reconstruction algorithm was evaluated on a previously published data set to allow head-to-head comparison of the PSB model with existing LV deformation reconstruction methods. We conclude that the PSB method can accurately reconstruct deformation and strain in the LV wall from tagged MR images and has several advantages relative to existing techniques.

Unsupervised reconstruction of a three-dimensional left ventricular strain from parallel tagged cardiac images.

A new algorithm, called the Unsupervised Tag ExTraction and Heart strain(E) Reconstruction (UNTETHER) algorithm, is presented for quantifying three‐dimensional (3D) myocardial strain in tagged cardiac MR images. Five human volunteers and five postinfarct patients were imaged. 3D strains measured by UNTETHER and a user‐supervised technique were compared. Each study was analyzed in 49 ± 8 min with UNTETHER, compared to ∼4 hr with the user‐supervised technique. For pooled human data, the correlation coefficient between the two methods for circumferential shortening (Ecc) was r = 0.91 at the mid‐wall (P < 0.0005). UNTETHER is capable of measuring wall motion abnormalities resulting from coronary artery disease, and has the potential to overcome the main limitations (time and user‐supervision requirements) to routine clinical use of tagged cardiac MRI. Magn Reson Med 49:743–754, 2003.