Leanne Harmann

Left atrial volume measurement with automated border detection by 3-dimensional echocardiography: comparison with magnetic resonance imaging

ObjectiveLeft atrial size is an important marker for adverse cardiovascular events. There is general consensus that left atrial volume index (LAVI) is the best measurement of size. The current LAVI measurement techniques are laborious. Semi-automated measurement with a 3-dimensional echocardiography (3DE) system may be a practical clinical alternative to measure LAVI, but it has not been adequately evaluated against Magnetic Resonance Imaging (MRI) gold standard. The aim of this study was to compare the accuracy of a commercially available 3D algorithm for measurement of LAVI against LAVI obtained from MRI and Area Length Method (ALM).DesignIn 27 consecutive subjects referred for cardiac MRI (age 54 ± 13 years, 63% male), LAVI was measured using 3 imaging modalities: 3DE, ALM, MRI and the results were correlated. ALM was measured using standard American Society of Echocardiography guidelines. The time required to measure LAVI by 3DE and ALM were compared.ResultsThere was a significant correlation in systolic and diastolic LA volumes and left atrial ejection fraction between 3DE and MRI (r = 0.86 for systole, r = 0.76 for diastole, r = 0.88 for ejection fraction, P < 0.0001 for all). There was also significant correlation of diastolic volumes between 3DE and ALM (r = 0.77, P < 0.0001). The time to obtain LAVI was shorter using 3DE versus ALM (56 ± 8 vs 135 ± 55 seconds, P < 0.0001).ConclusionThree-dimensional echocardiography with semiautomatic border detection is a practical alternative for obtaining the left atrial volume in a time-efficient manner compared to the current standard.

10 GY TOTAL BODY IRRADIATION INCREASES RISK OF CORONARY SCLEROSIS, DEGENERATION OF HEART STRUCTURE AND FUNCTION IN A RAT MODEL

Purpose: To determine the impact of 10 Gy total body irradiation (TBI) or local thorax irradiation, a dose relevant to a radiological terrorist threat, on lipid and liver profile, coronary microvasculature and ventricular function. Materials and methods: WAG/RijCmcr rats received 10 Gy TBI followed by bone marrow transplantation, or 10 Gy local thorax irradiation. Age-matched, non-irradiated rats served as controls. The lipid profile and liver enzymes, coronary vessel morphology, nitric oxide synthase (NOS) isoforms, protease activated receptor (PAR)-1 expression and fibrinogen levels were compared. Two-dimensional strain echocardiography assessed global radial and circumferential strain on the heart. Results: TBI resulted in a sustained increase in total and low density lipoprotein (LDL) cholesterol (190 ± 8 vs. 58 ± 6; 82 ± 8 vs. 13 ± 3 mg/dl, respectively). The density of small coronary arterioles was decreased by 32%. Histology revealed complete blockage of some vessels while cardiomyocytes remained normal. TBI resulted in cellular peri-arterial fibrosis whereas control hearts had symmetrical penetrating vessels with less collagen and fibroblasts. TBI resulted in a 32 ± 4% and 28 ± 3% decrease in endothelial NOS and inducible NOS protein, respectively, and a 21 ± 4% and 35 ± 5% increase in fibrinogen and PAR-1 protein respectively, after 120 days. TBI reduced radial strain (19 ± 8 vs. 46 ± 7%) and circumferential strain (−8 ± 3 vs. −15 ± 3%) compared to controls. Thorax-only irradiation produced no changes over the same time frame. Conclusions: TBI with 10 Gy, a dose relevant to radiological terrorist threats, worsened lipid profile, injured coronary microvasculature, altered endothelial physiology and myocardial mechanics. These changes were not manifest with local thorax irradiation. Non-thoracic circulating factors may be promoting radiation-induced injury to the heart.

Small- and Moderate-Size Right-to-Left Shunts Identified by Saline Contrast Echocardiography Are Normal and Unrelated to Migraine Headache

BACKGROUND We suspected, based on clinical experience, that the prevalence of both intracardiac and pulmonary arteriovenous malformations (PAVMs) is higher than previously reported in a healthy population when using modern ultrasound technology combined with a rigorous saline contrast echocardiogram (SCE) protocol. We hypothesized the prevalence of right-to-left shunts (RLSs) would be so high when using this sensitive technique that there would be no significant association of RLS with migraine headache. METHODS We recruited 104 healthy volunteers to undergo an SCE followed by completion of a migraine questionnaire. The SCEs were meticulously graded for shunt size and location based on left-sided heart contrast quantity and timing. The migraine headache questionnaire was graded by a neurologist blinded to SCE results. RESULTS One hundred four subjects underwent the study protocol. We found 71% of subjects exhibited evidence of RLS. Patent foramen ovale (PFO) was identified in 40 (38%), PAVM was identified in 29 (28%), and five subjects had evidence of both (5%). Based on questionnaires, 42 (40%) of the subjects had migraine headache (29% with aura). There was no significant association of migraine headache with PFO (OR, 0.59; 95% CI, 0.16-2.12; P = .54) or PAVM (OR, 0.8; 95% CI, 0.34-1.9; P = .67), although only 13 (13%) of the subjects had evidence of large RLS. CONCLUSIONS When using modern ultrasound technology combined with a rigorous SCE technique, the majority of healthy subjects demonstrate some degree of RLS. PAVM in an otherwise healthy population is common. Small- and moderate-size RLSs do not appear to be significantly associated with migraine headache.

Carotid plaque regression following 6-month statin therapy assessed by 3T cardiovascular magnetic resonance: comparison with ultrasound intima media thickness

BackgroundCardiovascular magnetic resonance (CMR) allows volumetric carotid plaque measurement that has advantage over 2-dimensional ultrasound (US) intima-media thickness (IMT) in evaluating treatment response. We tested the hypothesis that 6-month statin treatment in patients with carotid plaque will lead to plaque regression when measured by 3 Tesla CMR but not by IMT.MethodsTwenty-six subjects (67 ± 2 years, 7 females) with known carotid plaque (> 1.1 mm) and coronary or cerebrovascular atherosclerotic disease underwent 3T CMR (T1, T2, proton density and time of flight sequences) and US at baseline and following 6 months of statin therapy (6 had initiation, 7 had increase and 13 had maintenance of statin dosing). CMR plaque volume (PV) was measured in the region 12 mm below and up to 12 mm above carotid flow divider using software. Mean posterior IMT in the same region was measured. Baseline and 6-month CMR PV and US IMT were compared. Change in lipid rich/necrotic core (LR/NC) and calcification plaque components from CMR were related to change in PV.ResultsLow-density lipoprotein cholesterol decreased (86 ± 6 to 74 ± 4 mg/dL, p = 0.046). CMR PV decreased 5.8 ± 2% (1036 ± 59 to 976 ± 65 mm3, p = 0.018). Mean IMT was unchanged (1.12 ± 0.06 vs. 1.14 ± 0.06 mm, p = NS). Patients with initiation or increase of statins had -8.8 ± 2.8% PV change (p = 0.001) while patients with maintenance of statin dosing had -2.7 ± 3% change in PV (p = NS). There was circumferential heterogeneity in CMR plaque thickness with greatest thickness in the posterior carotid artery, in the region opposite the flow divider. Similarly there was circumferential regional difference in change of plaque thickness with significant plaque regression in the anterior carotid region in region of the flow divider. Change in LR/NC (R = 0.62, p = 0.006) and calcification (R = 0.45, p = 0.03) correlated with PV change.ConclusionsSix month statin therapy in patients with carotid plaque led to reduced plaque volume by 3T CMR, but ultrasound posterior IMT did not show any change. The heterogeneous spatial distribution of plaque and regional differences in magnitude of plaque regression may explain the difference in findings and support volumetric measurement of plaque. 3T CMR has potential advantage over ultrasound IMT to assess treatment response in individuals and may allow reduced sample size, duration and cost of clinical trials of plaque regression.

Protease-Activated Receptor 1 Inhibition by SCH79797 Attenuates Left Ventricular Remodeling and Profibrotic Activities of Cardiac Fibroblasts

Purpose: Fibroblast activity promotes adverse left ventricular (LV) remodeling that underlies the development of ischemic cardiomyopathy. Transforming growth factor-β (TGF-β) is a potent stimulus for fibrosis, and the extracellular signal-regulated kinases(ERK) 1/2 pathway also contributes to the fibrotic response. The thrombin receptor, protease-activated receptor 1 (PAR1), has been shown to play an important role in the excessive fibrosis in different tissues. The aim of this study was to investigate the influence of a PAR1 inhibitor, SCH79797, on cardiac fibrosis, tissue stiffness and postinfarction remodeling, and effects of PAR1 inhibition on thrombin-induced TGF-β and (ERK) 1/2 activities in cardiac fibroblasts. Methods: We used a rat model of myocardial ischemia–reperfusion injury, isolated cardiac fibroblasts, and 3-dimensional (3D) cardiac tissue models fabricated to ascertain the contribution of PAR1 activation on cardiac fibrosis and LV remodeling. Results: The PAR1 inhibitor attenuated LV dilation and improved LV systolic function of the reperfused myocardium at 28 days. This improvement was associated with a nonsignificant decrease in scar size (%LV) from 23 ± % in the control group (n = 10) to 16% ± 5.5% in the treated group (n = 9; P = .052). In the short term, the PAR1 inhibitor did not rescue infarct size or LV systolic function after 3 days. The PAR1 inhibition abolished thrombin-mediated ERK1/2 phosphorylation, TGF-β and type I procollagen production, matrix metalloproteinase-2/9 activation, myofibroblasts transformation in vitro, and abrogated the remodeling of 3D tissues induced by chronic thrombin treatment. Conclusion: These studies suggest PAR1 inhibition initiated after ischemic injury attenuates adverse LV remodeling through late-stage antifibrotic events.

Speckle-Tracking 2-Dimensional Strain Echocardiography: A New Noninvasive Imaging Tool to Evaluate Acute Rejection in Cardiac Transplantation

BACKGROUND There remains no reliable non-invasive method to detect cardiac transplant rejection. Recently, speckle-tracking 2-dimensional strain echocardiography (2DSE) was shown to be sensitive in the early detection of myocardial dysfunction in various models of cardiomyopathy. We aim to determine if 2DSE-derived functional indices can detect cardiac transplant rejection. METHODS Heterotopic rat cardiac transplantation was performed in histocompatible isografts or histoincompatible allografts. Histologic rejection scores were determined. Short-axis, mid-left ventricular (LV) echocardiography was performed on Day 6 after transplantation. Conventional measures of function were measured, (including LV fractional shortening and ejection fraction) as well as 2DSE parameters. RESULTS Despite class IIIB rejection in allografts and no rejection in isografts, there was no difference between isografts vs allografts in fractional shortening (15% +/- 3% vs 12% +/- 3%) or ejection fraction (36% +/- 5% vs 26% +/- 6%; both not significant). In contrast, 2DSE revealed decreases between isografts and allografts in global radial strain (12.6% +/- 5.6% vs 1.1% +/- 0.2%, p < 0.05), peak radial systolic strain rate (3.10 +/- 0.74/s vs 0.54 +/- 0.13/s, p < 0.001), and peak circumferential systolic strain rate (-1.99 +/- 0.55 vs -0.43 +/- 0.11/s; p < 0.01). CONCLUSIONS Systolic strain imaging using 2DSE differentiates myocardial function between experimental cardiac transplant rejection in allografts and non-rejection in isografts. Therefore, 2DSE may be useful in early non-invasive detection of transplant rejection.

Left Ventricular Ejection Time on Echocardiography Predicts Long-Term Mortality in Light Chain Amyloidosis

OBJECTIVE Light chain amyloidosis (AL) is associated with high mortality. The aim was to identify echocardiographic parameters that predict AL long-term mortality. METHODS Forty-two subjects with biopsy-proven AL (43% were female; aged 61 +/- 12 years) underwent echocardiography and were followed 29 +/- 16 months (median 29.4 months). Standard echocardiographic and clinical parameters and heart failure (HF) class were tested using univariate/multivariable Cox proportional hazard regression analyses to identify markers of mortality. RESULTS Twenty-three subjects died, with a 1-year mortality of 44%. Univariate predictors of mortality were HF class (P < .001), left ventricular systolic ejection time (ET) (P = .002), alkaline phosphatase (P < .001), and aspartate and alanine aminotransferase (P = .003 each). On multivariable analysis, only HF class (hazard ratio [HR] 4.86; 95% confidence interval [CI], 1.58-14.9; P = .006), ET (10 ms increase; HR 0.87; CI, 0.78-0.97; P = .01), and alkaline phosphatase (10 U/L increase; HR 1.04; CI, 1.01-1.06; P = .01) were prognostic. ET <or= 240 ms had a sensitivity of 61% and a specificity of 90% in predicting 1-year mortality and a sensitivity of 73% and a specificity of 90% in predicting 1-year cardiac mortality. CONCLUSION AL amyloidosis was associated with high long-term mortality. Among echocardiographic and clinical parameters, only ET and alkaline phosphatase had incremental value to HF class in predicting mortality. This may be useful to identify high-risk patients.

Cardiac Injury after 10 Gy Total Body Irradiation: Indirect Role of Effects on Abdominal Organs

The objective of this study was to determine whether radiation-induced injury to the heart after 10 Gy total body irradiation (TBI) is direct or indirect. Young male WAG/RijCmcr rats received a 10 Gy single dose using TBI, upper hemi-body (UHB) irradiation, lower hemi-body (LHB) irradiation, TBI with the kidneys shielded or LHB irradiation with the intestines shielded. Age-matched, sham-irradiated rats served as controls. The lipid profile, kidney injury, heart and liver morphology and cardiac function were determined up to 120 days after irradiation. LHB, but not UHB irradiation, increased the risk factors for cardiac disease as well as the occurrence of cardiac and kidney injury in a way that was quantitatively and qualitatively similar to that observed after TBI. Shielding of the kidneys prevented the increases in risk factors for cardiac disease. Shielding of the intestines did not prevent the increases in risk factors for cardiac disease. There was no histological evidence of liver injury 120 days after irradiation. Injury to the heart from irradiation appears to be indirect, supporting the notion that injury to abdominal organs, principally the kidneys, is responsible for the increased risk factors for and the occurrence of cardiac disease after TBI and LHB irradiation.

Intraventricular dyssynchrony in light chain amyloidosis: a new mechanism of systolic dysfunction assessed by 3-dimensional echocardiography

BackgroundLight chain amyloidosis (AL) is a rare but often fatal disease due to intractable heart failure. Amyloid deposition leads to diastolic dysfunction and often preserved ejection fraction. We hypothesize that AL is associated with regional systolic dyssynchrony. The aim is to compare left ventricular (LV) regional synchrony in AL subjects versus healthy controls using 16-segment dyssynchrony index measured from 3-dimension-al (3D) echocardiography.MethodsCardiac 3D echocardiography full volumes were acquired in 10 biopsy-proven AL subjects (60 ± 3 years, 5 females) and 10 healthy controls (52 ± 1 years, 5 females). The LV was subdivided into 16 segments and the time from end-diastole to the minimal systolic volume for each of the 16 segments was expressed as a percent of the cycle length. The standard deviations of these times provided a 16-segment dyssynchrony index (16-SD%). 16-SD% was compared between healthy and AL subjects.ResultsLeft ventricular ejection fraction was comparable (control vs. AL: 62.4 ± 0.6 vs. 58.6 ± 2.8%, p = NS). 16-SD% was significantly higher in AL versus healthy subjects (5.93 ± 4.4 vs. 1.67 ± 0.87%, p = 0.003). 16-SD% correlated with left ventricular mass index (R 0.45, p = 0.04) but not to left ventricular ejection fraction.ConclusionLight chain amyloidosis is associated with left ventricular regional systolic dyssynchrony. Regional dyssynchrony may be an unrecognized mechanism of heart failure in AL subjects.

Mitochondrial DNA Variant for Complex I Reveals a Role in Diabetic Cardiac Remodeling

Background: Mitochondrial dysfunction may influence myocardial remodeling in diabetes. Results: Impaired respiratory complex activity and energy depletion without mitochondrial uncoupling was identified in a new conplastic rat model of diabetes. Conclusion: mtDNA mutations are a risk factor for developing myocardial dysfunction in diabetes. Significance: Identifying mtDNA background is important for recognizing patients at risk for heart diseases. Myocardial remodeling and dysfunction are serious complications of type 2 diabetes mellitus (T2DM). Factors controlling their development are not well established. To specifically address the role of the mitochondrial genome, we developed novel conplastic rat strains, i.e. strains with the same nuclear genome but a different mitochondrial genome. The new animals were named T2DNmtFHH and T2DNmtWistar, where the acronym T2DN denotes their common nuclear genome (type 2 diabetic nephropathy (T2DN) rats) and mtFHH or mtWistar the origin of their mitochondria, Fawn Hooded Hypertensive (FHH) or Wistar rats, respectively. The T2DNmtFHH and T2DNmtWistar showed a similar progression of diabetes as determined by HbA1c, cholesterol, and triglycerides with normal blood pressure, thus enabling investigation of the specific role of the mitochondrial genome in cardiac function without the confounding effects of obesity or hypertension found in other models of diabetes. Echocardiographic analysis of 12-week-old animals showed no abnormalities, but at 12 months of age the T2DNmtFHH showed left ventricular remodeling that was verified by histology. Decreased complex I and complex IV but not complex II activity within the electron transport chain was found only in T2DNmtFHH, which was not explained by differences in protein content. Decreased cardiac ATP levels in T2DNmtFHH were in agreement with a lower ATP synthetic capacity by isolated mitochondria. Together, our data provide experimental evidence that mtDNA sequence variations have an additional role in energetic heart deficiency. The mitochondrial DNA background may explain the increased susceptibility of certain T2DM patients to develop myocardial dysfunction.