Left Ventricular Chamber Volume Research Articles

OP.8A.01] EXERCISE-INDUCED HYPERTENSION AND CARDIAC HYPERTROPHY IN EPINEPHRINE-DEFICIENT MICE

Objective: Phenylethanolamine-N-methyltransferase (Pnmt) is required for the conversion of norepinephrine to epinephrine. Bao et al (2007) described that Pnmt-knockout (Pnmt-KO) mice have an increased ratio of left ventricular (LV) posterior wall thickness to internal dimensions (LVPW/LVID) but not overall cardiac hypertrophy. Pnmt-KO mice showed normal resting blood pressure (BP) but became hypertensive during treadmill exercise. The aim of this study was to evaluate cardiac morphological and functional alterations after chronic exercise in Pnmt-KO mice. Design and method: PCR-based genotyping was performed at the Pnmt locus of 10-week-old Pnmt-KO (Pnmt-/-) and WT mice (129x1/SvJ). Epinephrine and norepinephrine were quantified by RP-HPLC-ED in adrenal glands. Animals were submitted to a 6-week exercise training program. BP was measured by a photoelectric pulse detector. Mice were anesthetized (sevoflurane, 8%) and cardiac morphology and function were evaluated by echocardiography followed by morphometric analysis. Results: Epinephrine levels were vestigial in Pnmt-KO compared with WT mice. There were no differences in systolic and diastolic BP between untrained Pnmt-KO and WT mice. However, trained Pnmt-KO mice showed a significant increase in systolic BP when compared to trained WT mice. Our findings also showed that the ratios between heart weight (HW/BW) and LV weight (LVW/BW) and body weight (BW) were significantly increased in trained compared to untrained Pnmt-KO mice. Trained Pnmt-KO mice presented higher HW/BW than trained WT mice. Untrained Pnmt-KO mice display echocardiographic results similar to those reported by Bao et al (2007) while LVPW and IVS thicknesses, LV end-diastolic internal dimension (LVIDd) and LV mass indexed for body surface area (LVMi) were significantly increased in trained Pnmt-KO mice, indicating overall LV hypertrophic changes. Indexed LV end-diastolic volume (LVEDVi), indexed stroke volume (SVi) and cardiac index (CI) were significantly higher in trained Pnmt-KO than untrained Pnmt-KO mice. Conclusions: In conclusion, the increased BP in Pnmt-KO mice in response to exercise appears to be associated with an increase in LV wall thickness and chamber volume suggesting hypertrophic remodelling of the LV in Pnmt-KO mice. Epinephrine appears to be essential for maintaining normal BP, probably through β2-adrenoceptors-induced vessel relaxation, and preventing LV hypertrophy in chronic exercise.

WE-FG-206-04: Comprehensive Evaluation of Left Ventricular (LV) Filling and Ejection Using High Frame Rate Cine MR Imaging: Key Technical and Methodological Requirements

Purpose: Unlike echocardiography which can quantify both LV filling and ejection, cine steady state free precession sequence (SSFP)-despite its high intrinsic signal and contrast to noise ratio, accuracy and precision of volume measurements-, is mostly relegated to quantifying LV ejection. The steady-state requirement typically constrains SSFP sequence to a breathhold (and limited temporal resolution). We describe: (a) free breathing cine SSFP approach that meets the SS requirement allowing high frame rate acquisition, (b) two MRI indices based on time-LV volume (TV) change during filling and compare against echocardiagraphic diastolic index (E/A ratio), and (c) evaluate the effect of temporal resolution on: LV volumes; ejection and filling rates; and normalized indices of systolic and diastolic function. Methods: A stack of contiguous LV short axis slices at high temporal resolution (τ=15 ms) was acquired using an in-house respiratory-triggered (RT), SS prepared, cardiac gated, free-breathing cine SSFP sequence (TR/TE/flip: 3.2 ms/1.5 ms/55°). All 24 study subjects provided written informed consent per IRB requirements. Subjects underwent both echo and MRI in one imaging session. From the expert-drawn contours, TV curve, and its derivative (dV/dt) were generated and these curves were downsampled to rates at 2τ,3τ,and 4τ. From TV and dV/dt curves during the early filling period (EFP) and late filling periods (LFP), volume based (VEFP/VLFP) and rate based (REFP/RLFP) diastolic indices were respectively defined, and calculated for each temporal resolution. Results: VEFP/VLFP and REFP/RLFP correlated well with E/Aecho. As temporal resolution declined from τ to 3τ, absolute percentage errors were: LV chamber volumes 20%.. Conclusion: By incorporating SS prep, RT can be used to obtain high frame rate cine SSFP sequence that can evaluate both LV systolic and diastolic function. Temporal resolution of cine SSFP is a key determinant of error in rate based diastolic indices. Research was partly supported by funding from Philips Healthcare.

Saxagliptin and Tadalafil Differentially Alter Cyclic Guanosine Monophosphate (cGMP) Signaling and Left Ventricular Function in Aortic-Banded Mini-Swine.

BackgroundCyclic guanosine monophosphate‐protein kinase G‐phosphodiesterase 5 signaling may be disturbed in heart failure (HF) with preserved ejection fraction, contributing to cardiac remodeling and dysfunction. The purpose of this study was to manipulate cyclic guanosine monophosphate signaling using the dipeptidyl‐peptidase 4 inhibitor saxagliptin and phosphodiesterase 5 inhibitor tadalafil. We hypothesized that preservation of cyclic guanosine monophosphate cGMP signaling would attenuate pathological cardiac remodeling and improve left ventricular (LV) function.Methods and ResultsWe assessed LV hypertrophy and function at the organ and cellular level in aortic‐banded pigs. Concentric hypertrophy was equal in all groups, but LV collagen deposition was increased in only HF animals. Prevention of fibrotic remodeling by saxagliptin and tadalafil was correlated with neuropeptide Y plasma levels. Saxagliptin better preserved integrated LV systolic and diastolic function by maintaining normal LV chamber volumes and contractility (end‐systolic pressure‐volume relationship, preload recruitable SW) while preventing changes to early/late diastolic longitudinal strain rate. Function was similar to the HF group in tadalafil‐treated animals including increased LV contractility, reduced chamber volume, and decreased longitudinal, circumferential, and radial mechanics. Saxagliptin and tadalafil prevented a negative cardiomyocyte shortening‐frequency relationship observed in HF animals. Saxagliptin increased phosphodiesterase 5 activity while tadalafil increased cyclic guanosine monophosphate levels; however, neither drug increased downstream PKG activity. Early mitochondrial dysfunction, evident as decreased calcium‐retention capacity and Complex II‐dependent respiratory control, was present in both HF and tadalafil‐treated animals.ConclusionsBoth saxagliptin and tadalafil prevented increased LV collagen deposition in a manner related to the attenuation of increased plasma neuropeptide Y levels. Saxagliptin appears superior for treating heart failure with preserved ejection fraction, considering its comprehensive effects on integrated LV systolic and diastolic function.

Normal values of left ventricular mass and cardiac chamber volumes assessed by 320-detector computed tomography angiography in the Copenhagen General Population Study.

Normal values of left ventricular mass (LVM) and cardiac chamber sizes are prerequisites for the diagnosis of individuals with heart disease. LVM and cardiac chamber sizes may be recorded during cardiac computed tomography angiography (CCTA), and thus modality specific normal values are needed. We studied 569 healthy subjects undergoing 320-detector CCTA as a part of the Copenhagen General Population Study. LVM as well as ventricular and atrial volumes was assessed with semi-automated software stratified by gender and age decades and indexed by body surface area (BSA). Mean age was 55 (range: 40-84) years, and 188 (33%) were men. BSA-indexed 97.5th percentile cut-off values: LVM = 80 and 65 gr/m(2), left ventricular volume = 97 and 83 mL/m(2), right ventricular volume = 120 and 102 mL/m(2), left atrial volume = 60 and 57 mL/m(2), and right atrial volume = 85 and 73 mL/m(2) for men and women, respectively. Men had greater absolute and indexed LVM and chamber volumes than women. For both genders, indexed ventricular volumes declined, whereas indexed atrial volumes increased in advancing age groups. For men, indexed LVM declined in advancing age groups. In multivariate analyses, gender, BSA, systolic blood pressure, and hard physical activity accounted for 63% of variance in LVM. In this cross-sectional general population study, men have greater indexed LVM and chamber volumes than women, and cardiac indexed volumes vary between age groups in both genders. These findings demonstrate the need for age- and gender-specific normal values for clinical diagnostic purposes.

Exercise-Induced Left Ventricular Remodeling Among Competitive Athletes

Background— Contemporary understanding of exercise-induced cardiac remodeling is based on cross-sectional data and relatively short duration longitudinal studies. Temporal progression of exercise-induced cardiac remodeling remains incompletely understood. Methods and Results— A longitudinal repeated-measures study design using 2-dimensional and speckle-tracking echocardiography was used to examine acute augmentation phase (AAP; 90 days) and more extended chronic maintenance phase (39 months) left ventricular (LV) structural and functional adaptations to endurance exercise training among competitive male rowers (n=12; age 18.6±0.5 years). LV mass was within normal limits at baseline (93±9 g/m 2 ), increased after AAP (105±7 g/m 2 ; P =0.001), and further increased after chronic maintenance phase (113±10 g/m 2 ; P <0.001 for comparison to post-AAP). AAP LV hypertrophy was driven by LV dilation (ΔLV end-diastolic volume, 9±3 mL/m 2 ; P =0.004) with stable LV wall thickness (ΔLV wall thickness, 0.3±0.1 mm; P =0.63). In contrast, chronic maintenance phase LV hypertrophy was attributable to LV wall thickening (Δ LV wall thickness, 1.1±0.4 mm; P =0.004) with stable LV chamber volumes (ΔLV end-diastolic volume, 1±1 mL/m 2 ; P =0.48). Early diastolic peak tissue velocity increased during AAP (−11.7±1.9 versus −13.6±1.3 cm/s; P <0.001) and remained similarly increased after chronic maintenance phase. Conclusions— In a small sample of competitive endurance athletes, exercise-induced cardiac remodeling follows a phasic response with increases in LV chamber size, early diastolic function, and systolic twist in an acute augmentation phase of exercise training. This is followed by a chronic phase of adaptation characterized by increasing wall thickness and regression in LV twist. Training duration is a determinant of exercise-induced cardiac remodeling and has implications for the assessment of myocardial structure and function in athletes.

Transendocardial Mesenchymal Stem Cells and Mononuclear Bone Marrow Cells for Ischemic Cardiomyopathy

Whether culture-expanded mesenchymal stem cells or whole bone marrow mononuclear cells are safe and effective in chronic ischemic cardiomyopathy is controversial. To demonstrate the safety of transendocardial stem cell injection with autologous mesenchymal stem cells (MSCs) and bone marrow mononuclear cells (BMCs) in patients with ischemic cardiomyopathy. A phase 1 and 2 randomized, blinded, placebo-controlled study involving 65 patients with ischemic cardiomyopathy and left ventricular (LV) ejection fraction less than 50% (September 1, 2009-July 12, 2013). The study compared injection of MSCs (n=19) with placebo (n = 11) and BMCs (n = 19) with placebo (n = 10), with 1 year of follow-up. Injections in 10 LV sites with an infusion catheter. Treatment-emergent 30-day serious adverse event rate defined as a composite of death, myocardial infarction, stroke, hospitalization for worsening heart failure, perforation, tamponade, or sustained ventricular arrhythmias. No patient had a treatment-emergent serious adverse events at day 30. The 1-year incidence of serious adverse events was 31.6% (95% CI, 12.6% to 56.6%) for MSCs, 31.6% (95% CI, 12.6%-56.6%) for BMCs, and 38.1% (95% CI, 18.1%-61.6%) for placebo. Over 1 year, the Minnesota Living With Heart Failure score improved with MSCs (-6.3; 95% CI, -15.0 to 2.4; repeated measures of variance, P=.02) and with BMCs (-8.2; 95% CI, -17.4 to 0.97; P=.005) but not with placebo (0.4; 95% CI, -9.45 to 10.25; P=.38). The 6-minute walk distance increased with MSCs only (repeated measures model, P = .03). Infarct size as a percentage of LV mass was reduced by MSCs (-18.9%; 95% CI, -30.4 to -7.4; within-group, P = .004) but not by BMCs (-7.0%; 95% CI, -15.7% to 1.7%; within-group, P = .11) or placebo (-5.2%; 95% CI, -16.8% to 6.5%; within-group, P = .36). Regional myocardial function as peak Eulerian circumferential strain at the site of injection improved with MSCs (-4.9; 95% CI, -13.3 to 3.5; within-group repeated measures, P = .03) but not BMCs (-2.1; 95% CI, -5.5 to 1.3; P = .21) or placebo (-0.03; 95% CI, -1.9 to 1.9; P = .14). Left ventricular chamber volume and ejection fraction did not change. Transendocardial stem cell injection with MSCs or BMCs appeared to be safe for patients with chronic ischemic cardiomyopathy and LV dysfunction. Although the sample size and multiple comparisons preclude a definitive statement about safety and clinical effect, these results provide the basis for larger studies to provide definitive evidence about safety and to assess efficacy of this new therapeutic approach. clinicaltrials.gov Identifier: NCT00768066.

Mid-wall fibrosis on delayed enhancement CMR - a marker for adverse left ventricular chamber remodeling independent of cardiomyopathic etiology

Background Mid-wall fibrosis (MWF) is a hallmark of non-ischemic cardiomyopathy (NICM) that confers increased risk for sudden cardiac death and mortality. The relationship between MWF and left ventricular (LV) remodeling is unknown. Methods The population comprised patients with advanced systolic dysfunction (LVEF ≤ 40%) undergoing CMR (1.5T, General Electric Signa). Ischemic vs. NICM etiology was classified in accordance with established convention based on obstructive CAD on invasive angiography. Delayed enhancement CMR (IR-GRE acquired 10-30 minutes post gadolinium [0.2 mmol/kg]) was used to identify MWF, defined as hyperenhancement confined to the mid-myocardial or epicardial aspect of the interventricular septum. LV mass and chamber volume were quantified by planimetry of contiguous SSFP cine-CMR short axis slices, with ejection fraction (EF) calculated as the proportional difference between end-diastolic (EDV) and end-systolic (ESV) volumes. Results 523 patients (61 ± 14 yo, 72% M, 66% ischemic CM) were studied: MWF was present in 16%, and was 6-fold more common in patients with angiographically classified NICM (37% vs. 6%; p < 0.001). Regarding LV remodeling, MWF was associated with higher EDV (134 ± 39 ml vs. 114 ± 34 ml; p < 0.001) and LV mass (102 ± 24 vs. 96 ± 28 gm; p < 0.001) and lower LVEF (26 ± 8% vs. 30 ± 8%; p ≤ 0.05). MWF was nearly 3-fold more common among patients in the highest tertile of EDV vs. the remainder of the population (29% vs. 10%; p < 0.001). Multivariate regression analysis was performed to further assess markers for MWF: Restricted to imaging indices, results (Table 1A) demonstrated EF and EDV to be independently associated with MWF (OR = 1.46, CI 1.03-2.10; p < 0.05, OR = 1.13, CI 1.04-1.20; p < 0.05, respectively) after controlling for mass (OR = 0.95, CI 0.85-1.00; p = 0.29). Regarding clinical variables, results (Table 1B) confirmed a strong association with NICM (OR = 8.4, CI 4.78-14.72; p < 0.001), independent of other clinical indices. A combined model incorporating both clinical and imaging variables demonstrated both NICM and LV volume to be independently associated with MWF even after controlling for EF (Table 1C). Overall strength of the combined clinical/imaging (c 2 = 91.2; p < 0.001) model for MWF was higher than that of isolated clinical (c 2 = 76.7; p < 0.001) and imaging (c 2 = 26.0; p < 0.001) models.

Improved diagnosis and prognosis using Decisions Informed by Combining Entities (DICE): results from the NHLBI-sponsored Women's Ischemia Syndrome Evaluation (WISE).

To introduce an algorithmic approach to improve the interpretation of myocardial perfusion images in women with suspected myocardial ischemia. Gated single photon emission computed tomography (SPECT) and magnetic resonance (MR) myocardial perfusion imaging (MPI) approaches have relatively poor diagnostic and prognostic value in women with suspected myocardial ischemia. Here we introduce an approach: Decisions Informed by Combining Entities (DICE) that forms a mathematical model utilizing MPI and cardiac dimensions generated by one modality to predict the perfusion status of another modality. The effect of the model is to systematically incorporate cardiac metrics that influence the interpretation of perfusion images, leading to greater consistency in designation of myocardial perfusion status between studies. Women (n=213), with suspected myocardial ischemia, underwent MPI assessment for regional perfusion defects using two modalities: gated SPECT (n=207) and MR imaging (n=203). To determine perfusion status, MR data were evaluated qualitatively and semi-quantitatively while SPECT data were evaluated using conventional clinical criteria. These perfusion status readings were designated "Original". Four regression models were generated to model perfusion status obtained with one modality [e.g., semi-quantitative magnetic resonance imaging (MRI)] against another modality (e.g., SPECT) and a threshold applied (DICE modeling) to designate perfusion status as normal or low. The DICE models included perfusion status, left ventricular (LV) chamber volumes and myocardial wall thickness. Women were followed for 40±16 months for the development of first major adverse cardiovascular event (MACE: CV death, nonfatal myocardial infarction (MI) or hospitalization for congestive heart failure). Original and DICE perfusion status were compared in their ability to detect high-grade coronary artery disease (CAD) and for prediction of MACE. Adverse events occurred in 25 (12%) women and CAD was present in 34 (16%). In receiver-operator characteristic (ROC) analysis for CAD detection, the average area under the curve (AUC) for DICE vs. Original status was 0.77±0.03 vs. 0.70±0.03, P<0.01. Similarly, in Kaplan-Meier survival analysis the average log-rank statistic was higher for DICE vs. the Original readings (10.6±5.2 vs. 3.0±0.6, P<0.05). While two data sets are required to generate the DICE models no knowledge of follow-up results is needed. DICE modeling improved diagnostic and prognostic value vs. the Original interpretation of the myocardial perfusion status.

Predictors of response to cardiac resynchronization therapy on pre-implantation cardiovascular magnetic resonance imaging

Background Cardiac resynchronization therapy (CRT) is an established treatment for severe heart failure. However, up to 40% of patients do not respond. While regional scar distribution has received focused attention, the predictive utility of global markers of remodeling and irreversible injury has not been well explored. Methods Sixty-eight patients receiving CRT underwent pre-implant cardiovascular MRI followed by serial echocardiography at 3 and 6 months. Blinded measurement of Left Ventricular (LV) and Right Ventricular (RV) chamber dimensions, volumes and mass were performed from short axis cine datasets. LV dysynchrony was measured by septal to lateral wall delay. Total LV scar burden was determined from Late Gadolinium Enhancement (LGE) images using manual contour tracing of endocardial and epicardial borders with application of a signal threshold ≥5SD above reference myocardium. Response to CRT was defined as a reduction in LV end-systolic volume (ESV) ≥15% at 6 months. Results The mean age was 66.3 ± 8.9 years with a mean LV Ejection fraction (EF) of 25.2 ± 7.2%. Overall, 47 patients (69%) responded. Among all baseline measures LVEDV (p=0.03), LVESV (p=0.045), RV EF (p=0.0349) and total scar burden (p=0.018) were the only significant predictors of CRT response. Multivariate analysis showed total scar burden to be the only independent predictor of CRT response (p=0.015). Conclusions Pre-implantation MRI offers markers for the prediction of response to CRT. Of these, total scar burden appears to be an independent predictor of response and may be of assistance in the selection of optimal candidates. Funding None

Enhanced resistance to permeability transition in interfibrillar cardiac mitochondria in dogs: effects of aging and long-term aldosterone infusion

Functional differences between subsarcolemmal and interfibrillar cardiac mitochondria (SSM and IFM) have been observed with aging and pathological conditions in rodents. Results are contradictory, and there is little information from large animal models. We assessed the respiratory function and resistance to mitochondrial permeability transition (MPT) in SSM and IFM from healthy young (1 yr) and old (8 yr) female beagles and in old beagles with hypertension and left ventricular (LV) wall thickening induced by 16 wk of aldosterone infusion. MPT was assessed in SSM and IFM by Ca(2+) retention and swelling. Healthy young and old beagles had similar mitochondrial structure, respiratory function, and Ca(2+)-induced MPT within SSM and IFM subpopulations. On the other hand, oxidative capacity and resistance to Ca(2+)-induced MPT were significantly greater in IFM compared with SSM in all groups. Old beagles treated with aldosterone had greater LV wall thickness and worse diastolic filling but normal LV chamber volume and systolic function. Treatment with aldosterone did not alter mitochondrial respiratory function but accelerated Ca(2+)-induced MPT in SSM, but not IFM, compared with healthy old and young beagles. In conclusion, in a large animal model, oxidative capacity and resistance to MPT were greater in IFM than in SSM. Furthermore, aldosterone infusion increased susceptibility to MPT in SSM, but not IFM. Together this suggests that SSM are less resilient to acute stress than IFM in the healthy heart and are more susceptible to the development of pathology with chronic stress.

Sudden Death Due to Infiltration of Left Bundle Branches by Interventricular Septal Cardiac Fibroma

Cardiac fibromas are benign conditions; however, their location and size may cause ventricular arrhythmias and sudden cardiac death. We report a case of a 68-year-old female who died suddenly. Postmortem investigation detected a huge cardiac fibroma in the pars muscularis of the interventricular septum, occupying almost the entire muscular septum, and restricting the volume of left ventricular chamber. Histological examination revealed numerous foci of calcification in the alternating complex interlacing or strictly parallel collagenous fiber mass. Tumor mass was mainly demarcated, but in some places, fibrous infiltration of surrounding working cardiac muscle was found. We present a case when direct tumor involvement in the descending left bundle branches was evidenced. Mainly, the branches of septal fascicle were disrupted, entrapped, and degenerated by the tumor mass. This case report emphasizes that postmortem histological examination of conduction system in all sudden cardiac death cases may substantially improve the accuracy of postmortem diagnosis.

Cardiac remodeling with rhythm versus rate control strategies for atrial fibrillation in patients with heart failure: Insights from the AF-CHF echocardiographic sub-study

BackgroundIn patients with heart failure and atrial fibrillation, the AF-CHF (Atrial Fibrillation and Congestive Heart Failure) trial did not demonstrate the superiority of rhythm control (RhyC) over a rate control (RaC) strategy on cardiovascular mortality. Nevertheless, deleterious hemodynamic effects of atrial fibrillation can lead to further decrease in left ventricular (LV) function and progression of symptoms. This echocardiographic sub-study was designed to compare the effects of the two treatment strategies on LV ejection fraction (LVEF), chamber volumes and dimensions, valvular regurgitation and functional status. Methods and resultsA total of 59 patients (29 RhyC, 30 RaC) aged 67±8years (14% women), enrolled in the AF-CHF trial at the Montreal Heart Institute underwent standardized echocardiograms at baseline and at 12months. Mean LVEF at baseline was severely depressed (RhyC: 27.0±4.9% and RaC: 27.6±7.4%, p=0.73), and improved to a similar degree in both groups (RhyC: +8.0±10.4% and RaC: +4.5±10.6, both p<0.05; p=0.19 for RhyC versus RaC). Other echocardiographic parameters, such as LV end-systolic volume index and degree of mitral and tricuspid regurgitation, remained unchanged. New York Heart Association functional class and distance walked in 6min improved significantly in both groups (RhyC: +48.9±78.7m and RaC: +47.2±96.7m, both p≤0.01), with no difference between RhyC and RaC strategies. ConclusionsImprovements in LVEF and functional status are observed after 12months in patients with heart failure and atrial fibrillation, regardless of whether rate or rhythm control strategies are used.

Predicting atrial fibrillation recurrence with circulating inflammatory markers in patients in sinus rhythm at high risk for atrial fibrillation: data from the GISSI atrial fibrillation trial

BackgroundInflammation may play a significant role in the pathogenesis of atrial fibrillation (AF).ObjectivesTo examine the roles of three systemic inflammatory markers in predicting recurrent AF.MethodsThe association between the plasma concentrations...

Impact of diastolic dysfunction severity on global left ventricular volumetric filling - assessment by automated segmentation of routine cine cardiovascular magnetic resonance.

ObjectivesTo examine relationships between severity of echocardiography (echo) -evidenced diastolic dysfunction (DD) and volumetric filling by automated processing of routine cine cardiovascular magnetic resonance (CMR).BackgroundCine-CMR provides high-resolution assessment of left ventricular (LV) chamber volumes. Automated segmentation (LV-METRIC) yields LV filling curves by segmenting all short-axis images across all temporal phases. This study used cine-CMR to assess filling changes that occur with progressive DD.Methods115 post-MI patients underwent CMR and echo within 1 day. LV-METRIC yielded multiple diastolic indices - E:A ratio, peak filling rate (PFR), time to peak filling rate (TPFR), and diastolic volume recovery (DVR80 - proportion of diastole required to recover 80% stroke volume). Echo was the reference for DD.ResultsLV-METRIC successfully generated LV filling curves in all patients. CMR indices were reproducible (≤ 1% inter-reader differences) and required minimal processing time (175 ± 34 images/exam, 2:09 ± 0:51 minutes). CMR E:A ratio decreased with grade 1 and increased with grades 2-3 DD. Diastolic filling intervals, measured by DVR80 or TPFR, prolonged with grade 1 and shortened with grade 3 DD, paralleling echo deceleration time (p < 0.001). PFR by CMR increased with DD grade, similar to E/e' (p < 0.001). Prolonged DVR80 identified 71% of patients with echo-evidenced grade 1 but no patients with grade 3 DD, and stroke-volume adjusted PFR identified 67% with grade 3 but none with grade 1 DD (matched specificity = 83%). The combination of DVR80 and PFR identified 53% of patients with grade 2 DD. Prolonged DVR80 was associated with grade 1 (OR 2.79, CI 1.65-4.05, p = 0.001) with a similar trend for grade 2 (OR 1.35, CI 0.98-1.74, p = 0.06), whereas high PFR was associated with grade 3 (OR 1.14, CI 1.02-1.25, p = 0.02) DD.ConclusionsAutomated cine-CMR segmentation can discern LV filling changes that occur with increasing severity of echo-evidenced DD. Impaired relaxation is associated with prolonged filling intervals whereas restrictive filling is characterized by increased filling rates.

Preservation of ventricular performance at early stages of diabetic cardiomyopathy involves changes in myocyte size, number and intercellular coupling

In a rat model of diabetic cardiomyopathy, we tested whether specific changes in myocyte turnover and intercellular coupling contribute to preserving ventricular performance after a short period of hyperglycemia. In 41 rats with streptozotocin-induced diabetes and 24 control animals, cardiac electromechanical properties were assessed by telemetry ECG, epicardial potential mapping, and hemodynamic measurements to document normal ventricular function. Myocardial remodeling, expression of gap-junction proteins and myocyte regeneration were evaluated by tissue morphometry, immunohistochemistry and immunoblotting. Ventricular myocyte number and volume were also determined. In diabetic hearts, after 3 weeks of hyperglycemia, left ventricular mass was lowered by 23%, while left ventricular wall thickness and chamber volume were maintained, in the absence of fibrosis and myocyte hypertrophy. In the presence of a marked DNA oxidative damage, an increased rate of DNA replication and mitotic divisions associated with generation of new myocytes were detected. The number of cells expressing the receptor for Stem Cell Factor (c-kit) and their rate of proliferation were preserved in the left ventricle while the atrial storage of these primitive cells was severely reduced by diabetes-induced oxidative stress. Despite a down-regulation of Connexin43 and over-expression of both Connexin40 and Connexin45, the junctional proteins were normally distributed in diabetic ventricular myocardium,justifying the preserved tissue excitability and conduction velocity. In conclusion, before the appearance of the diabetic cardiomyopathic phenotype,myocardial cell proliferation associated with gap junction protein remodeling may contribute to prevent marked alterations of cardiac structure and electrophysiological properties, preserving ventricular performance.

Hemodynamic effects of vacuum-assisted closure therapy in cardiac surgery: Assessment using magnetic resonance imaging

The hemodynamic effects of vacuum-assisted closure therapy in cardiac surgery are debated. The aim of the present study was to quantify cardiac output and left ventricular chamber volumes after vacuum-assisted closure using magnetic resonance imaging, which is known to be the most accurate method for quantifying these measures. Six pigs had median sternotomy followed by vacuum-assisted closure treatment in the presence and absence of a paraffin gauze interface dressing. Cardiac output and stroke volume were examined using magnetic resonance imaging flow quantification (breath-hold and real-time). Chamber volumes were assessed using cine magnetic resonance imaging. Cardiac output and stroke volume decreased immediately after application of negative pressures of 75, 125, and 175 mm Hg (13% +/- 1% decrease in cardiac output). Interposition of 4 layers of paraffin gauze dressing over the heart during vacuum-assisted closure therapy resulted in a smaller decrease in cardiac output (8% +/- 1%). Vacuum-assisted closure therapy results in an immediate decrease in cardiac output, although to a lesser extent than shown previously. Covering the heart with a wound interface dressing lessens the hemodynamic effects of vacuum-assisted closure.

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Papillary Muscle Repositioning in Mitral Valve Replacement in Patients With Left Ventricular Dysfunction

The aim of this study was to investigate the feasibility of performing papillary muscle repositioning for mitral valve replacement procedures in patients with left ventricular dysfunction and to determine the early and late effects of this procedure on clinical outcome and left ventricular mechanics. One hundred patients with ejection fraction less than 40, who were candidates for isolated surgical correction of mitral insufficiency, had mitral valve replacement and were prospectively randomly assigned to either total chordal-sparing or papillary muscle repositioning. Fifty subjects underwent papillary muscle repositioning (PMR group), and the remaining 50 had complete preservation of all chordal structures with mitral valve replacement (CMVR group). Echocardiography was performed preoperatively, at discharge, and after 2 years to determine dimensions, left ventricular shape, and function. End-diastolic and -systolic volumes decreased in both groups initially and continued to decline. Decreasing volumes, however, were more significant in the PMR group, in which the significant decrease in the sphericity index continued for another 2 years. In contrast, the sphericity index in the CMVR group had no significant changes at discharge and at 2 years. In terms of systolic performance, ejection fraction had no significant changes in the CMVR group, whereas ejection fraction significantly increased in the PMR group. Papillary muscle repositioning may result in more favorable left ventricular remodeling compared with complete retention of the mitral subvalvular apparatus during mitral valve replacement. It confers a significant early and late advantage by causing significant reductions in the left ventricular chamber volume, sphericity index, and systolic performance.

Dietary iron deficiency induces ventricular dilation, mitochondrial ultrastructural aberrations and cytochrome c release: involvement of nitric oxide synthase and protein tyrosine nitration

Iron deficiency is associated with multiple health problems, including the cardiovascular system. However, the mechanism of action of iron-deficiency-induced cardiovascular damage is unclear. The aim of the present study was to examine the effect of dietary iron deficiency on cardiac ultrastructure, mitochondrial cytochrome c release, NOS (nitric oxide synthase) and several stress-related protein molecules, including protein nitrotyrosine, the p47phox subunit of NADPH oxidase, caveolin-1 and RhoA. Male weanling rats were fed with either control or iron-deficient diets for 12 weeks. Cardiac ultrastructure was examined by transmission electron microscopy. Western blot analysis was used to evaluate cytochrome c, endothelial and inducible NOS, NADPH oxidase, caveolin-1 and RhoA. Protein nitrotyrosine formation was measured by ELISA. Rats fed an iron-deficient diet exhibited increased heart weight and size compared with the control group. Heart width, length and ventricular free wall thickness were similar between the two groups. However, the left ventricular dimension and chamber volume were significantly enhanced in the iron-deficient group compared with controls. Ultrastructural examination revealed mitochondrial swelling and abnormal sarcomere structure in iron-deficient ventricular tissues. Cytochrome c release was significantly enhanced in iron-deficient rats. Protein expression of eNOS (endothelial NOS) and iNOS (inducible NOS), and protein nitrotyrosine formation were significantly elevated in cardiac tissue or mitochondrial extraction from the iron-deficient group. Significantly up-regulated NADPH oxidase, caveolin-1 and RhoA expression were also detected in ventricular tissue of the iron-deficient group. Taken together, these results suggest that dietary iron deficiency may have induced cardiac hypertrophy characterized by aberrant mitochondrial and irregular sarcomere organization, which was accompanied by increased reactive nitrogen species and RhoA expression.

Cardiac stem cells delivered intravascularly traverse the vessel barrier, regenerate infarcted myocardium, and improve cardiac function

The ability of cardiac stem cells (CSCs) to promote myocardial repair under clinically relevant conditions (i.e., when delivered intravascularly after reperfusion) is unknown. Thus, rats were subjected to a 90-min coronary occlusion; at 4 h after reperfusion, CSCs were delivered to the coronary arteries via a catheter positioned into the aortic root. Echocardiographic analysis showed that injection of CSCs attenuated the increase in left ventricular (LV) end-diastolic dimensions and impairment in LV systolic performance at 5 weeks after myocardial infarction. Pathologic analysis showed that treated hearts exhibited a smaller increase in LV chamber diameter and volume and a higher wall thickness-to-chamber radius ratio and LV mass-to-chamber volume ratio. CSCs induced myocardial regeneration, decreasing infarct size by 29%. A diploid DNA content and only two chromosomes 12 were found in new cardiomyocytes, indicating that cell fusion did not contribute to tissue reconstitution. In conclusion, intravascular injection of CSCs after reperfusion limits infarct size, attenuates LV remodeling, and ameliorates LV function. This study demonstrates that CSCs are effective when delivered in a clinically relevant manner, a clear prerequisite for clinical translation, and that these beneficial effects are independent of cell fusion. The results establish CSCs as candidates for cardiac regeneration and support an approach in which the heart's own stem cells could be collected, expanded, and stored for subsequent therapeutic repair.