Cardiovascular Imaging in Infective Endocarditis: A Multimodality Approach.

Multimodality imaging plays a pivotal role in the evaluation and management of infective endocarditis (IE)-a condition with high morbidity and mortality. The diagnosis of IE is primarily based on the modified Duke criteria with echocardiography as the first-line imaging modality. Both transthoracic and transesophageal echocardiography delineate vegetation location and size, assess for paravalvular extension of infection, and have the added advantage of defining the hemodynamic effects of valvular or device infection. Native and prosthetic valve IE, infections relating to cardiac implantable electronic devices, and indwelling catheters are effectively evaluated with echocardiography. However, complementary imaging is occasionally required when there remains diagnostic uncertainty following transesophageal echocardiography. Multidetector computed tomography and nuclear imaging techniques such as positron emission tomography and white blood cell scintigraphy have been shown to reduce the rate of misdiagnosed IE particularly in the setting of prosthetic valve endocarditis, paravalvular extension of infection, and cardiac implantable electronic devices. In this review, we describe a modern approach to cardiac imaging in native and prosthetic valve endocarditis, as well as cardiac implantable electronic devices including pacing devices and left ventricular assist devices. Current guidelines addressing the role of multimodality imaging in IE are discussed. The utility of imaging in the assessment of local and distant endocarditis complications such as pericardial sequelae, myocarditis, and embolic events is also addressed.

Atrial Tissue Pro-Fibrotic M2 Macrophage Marker CD163+, Gene Expression of Procollagen and B-Type Natriuretic Peptide.

Background Atrial tissue fibrosis is linked to inflammatory cells, yet is incompletely understood. A growing body of literature associates peripheral blood levels of the antifibrotic hormone BNP (B-type natriuretic peptide) with atrial fibrillation (AF). We investigated the relationship between pro-fibrotic tissue M2 macrophage marker Cluster of Differentiation (CD)163+, atrial procollagen expression, and BNP gene expression in patients with and without AF. Methods and Results In a cross-sectional study design, right atrial tissue was procured from 37 consecutive, consenting, stable patients without heart failure or left ventricular systolic dysfunction, of whom 10 had AF and 27 were non-AF controls. Samples were analyzed for BNP and fibro-inflammatory gene expression, as well as fibrosis and CD163+. Primary analyses showed strong correlations (all P<0.008) between M2 macrophage CD163+ staining, procollagen gene expression, and myocardial BNP gene expression across the entire cohort. In secondary analyses without multiplicity adjustments, AF patients had greater left atrial volume index, more valve disease, higher serum BNP, and altered collagen turnover markers versus controls (all P<0.05). AF patients also showed higher atrial tissue M2 macrophage CD163+, collagen volume fraction, gene expression of procollagen 1 and 3, as well as reduced expression of the BNP clearance receptor NPRC (all P<0.05). Atrial procollagen 3 gene expression was correlated with fibrosis and BNP gene expression was correlated with serum BNP. Conclusions Elevated atrial tissue pro-fibrotic M2 macrophage CD163+ is associated with increased myocardial gene expression of procollagen and anti-fibrotic BNP and is higher in patients with AF. More work on modulation of BNP signaling for treatment and prevention of AF may be warranted.

Usefulness of Mitral Regurgitant Volume Quantified Using Magnetic Resonance Imaging to Predict Left Ventricular Remodeling After Mitral Valve "Correction".

MRI studies have shown a tight correlation between mitral regurgitant volume and left ventricular end-diastolic volume (LV EDV) in patients with primary chronic mitral regurgitation (MR). They have also shown a tight correlation between regurgitant volume and the decrease in LVEDV following mitral valve surgery. The purpose of this study is to validate an empiric calculation that can be used preoperatively to predict the amount of left ventricular remodeling following mitral valve correction. This is a prospective multicenter study of 63 (61 ± 13 years, male 65%) patients who underwent an MRI before and after mitral valve correction. Pre and postmitral valve correction ventricular volumes and ejection fractions were quantified. The predicted change in LV EDV was empirically calculated as mitral regurgitant volume/left ventricular ejection fraction. The observed change in LV EDV was compared to the predicted change in LV EDV. The LVEDV decreased in 61 (97%) patients following mitral valve correction (237 ± 66 ml vs 164 ± 46 ml, p <0.0001). Correlation between the observed and predicted change in LVEDV was good for the entire cohort (r = 0.77, p <0.0001) and excellent in patients with <10 ml of residual MR (r = 0.87, p <0.0001). This tight correlation was seen in both patients with primary (0.86, p <0.0001) and secondary MR (0.97, p <0.0001) and <10 ml of residual MR. Multivariate predictors of LV remodeling were MR volume, primary MR, and LVESV. In conclusion cardiac MRI volumetric measurements accurately predict LV remodeling following mitral valve correction. This finding supports the notion that MRI accurately quantifies the severity of chronic mitral regurgitation and a cardiac MRI should be strongly considered before mitral valve correction.

Ranolazine in Symptomatic Diabetic Patients Without Obstructive Coronary Artery Disease: Impact on Microvascular and Diastolic Function.

BACKGROUND: Treatments for patients with myocardial ischemia in the absence of angiographic obstructive coronary artery disease are limited. In these patients, particularly those with diabetes mellitus, diffuse coronary atherosclerosis and microvascular dysfunction is a common phenotype and may be accompanied by diastolic dysfunction. Our primary aim was to determine whether ranolazine would quantitatively improve exercise-stimulated myocardial blood flow and cardiac function in symptomatic diabetic patients without obstructive coronary artery disease. METHODS AND RESULTS: We conducted a double-blinded crossover trial with 1:1 random allocation to the order of ranolazine and placebo. At baseline and after each 4-week treatment arm, left ventricular myocardial blood flow and coronary flow reserve (CFR; primary end point) were measured at rest and after supine bicycle exercise using 13N-ammonia myocardial perfusion positron emission tomography. Resting echocardiography was also performed. Multilevel mixed-effects linear regression was used to determine treatment effects. Thirty-five patients met criteria for inclusion. Ranolazine did not significantly alter rest or postexercise left ventricular myocardial blood flow or CFR. However, patients with lower baseline CFR were more likely to experience improvement in CFR with ranolazine (r=-0.401, P=0.02) than with placebo (r=-0.188, P=0.28). In addition, ranolazine was associated with an improvement in E/septal e' (P=0.001) and E/lateral e' (P=0.01). CONCLUSIONS: In symptomatic diabetic patients without obstructive coronary artery disease, ranolazine did not change exercise-stimulated myocardial blood flow or CFR but did modestly improve diastolic function. Patients with more severe baseline impairment in CFR may derive more benefit from ranolazine. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01754259.

Comparison of Echocardiography, Cardiac Magnetic Resonance, and Computed Tomographic Imaging for the Evaluation of Left Ventricular Myocardial Function: Part 1 (Global Assessment).

Assessing left ventricular function is an essential part of the cardiovascular evaluation as it plays an important role in managing the patient and predicting prognosis. Recent advances in the imaging modalities currently allow a non-invasive comprehensive assessment of cardiac mechanics and precise estimation of cardiovascular hemodynamics. In this review, we will discuss and compare the currently available techniques and novel approaches utilized by echocardiography, cardiac magnetic resonance, and computed tomography for the assessment of global left ventricular performance.

Comparison of Echocardiography, Cardiac Magnetic Resonance, and Computed Tomographic Imaging for the Evaluation of Left Ventricular Myocardial Function: Part 2 (Diastolic and Regional Assessment).

Assessing left ventricular diastolic and regional function is a crucial part of the cardiovascular evaluation. Diastolic function is as important as systolic function for left ventricular performance because it is the determinant of the ability of the left atrium and ventricle to fill at relatively low pressures. Additionally, diastolic function plays an important role in the management and prognosis of patients with symptoms and signs of heart failure. Technical advances in the imaging modalities have allowed a comprehensive noninvasive assessment of global and regional cardiac mechanics and precise estimation of cardiovascular hemodynamics. In this review, we will discuss and compare clinically available techniques and novel approaches using echocardiography, cardiac magnetic resonance, and computed tomography for the assessment of diastolic and regional left ventricular function.

Epigenetic Therapy for the Treatment of Hypertension-Induced Cardiac Hypertrophy and Fibrosis.

BACKGROUND: The development of heart failure is associated with changes in the size, shape, and structure of the heart that has a negative impact on cardiac function. These pathological changes involve excessive extracellular matrix deposition within the myocardial interstitium and myocyte hypertrophy. Alterations in fibroblast phenotype and myocyte activity are associated with reprogramming of gene transcriptional profiles that likely requires epigenetic alterations in chromatin structure. The aim of our work was to investigate the potential of a currently licensed anticancer epigenetic modifier as a treatment option for cardiac diseases associated with hypertension-induced cardiac hypertrophy and fibrosis. METHODS AND RESULTS: The effects of DNA methylation inhibition with 5-azacytidine (5-aza) were examined in a human primary fibroblast cell line and in a spontaneously hypertensive rat (SHR) model. The results from this work allude to novel in vivo antifibrotic and antihypertrophic actions of 5-aza. Administration of the DNA methylation inhibitor significantly improved several echocardiographic parameters associated with hypertrophy and diastolic dysfunction. Myocardial collagen levels and myocyte size were reduced in 5-aza-treated SHRs. These findings are supported by beneficial in vitro effects in cardiac fibroblasts. Collagen I, collagen III, and α-smooth muscle actin were reduced in a human ventricular cardiac fibroblast cell line treated with 5-aza. CONCLUSION: These findings suggest a role for epigenetic modifications in contributing to the profibrotic and hypertrophic changes evident during disease progression. Therapeutic intervention with 5-aza demonstrated favorable effects highlighting the potential use of this epigenetic modifier as a treatment option for cardiac pathologies associated with hypertrophy and fibrosis.

Monocyte and macrophage subsets along the continuum to heart failure: Misguided heroes or targetable villains?

The important contribution of monocytes and macrophages to cardiovascular disease and heart failure pathophysiology has attracted significant attention in the past several years. Moreover, subsets of these cells have been shown to partake in the initiation and exacerbation of several cardiovascular pathologies including atherosclerosis, myocardial infarction, pressure overload, cardiac ischemia and fibrosis. This review focuses on the role of monocytes and macrophages along the continuum to heart failure and the contribution of different cell subsets in promoting or inhibiting cardiac injury or repair. It outlines a primary role for the monocyte/macrophage system as an important regulator of cardiac inflammation and extracellular matrix remodelling in early and late stage heart disease with particular focus on phenotypic plasticity and the inflammatory and fibrotic functions of these cells. It also summarizes evidence from pre-clinical and clinical studies evaluating monocyte type regulation and its functional significance for development of cardiovascular disease and heart failure. Finally, current and prospective therapeutic approaches based on monocyte and macrophage manipulation for the treatment of cardiovascular disease and heart failure are discussed. Based on these data, future work in this fertile research area may aid in identifying potential diagnostic biomarkers and novel therapies for chronic heart failure.

Serum Amyloid P-Component Prevents Cardiac Remodeling in Hypertensive Heart Disease.

The potential for serum amyloid P-component (SAP) to prevent cardiac remodeling and identify worsening diastolic dysfunction (DD) was investigated. The anti-fibrotic potential of SAP was tested in an animal model of hypertensive heart disease (spontaneously hypertensive rats treated with SAP [SHR - SAP] × 12 weeks). Biomarker analysis included a prospective study of 60 patients with asymptomatic progressive DD. Compared with vehicle-treated Wistar-Kyoto rats (WKY-V), the vehicle-treated SHRs (SHR-V) exhibited significant increases in left ventricular mass, perivascular collagen, cardiomyocyte size, and macrophage infiltration. SAP administration was associated with significantly lower left ventricular mass (p < 0.01), perivascular collagen (p < 0.01), and cardiomyocyte size (p < 0.01). Macrophage infiltration was significantly attenuated in the SHR-SAP group. Biomarker analysis showed significant decreases in SAP concentration over time in patients with progressive DD (p < 0.05). Our results indicate that SAP prevents cardiac remodeling by inhibiting recruitment of pro-fibrotic macrophages and that depleted SAP levels identify patients with advancing DD suggesting a role for SAP therapy.

Exaggerated inflammation and monocytosis associate with diastolic dysfunction in heart failure with preserved ejection fraction: evidence of M2 macrophage activation in disease pathogenesis.

BACKGROUND: Heart failure with preserved ejection fraction (HFPEF) is a major health problem associated with myocardial leukocyte infiltration, inflammation, and fibrosis. Monocyte and macrophage subsets play a role in HFPEF but have not been studied. We analyzed peripheral blood monocyte phenotype and plasma markers of monocyte activation in patients with HFPEF, asymptomatic LV diastolic dysfunction (aLVDD), and asymptomatic hypertension (aHTN). METHODS AND RESULTS: Peripheral blood was collected from 23 aHTN, 30 aLVDD, and 30 HFPEF patients. Peripheral cytokines of classic/pro-inflammatory (tumor necrosis factor alpha, interleukin (IL) 12, IL-6, monocyte chemoattractant protein 1, C-X-C motif chemokine 10) and alternative/anti-inflammatory monocytes (chemokine-C-C motif ligand (CCL) 17, CCL-18, soluble CD163) were increased in aLVDD and HFPEF. Peripheral blood mononuclear cells and monocytes were purified and surface-stained for CD14, CD16, CD163, and CD206. Peripheral monocyte percentage was increased in aLVDD and HFPEF and correlated with echocardiographic LVDD indices. Classic/pro-inflammatory monocyte numbers were increased in aLVDD and HFPEF, and alternative/anti-inflammatory monocyte numbers were increased in HFPEF. CD163 M2-macrophage receptor was reduced in HFPEF. Culture of healthy donor monocytes (n = 3) with HFPEF patient-derived sera (n = 6) promoted M2 macrophage features as evidenced by altered morphology and genes (CD206, IL-10). CONCLUSIONS: Increased peripheral inflammation, monocytosis, and monocyte differentiation to anti-inflammatory/profibrotic M2 macrophages likely associate with HFPEF and its precedent asymptomatic LVDD phase.

Cardiomyopathy in offspring of pregestational diabetic mouse pregnancy.

PURPOSE: To investigate cardiomyopathy in offspring in a mouse model of pregestational type 1 diabetic pregnancy. METHODS: Pregestational diabetes was induced with STZ administration in female C57BL6/J mice that were subsequently mated with healthy C57BL6/J males. Offspring were sacrificed at embryonic day 18.5 and 6-week adolescent and 12-week adult stages. The size and number of cardiomyocyte nuclei and also the extent of collagen deposition within the hearts of diabetic and control offspring were assessed following cardiac tissue staining with either haematoxylin and eosin or Picrosirius red and subsequently quantified using automated digital image analysis. RESULTS: Offspring from diabetic mice at embryonic day 18.5 had a significantly higher number of cardiomyocyte nuclei present compared to controls. These nuclei were also significantly smaller than controls. Collagen deposition was shown to be significantly increased in the hearts of diabetic offspring at the same age. No significant differences were found between the groups at 6 and 12 weeks. CONCLUSIONS: Our results from offspring of type 1 diabetic mice show increased myocardial collagen deposition in late gestation and have increased myocardial nuclear counts (hyperplasia) as opposed to increased myocardial nuclear size (hypertrophy) in late gestation. These changes normalize postpartum after removal from the maternal intrauterine environment.

Extracellular matrix sub-types and mechanical stretch impact human cardiac fibroblast responses to transforming growth factor beta.

Understanding the impact of extracellular matrix sub-types and mechanical stretch on cardiac fibroblast activity is required to help unravel the pathophysiology of myocardial fibrotic diseases. Therefore, the purpose of this study was to investigate pro-fibrotic responses of primary human cardiac fibroblast cells exposed to different extracellular matrix components, including collagen sub-types I, III, IV, VI and laminin. The impact of mechanical cyclical stretch and treatment with transforming growth factor beta 1 (TGFß1) on collagen 1, collagen 3 and alpha smooth muscle actin mRNA expression on different matrices was assessed using quantitative real-time PCR. Our results revealed that all of the matrices studied not only affected the expression of pro-fibrotic genes in primary human cardiac fibroblast cells at rest but also affected their response to TGFß1. In addition, differential cellular responses to mechanical cyclical stretch were observed depending on the type of matrix the cells were adhered to. These findings may give insight into the impact of selective pathological deposition of extracellular matrix proteins within different disease states and how these could impact the fibrotic environment.