Prostanoids in Cardiac and Vascular Remodeling.

Prostanoids are biologically active lipids generated from arachidonic acid by the action of the COX (cyclooxygenase) isozymes. NSAIDs, which reduce the biosynthesis of prostanoids by inhibiting COX activity, are effective anti-inflammatory, antipyretic, and analgesic drugs. However, their use is limited by cardiovascular adverse effects, including myocardial infarction, stroke, hypertension, and heart failure. While it is well established that NSAIDs increase the risk of atherothrombotic events and hypertension by suppressing vasoprotective prostanoids, less is known about the link between NSAIDs and heart failure risk. Current evidence indicates that NSAIDs may increase the risk for heart failure by promoting adverse myocardial and vascular remodeling. Indeed, prostanoids play an important role in modulating structural and functional changes occurring in the myocardium and in the vasculature in response to physiological and pathological stimuli. This review will summarize current knowledge of the role of the different prostanoids in myocardial and vascular remodeling and explore how maladaptive remodeling can be counteracted by targeting specific prostanoids.

Evaluating left atrial strain and left ventricular diastolic strain rate as markers for diastolic dysfunction in patients with mitral annular calcification.

BACKGROUND: Mitral annular calcification (MAC) poses many challenges to the evaluation of diastolic function using standard echocardiography. Left atrial (LA) strain and left ventricular early diastolic strain rate (DSr) measured by speckle-tracking echocardiography (STE) are emerging techniques in the noninvasive evaluation of diastolic function. We aim to evaluate the utility of LA strain and early DSr in predicting elevated left ventricular filling pressures (LVFP) in patients with MAC and compare their effectiveness to ratio of mitral inflow velocity in early and late diastole (E/A). METHODS: We included adult patients with MAC who presented between January 1 and December 31, 2014 and received a transthoracic echocardiogram (TTE) and cardiac catheterization with measurement of LVFP within a 24-h period. We used Spearman's rank correlation coefficient to assess associations of LA reservoir strain and average early DSr with LVFP. Receiver operating characteristic (ROC) curves were computed to assess the effectiveness of LA strain and DSr in discriminating elevated LVFP as a dichotomized variable and to compare their effectiveness with E/A ratio categorized according to grade of diastolic dysfunction. RESULTS: Fifty-five patients were included. LA reservoir strain demonstrated poor correlation with LVFP (Spearman's rho = 0.03, p = 0.81) and poor discriminatory ability for detecting elevated LVFP (AUC = 0.54, 95% CI 0.38-0.69). Categorical E/A ratio alone also demonstrated poor discriminatory ability (AUC = 0.53, 95% CI 0.39-0.67), and addition of LA reservoir strain did not significantly improve effectiveness (AUC = 0.58, 95% CI 0.42-0.74, p = 0.56). Average early DSr also demonstrated poor correlation with LVFP (Spearman's rho = -0.19, p = 0.16) and poor discriminatory ability for detecting elevated LVFP (AUC = 0.59, 95% CI 0.44-0.75). Addition of average early DSr to categorical E/A ratio failed to improve effectiveness (AUC = 0.62, 95% CI 0.46-0.77 vs. AUC = 0.54, 95% CI 0.39-0.69, p = 0.38). CONCLUSIONS: In our sample, LA reservoir strain and DSr do not accurately predict diastolic filling pressure. Further research is required before LA strain and early DSr can be routinely used in clinical practice to assess filling pressure in patients with MAC.

Left atrial strain, embolic stroke of undetermined source, and atrial fibrillation detection.

BACKGROUND: Atrial cardiopathy is a proposed mechanism of embolic stroke of undetermined source (ESUS). Left atrial (LA) strain may identify early atrial cardiopathy prior to structural changes. We aim to study the associations between LA strain, ESUS, and atrial fibrillation (AF) detection in ESUS. METHODS: The study population included patients with ESUS and noncardioembolic (NCE) stroke presenting to the Rhode Island Hospital Stroke Center between January 2016 and June 2017 who underwent transthoracic echocardiography. Speckle tracking echocardiography (STE) was used to measure the three phases of LA strain (reservoir, conduit, and contractile). Binary logistic regression analysis was performed to determine the associations between LA strain and stroke subtype (ESUS vs. NCE) as well as follow-up detection of AF in ESUS patients. RESULTS: We identified 656 patients, 307 with ESUS and 349 with NCE. In binary logistic regression, the lowest tertiles of LA reservoir (adjusted OR 1.944, 95% CI 1.266-2.986, p = .002), contractile (aOR 1.568, 95% CI 1.035-2.374, p = .034), and conduit strain (aOR 2.288, 95% CI 1.448-3.613, p = .001) were more likely to be significantly associated with ESUS compared to NCE stroke. Among all ESUS patients, the lowest tertiles of LA reservoir strain (OR 2.534, 95% CI 1.029-6.236, p = .043), contractile strain (OR 2.828, 95% CI 1.158-6.903, p = .022), and conduit strain (OR 2.614, 95% CI 1.003-6.815, p = .049) were significantly associated with subsequent detection of AF. CONCLUSION: Reduced LA strain is associated with ESUS occurrence and AF detection in ESUS patients. Therefore, quantification of LA strain in ESUS patients may improve risk stratification and guide secondary prevention strategies.

Insight into different phenotypic presentations of heart failure with preserved ejection fraction.

Heart failure (HF) with preserved ejection fraction (HFpEF) accounts for half of all HF diagnoses, and its prevalence is increasing at an alarming rate. Lately, it has been recognized as a clinical syndrome due to diverse underlying etiology and pathophysiological mechanisms. The classic echocardiographic features of HFpEF have been well described as preserved ejection fraction (≥50%), left ventricular hypertrophy, and left atrial enlargement. However, echocardiography can play a key role in identifying the principal underlying mechanism responsible for HFpEF in the individual patient. The recognition of different phenotypic presentations of HFpEF (infiltrative, metabolic, genetic, and inflammatory) can assist the clinician in tailoring the appropriate management, and offer prognostic information. The goal of this review is to highlight several key phenotypes of HFpEF and illustrate the classic clinical scenario and echocardiographic features of each phenotype with real patient cases.

Systolic Strain by Speckle-Tracking Echocardiography Is a Feasible and Sensitive Measure of Right Ventricular Dysfunction in Acute Respiratory Failure Patients on Mechanical Ventilation.

Right ventricular (RV) dysfunction is common in acute respiratory failure and associated with worse outcomes, but it can be difficult to detect in the ICU setting. Speckle-tracking echocardiography (STE) can identify early changes in RV systolic function and be quantified as systolic strain. We measured the feasibility of RV global longitudinal systolic strain (RV GLS) in respiratory failure patients and its association with clinical outcomes. DESIGN: Retrospective cohort. SETTING: Two tertiary hospital medical ICUs in Providence, RI, from March 2015 to January 2018. PATIENTS: Two hundred twenty-three patients with acute respiratory failure requiring mechanical ventilation (MV) with available echocardiograms. MEASUREMENTS AND MAIN RESULTS: Clinical data were extracted from medical records. RV GLS was measured via STE (TOMTEC, Chicago, IL), along with standard echocardiographic measurements by two independent readers blinded to outcomes. The average age was 65 years (range, 21-90 yr), 121 (54%) were men, and the most common etiology of respiratory failure was pneumonia (n = 83, 37%). The average RV GLS was -16% (sd ± 7). The intraobserver correlation coefficients were 0.78 and 0.94, whereas the interobserver correlation coefficient was 0.61 for RV GLS. In the majority of echocardiograms (n = 178, 80%), all wall segments were tracked appropriately by operator visual inspection. Worse RV GLS was associated with greater hospital mortality (odds ratio, 1.03; 95% CI, 1.00-1.07; p = 0.03), such that every 1% decrement in RV GLS was associated with up to a 7% increase in the risk of death. RV GLS was 90% sensitive for the detection of RV dysfunction compared with tricuspid annular plane systolic excursion. CONCLUSIONS: The measurement of RV GLS by STE in subjects on MV is feasible, reproducible, and sensitive for the detection of RV dysfunction. RV GLS may predict poor outcomes in acute respiratory failure.

A 34-Year-Old Woman with Third-Degree Heart Block and Atrial Flutter Associated with Lyme Carditis: A Case Report.

BACKGROUND Lyme disease is a tick-borne illness caused by bacteria of the Borrelia genus, endemic to the northeastern region of the United States. It typically presents with fevers, myalgias, and erythema migrans, but it can result in disseminated symptoms if left untreated. Lyme carditis is a rare, but potentially fatal complication of Lyme disease, occurring in up to 4-10% of untreated cases. Typically, it presents with atrioventricular conduction abnormalities, which resolve with intravenous antibiotics and temporary pacing if indicated. Diverse cardiac pathology, however, has been associated with Lyme carditis, which may be underrecognized in practice. CASE REPORT A 34-year-old woman with no significant medical history presented with fatigue, dizziness, and shortness of breath, 2 weeks after camping in Rhode Island. Her presenting electrocardiogram demonstrated third-degree heart block. She was noted to have targetoid rashes on her left shoulder and breast on physical examination. On laboratory work-up, she was found to have positive Lyme total antibody enzyme immunoassay and positive Lyme western immunoblot. The findings were diagnostic for Lyme carditis. The patient's cardiac rhythm subsequently converted to slow atrial flutter with variable ventricular response unresponsive to antibiotic therapy. Given evidence suggesting that atrioventricular conduction was preserved, synchronized electrical cardioversion was pursued and was ultimately successful in rhythm conversion to normal sinus rhythm. CONCLUSIONS Although Lyme carditis is rare, this diagnosis should be of high clinical consideration in presentations of cardiac conduction abnormalities with acute onset and without other obvious cause, particularly in Lyme-endemic regions such as the northeastern United States.

Early vs. Late Onset Cardiac Injury and Mortality in Hospitalized COVID-19 Patients in Wuhan.

Background: Increasing evidence points to cardiac injury (CI) as a common coronavirus disease 2019 (COVID-19) related complication. The characteristics of early CI (occurred within 72 h of admission) and late CI (occurred after 72 h of admission) and its association with mortality in COVID-19 patients is unknown. Methods: This retrospective study analyzed patients confirmed with COVID-19 in Union Hospital (Wuhan, China) from Jan 29th to Mar 15th, 2020. Clinical outcomes (discharge, or death) were monitored to April 15, 2020, the latest date of follow-up. Demographic, clinical, laboratory, as well as treatment and prognosis were collected and analyzed in patients with early, late CI and without CI. Results: A total of 196 COVID-19 patients were included for analysis. The median age was 65 years [interquartile range (IQR) 56-73 years], and 112 (57.1%) were male. Of the 196 COVID-19 patients, 49 (25.0%) patients had early and 20 (10.2%) patients had late CI, 56.6% developed Acute-Respiratory-Distress-Syndrome (ARDS) and 43 (21.9%) patients died. Patients with any CI were more likely to have developed ARDS (87.0 vs. 40.2%) and had a higher in-hospital mortality than those without (52.2 vs. 5.5%, P < 0.001). Among CI subtypes, a significantly higher risk of in-hospital death was found in patients with early CI with recurrence [19/49 patients, adjusted odds ratio (OR) = 7.184, 95% CI 1.472-35.071] and patients with late CI (adjusted OR = 5.019, 95% CI 1.125-22.388) compared to patients with early CI but no recurrence. Conclusions: CI can occur early on or late after, the initial 72 h of admission and is associated with ARDS and an increased risk of in-hospital mortality. Both late CI and recurrent CI after the initial episode were associated with worse outcomes than patients with early CI alone. This study highlights the importance of early examination and periodical monitoring of cardiac biomarkers, especially for patients with early CI or at risk of clinical deterioration.

Evaluating a decision tool for diagnosing diastolic dysfunction and estimation of left ventricular filling pressures in the presence of mitral annular calcium.

OBJECTIVES: This study sought to evaluate a decision algorithm for the estimation of left ventricular filling pressure (LVFP) in patients with mitral annular calcification (MAC). BACKGROUND: In a single center study, Abudiab et al evaluated echocardiographic parameters to estimate LVFP in patients with MAC against invasive hemodynamic measurements and developed a decision algorithm which demonstrated high predictive accuracy. METHODS: Retrospectively, 55 patients (mean age 68.5 ± 11.5) with MAC and a left heart catheterization within 24 hours of an echocardiogram were identified. The decision algorithm was applied using echo data to classify patients as having normal or elevated LVFP which was then compared with the invasively obtained LVFP. RESULTS: The algorithm performed poorly at predicting pre-A LVFP as normal or high (P = .182). Accuracy for the algorithm was 0.59 [0.46, 0.72] (mean [95% CI]), sensitivity was 0.45 [0.28, 0.62], specificity was 0.73 [0.54, 0.86], false positive rate was 0.27 [0.14, 0.46], and false negative rate was 0.55 [0.38, 0.72]. E/A ratio, IVRT, and E/e'ratio showed no significant relationship to actual patient LVFP. CONCLUSIONS: The Abudiab et al algorithm failed to demonstrate comparable sensitivity, specificity, and accuracy in our sample. Additional study is necessary to refine this tool prior to more widespread use in clinical practice.

Prognostic Value of Right Ventricular Two-Dimensional and Three-Dimensional Speckle-Tracking Strain in Pulmonary Arterial Hypertension: Superiority of Longitudinal Strain over Circumferential and Radial Strain.

BACKGROUND: Right ventricular (RV) dysfunction is a predictor of adverse outcomes in patients with pulmonary arterial hypertension (PAH). Three-dimensional (3D) speckle-tracking echocardiography (STE) has been increasingly used to quantify RV function. However, the strain parameters evaluated by two-dimensional (2D) STE and 3D STE, which provide the most valuable clinical information, remain unknown. The purpose of our study was to investigate whether RV longitudinal strain (LS) provided a superior estimation of RV systolic performance and prognostic information compared with other strain vectors. METHODS: We prospectively studied 54 treatment-naïve patients with PAH and 35 normal controls. Pulmonary artery systolic pressure classified patients with PAH into three subgroups. Patients with PAH underwent echocardiography, cardiac magnetic resonance (CMR) imaging, 6-minute walking tests, and right-sided cardiac catheterization before and six months after vasodilator therapy. The 2D LS, 3D LS, circumferential strain (CS), and radial strain (RS) of RV free wall were calculated by 2D and 3D STE. RV ejection fraction (RVEF) was obtained from CMR. The patients were followed for a predefined endpoint of PAH-related hospitalization and death. RESULTS: Our findings revealed that 2D and 3D LS showed significant reduction in mild PAH patients, whereas CS and RS were decreased in moderate and severe PAH patients. Right ventricular 3D LS had a similar correlation with CMR RVEF and hemodynamic parameters as 2D LS and the other strain vectors. The 2D and 3D LS improved 6 months after vasodilator therapy (P < .001 for both). After a median follow-up of 28 months, 20 patients had endpoint events. Receiver operating characteristic curve analysis demonstrated that RV 3D LS displayed a similar diagnostic performance for detecting adverse cardiac events as 2D LS (area under the curve: 0.84 vs 0.76, P = .11). Separate multivariable Cox analysis showed that RV 2D LS (hazard ratio [HR] = 1.19; 95% CI, 1.03～1.45; P = .01) and 3D LS (HR = 1.28; 95% CI, 1.08～1.52; P = .005) were significant predictors of adverse outcomes. CONCLUSIONS: Patients with PAH show reduced RV strain. Two-dimensional and 3D LS can track clinical improvement following vasodilator therapy and provide valuable prognostic information.

Perspectives on Current Training Guidelines for Cardiac Imaging and Recommendations for the Future.

PURPOSE OF REVIEW: To summarize current training guidelines for cardiac imaging and provide recommendations for future guidelines. RECENT FINDINGS: The current structure of training in cardiac imaging is largely dictated by modality-specific guidelines. While there has been debate on how to define the advanced cardiac imager for over a decade, a uniform consensus has not emerged. We report the perspectives of three key stakeholders in this debate: a senior faculty member-former fellowship program director, a cardiology fellow, and an academic junior faculty imaging expert. The observations of these stakeholders suggest that there is no consensus on the definition of advanced cardiac imaging, leading to ambiguity in training guidelines. This may have negative impact on recruitment of fellows into cardiac imaging careers. Based on the current status of training in cardiac imaging, the authors suggest that the relevant professional groups reconvene to form a consensus in defining advanced cardiac imaging, in order to guide future revisions of training guidelines.

Effects of organic and inorganic nitrate on aortic and carotid haemodynamics in heart failure with preserved ejection fraction.

AIMS: To assess the haemodynamic effects of organic vs. inorganic nitrate administration among patients with heart failure with preserved ejection fraction (HFpEF). METHODS AND RESULTS: We assessed carotid and aortic pressure-flow relations non-invasively before and after the administration of 0.4 mg of sublingual nitroglycerin (n = 26), and in a separate sub-study, in response to 12.9 mmoL of inorganic nitrate (n = 16). Nitroglycerin did not consistently reduce wave reflections arriving at the proximal aorta (change in real part of reflection coefficient, 1st harmonic: -0.09; P = 0.01; 2nd harmonic: -0.045, P = 0.16; 3rd harmonic: +0.087; P = 0.05), but produced profound vasodilatation in the carotid territory, with a significant reduction in systolic blood pressure (133.6 vs. 120.5 mmHg; P = 0.011) and a marked reduction in carotid bed vascular resistance (19 580 vs. 13 078 dynes · s/cm5 ; P = 0.001) and carotid characteristic impedance (3440 vs. 1923 dynes · s/cm5 ; P = 0.002). Inorganic nitrate, in contrast, consistently reduced wave reflections across the first three harmonics (change in real part of reflection coefficient, 1st harmonic: -0.12; P = 0.03; 2nd harmonic: -0.11, P = 0.01; 3rd harmonic: -0.087; P = 0.09) and did not reduce blood pressure, carotid bed vascular resistance, or carotid characteristic impedance (P = NS). CONCLUSIONS: Nitroglycerin produces marked vasodilatation in the carotid circulation, with a pronounced reduction in blood pressure and inconsistent effects on central wave reflections. Inorganic nitrate, in contrast, produces consistent reductions in wave reflections, and unlike nitroglycerin, it does so without significant hypotension or cerebrovascular dilatation. These haemodynamic differences may underlie the different effects on exercise capacity and side effect profile of inorganic vs. organic nitrate in HFpEF.

Isosorbide Dinitrate, With or Without Hydralazine, Does Not Reduce Wave Reflections, Left Ventricular Hypertrophy, or Myocardial Fibrosis in Patients With Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Wave reflections, which are increased in patients with heart failure with preserved ejection fraction, impair diastolic function and promote pathologic myocardial remodeling. Organic nitrates reduce wave reflections acutely, but whether this is sustained chronically or affected by hydralazine coadministration is unknown. METHODS AND RESULTS: We randomized 44 patients with heart failure with preserved ejection fraction in a double-blinded fashion to isosorbide dinitrate (ISDN; n=13), ISDN+hydralazine (ISDN+hydral; n=15), or placebo (n=16) for 6 months. The primary end point was the change in reflection magnitude (RM; assessed with arterial tonometry and Doppler echocardiography). Secondary end points included change in left ventricular mass and fibrosis, measured with cardiac magnetic resonance imaging, and the 6-minute walk distance. ISDN reduced aortic characteristic impedance (mean baseline=0.15 [95% CI, 0.14-0.17], 3 months=0.11 [95% CI, 0.10-0.13], 6 months=0.10 [95% CI, 0.08-0.12] mm Hg/mL per second; P=0.003) and forward wave amplitude (Pf, mean baseline=54.8 [95% CI, 47.6-62.0], 3 months=42.2 [95% CI, 33.2-51.3]; 6 months=37.0 [95% CI, 27.2-46.8] mm Hg, P=0.04), but had no effect on RM (P=0.64), left ventricular mass (P=0.33), or fibrosis (P=0.63). ISDN+hydral increased RM (mean baseline=0.39 [95% CI, 0.35-0.43]; 3 months=0.31 [95% CI, 0.25-0.36]; 6 months=0.44 [95% CI, 0.37-0.51], P=0.03), reduced 6-minute walk distance (mean baseline=343.3 [95% CI, 319.2-367.4]; 6 months=277.0 [95% CI, 242.7-311.4] meters, P=0.022), and increased native myocardial T1 (mean baseline=1016.2 [95% CI, 1002.7-1029.7]; 6 months=1054.5 [95% CI, 1036.5-1072.3], P=0.021). A high proportion of patients experienced adverse events with active therapy (ISDN=61.5%, ISDN+hydral=60.0%; placebo=12.5%; P=0.007). CONCLUSIONS: ISDN, with or without hydralazine, does not exert beneficial effects on RM, left ventricular remodeling, or submaximal exercise and is poorly tolerated. ISDN+hydral appears to have deleterious effects on RM, myocardial remodeling, and submaximal exercise. Our findings do not support the routine use of these vasodilators in patients with heart failure with preserved ejection fraction. CLINICAL TRIAL REGISTRATION: URL: www.clinicaltrials.gov. Unique identifier: NCT01516346.

The (dys)functional extracellular matrix.

The extracellular matrix (ECM) is a major component of the biomechanical environment with which cells interact, and it plays important roles in both normal development and disease progression. Mechanical and biochemical factors alter the biomechanical properties of tissues by driving cellular remodeling of the ECM. This review provides an overview of the structural, compositional, and mechanical properties of the ECM that instruct cell behaviors. Case studies are reviewed that highlight mechanotransduction in the context of two distinct tissues: tendons and the heart. Although these two tissues demonstrate differences in relative cell-ECM composition and mechanical environment, they share similar mechanisms underlying ECM dysfunction and cell mechanotransduction. Together, these topics provide a framework for a fundamental understanding of the ECM and how it may vary across normal and diseased tissues in response to mechanical and biochemical cues. This article is part of a Special Issue entitled: Mechanobiology.

Cardiac AAV9 Gene Delivery Strategies in Adult Canines: Assessment by Long-term Serial SPECT Imaging of Sodium Iodide Symporter Expression.

Heart failure is a leading cause of morbidity and mortality, and cardiac gene delivery has the potential to provide novel therapeutic approaches. Adeno-associated virus serotype 9 (AAV9) transduces the rodent heart efficiently, but cardiotropism, immune tolerance, and optimal delivery strategies in large animals are unclear. In this study, an AAV9 vector encoding canine sodium iodide symporter (NIS) was administered to adult immunocompetent dogs via epicardial injection, coronary infusion without and with cardiac recirculation, or endocardial injection via a novel catheter with curved needle and both end- and side-holes. As NIS mediates cellular uptake of clinical radioisotopes, expression was tracked by single-photon emission computerized tomography (SPECT) imaging in addition to Western blot and immunohistochemistry. Direct epicardial or endocardial injection resulted in strong cardiac expression, whereas expression after intracoronary infusion or cardiac recirculation was undetectable. A threshold myocardial injection dose that provides robust nonimmunogenic expression was identified. The extent of transmural myocardial expression was greater with the novel catheter versus straight end-hole needle delivery. Furthermore, the authors demonstrate that cardiac NIS reporter gene expression and duration can be quantified using serial noninvasive SPECT imaging up to 1 year after vector administration. These data are relevant to efforts to develop cardiac gene delivery as heart failure therapy.

Clocks and cardiovascular function.

Circadian clocks in central and peripheral tissues enable the temporal synchronization and organization of molecular and physiological processes of rhythmic animals, allowing optimum functioning of cells and organisms at the most appropriate time of day. Disruption of circadian rhythms, from external or internal forces, leads to widespread biological disruption and is postulated to underlie many human conditions, such as the incidence and timing of cardiovascular disease. Here, we describe in vivo and in vitro methodology relevant to studying the role of circadian rhythms in cardiovascular function and dysfunction.

Prospective risk factors for increased central augmentation index in men and women.

BACKGROUND: Arterial wave reflections are important determinants of central pressure pulsatility and left ventricular afterload. The augmentation index (AIx) is the most widely used surrogate of arterial wave reflections. Despite multiple cross-sectional studies assessing the correlates of AIx, little prospective data exist regarding changes in AIx over time. We aimed to assess the predictors of changes in AIx over time in adults from the general population. METHODS: We performed radial arterial tonometry assessments a median of 3.18 ± 0.4 years apart on 143 nondiabetic adult participants in the population-based PREVENCION study. Central AIx was obtained using the generalized transfer function of the Sphygmocor device. RESULTS: Predictors of the change in AIx over time were investigated. Among men (n = 67), the change in AIx was predicted by abdominal obesity (standardized ß for waist circumference = 0.34; P = 0.002), impaired fasting glucose (standardized ß = 0.24; P = 0.009), and the change in heart rate (standardized ß = -0.78; P < 0.001). Among women (n = 76), the change in AIx was predicted by non-high-density lipoprotein cholesterol (standardized ß = 0.33; P = 0.001), C-reactive protein levels (standardized ß = 0.24; P = 0.02), change in mean arterial pressure (standardized ß = 0.33; P = 0.001), and change in heart rate (standardized ß = -0.52; P < 0.001). CONCLUSIONS: Metabolic and inflammatory factors predicted changes in AIx over time, with important sex differences. Metabolic factors, such as abdominal obesity and impaired fasting glucose, predicted changes in AIx in men, whereas C-reactive protein and non-high-density lipoprotein cholesterol levels predicted changes in women. Our findings highlight the impact of sex on arterial properties and may guide the design of interventions to favorably impact changes in late systolic pressure augmentation.

Evidence for coregulation of myocardial gene expression by MEF2 and NFAT in human heart failure.

BACKGROUND: Pathological stresses induce heart failure in animal models through activation of multiple cardiac transcription factors (TFs) working cooperatively. However, interactions among TFs in human heart failure are less understood. Here, we use genomic data to examine the evidence that 5 candidate TF families coregulate gene expression in human heart failure. METHODS AND RESULTS: RNA isolates from failing (n=86) and nonfailing (n=16) human hearts were hybridized with Affymetrix HU133A arrays. For each gene on the array, we determined conserved MEF2, NFAT, NKX , GATA , and FOX binding motifs within the -1-kb promoter region using human-murine sequence alignments and the TRANSFAC database. Across 9076 genes expressed in the heart, TF-binding motifs tended to cluster together in nonrandom patterns within promoters of specific genes (P values ranging from 10(-2) to 10(-21)), suggesting coregulation. We then modeled differential expression as a function of TF combinations present in promoter regions. Several combinations predicted increased odds of differential expression in the failing heart, with the highest odds ratios noted for genes containing both MEF2 and NFAT binding motifs together in the same promoter region (peak odds ratio, 3.47; P=0.005). CONCLUSIONS: These findings provide genomic evidence for coregulation of myocardial gene expression by MEF2 and NFAT in human heart failure. In doing so, they extend the paradigm of combinatorial regulation of gene expression to the human heart and identify new target genes for mechanistic study. More broadly, we demonstrate how integrating diverse sources of genomic data yields novel insight into human cardiovascular disorders.