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Background: Increased left ventricular (LV) mass is associated with adverse cardiovascular events including heart failure (HF). Both increased LV mass and HF disproportionately affect Black individuals. To understand the underlying mechanisms, we undertook a proteomic screen in a Black cohort and compared the findings to results from a White cohort., Methods: We measured 1305 plasma proteins using the SomaScan platform in 1772 Black participants (mean age, 56 years; 62% women) in JHS (Jackson Heart Study) with LV mass assessed by 2-dimensional echocardiography. Incident HF was assessed in 1600 participants. We then compared protein associations in JHS to those observed in White participants from FHS (Framingham Heart Study; mean age, 54 years; 56% women)., Results: In JHS, there were 110 proteins associated with LV mass and 13 proteins associated with incident HF hospitalization with false discovery rate <5% after multivariable adjustment. Several proteins showed expected associations with both LV mass and HF, including NT-proBNP (N-terminal pro-B-type natriuretic peptide; β=0.04; P =2×10 -8 ; hazard ratio, 1.48; P =0.0001). The strongest association with LV mass was novel: LKHA4 (leukotriene-A4 hydrolase; β=0.05; P =5×10 -15 ). This association was confirmed on an alternate proteomics platform and further supported by related metabolomic data. Fractalkine/CX3CL1 (C-X3-C Motif Chemokine Ligand 1) showed a novel association with incident HF (hazard ratio, 1.32; P =0.0002). While established biomarkers such as cystatin C and NT-proBNP showed consistent associations in Black and White individuals, LKHA4 and fractalkine were significantly different between the two groups., Conclusions: We identified several novel biological pathways specific to Black adults hypothesized to contribute to the pathophysiologic cascade of LV hypertrophy and incident HF including LKHA4 and fractalkine.

A patent foramen ovale (PFO) is implicated in several pathologic processes, including that of cryptogenic stroke (cCVA). Recent trials identify "high-risk" PFOs in patients with cCVA as likely to benefit from percutaneous closure. The younger the patient (<60 years old) the more likely a PFO may be attributable to the cCVA. The RoPE Score index helps determine the likelihood that an existing PFO is related to a cCVA. This may help guide the clinician and patient when contemplating percutaneous PFO closure. When evaluating a patient for possible percutaneous closure, one should identify the CVA as a typical ischemic type stroke. In order to "rule-out" other causes of CVA, imaging of the intracranial arteries, cervical, and aortic arch vessels should be performed. Small vessel disease or a lacunar-type infarct should be excluded. To rule out atrial fibrillation, prolonged monitoring should be performed. An index has been developed to determine the probability that a PFO is the causative etiology and calculates the risk of recurrence. This may help guide the clinician and patient in the decision for PFO closure. In addition, one should consider a work-up for a hypercoagulable state. We will obtain an ultrasound of the lower extremities or consider deep pelvic vein thrombosis (prolonged sitting or malignancy). If the closure is to be performed, the Food and Drug Administration (FDA) has approved the Amplatzer PFO Occluder and the GORE Cardioform Septal Occluder for percutaneous closure. These devices are both approved in patients predominately between ages 18 and 60 years with a cCVA due to presumed paradoxical embolism as verified by a neurologist and cardiologist and when other causes of ischemic CVA have been excluded. "High-risk" PFOs appear to achieve the most potential benefit from percutaneous closure., (© 2018 Wiley Periodicals, Inc.)

Background: Left ventricular false tendons (LVFTs) are chord-like structures that traverse the LV cavity and are generally considered to be benign. However, they have been associated with arrhythmias, LV hypertrophy and LV dilation in some small studies. We hypothesize that LVFTs are associated with LV structural and functional changes assessed by echocardiography., Methods: We retrospectively evaluated echocardiographic and clinical parameters of 126 patients identified as having LVFTs within the past 2 years and compared them to 85 age-matched controls without LVFTs., Results: There were no significant differences in age (52 ± 18 versus 54 ± 18 years, P = 0.37), sex (55% versus 59% men, P = 0.49), race (36% versus 23% white, P = 0.07), systolic blood pressure (131 ± 22 versus 132 ± 23mmHg, P = 0.76) or body mass index (BMI, 31 ± 8 versus 29 ± 10kg/m 2 , P = 0.07) between controls and patients with LVFTs, respectively. Patients with LVFTs had more prevalent heart failure (43% versus 21%, P = 0.001). Patients with LVFTs had more LV dilation, were 2.5 times more likely to have moderate-to-severe mitral regurgitation, had more severe diastolic dysfunction and reduced LV systolic function (18% lower) compared with controls (all P < 0.05). After adjustment for covariates, basal and middle LVFT locations were associated with reduced LV systolic function (P < 0.01), and middle LVFTs were associated with LV dilation (P < 0.01)., Conclusions: Our findings suggest that LVFTs may not be benign variants, and basal and middle LVFTs may have more deleterious effects. Further prospective studies should be performed to determine their pathophysiological significance and whether they play a causal role in LV dysfunction., (Copyright © 2017 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.)

Background: Enlargement of the proximal aorta is associated with aortic wall tissue remodeling, including fragmentation of the elastin fibers, increased synthesis of collagen, and calcification, all of which are associated with aortic wall stiffening. We hypothesized that the proximal aortic diameter (AoD) is associated with cardiovascular events in a community-based cohort of blacks., Methods and Results: We investigated the associations between AoD and cardiovascular events among 3018 black participants (mean age, 55.9 years; 69% women) without past history of cardiovascular disease in the Jackson Heart Study. AoD was measured using echocardiography at the level of the sinuses of Valsalva at end diastole. Cardiovascular event was defined as incident myocardial infarction, fatal coronary artery disease, stroke, or heart failure hospitalization. Cox proportional hazards regression models were used to evaluate the association between baseline AoD and cardiovascular events. Over a median follow-up of 8.3 years, there were 258 cardiovascular events (incident rate, 10.5 per 1000 person-years). After adjustment for traditional risk factors, increased AoD was significantly associated with cardiovascular events (hazard ratio per 1-cm increase, 1.72; 95% CI, 1.10-2.69; P <0.05). Participants in the top AoD quintile had a higher incidence of cardiovascular events compared to those not in the top quintile (hazard ratio, 1.47; 95% CI, 1.11-1.94; P <0.005) after adjustment for risk factors., Conclusions: Greater AoD was associated with an increased risk of cardiovascular events in a community-based cohort of blacks. AoD may be useful as a predictor of incident cardiovascular events and further investigation is warranted., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Heart failure (HF) is a global pandemic with a growing prevalence and is a growing burden on the healthcare system. Machine learning (ML) has the potential to revolutionize medicine and can be applied in many different forms to aid in the prevention of symptomatic HF (stage C). HF prevention currently has several challenges, specifically in the detection of pre-HF (stage B). HF events are missed in contemporary models, limited therapeutic options are proven to prevent HF, and the prevention of HF with preserved ejection is particularly lacking. ML has the potential to overcome these challenges through existing and future models. ML has limitations, but the many benefits of ML outweigh these limitations and risks in most scenarios. ML can be applied in HF prevention through various strategies such as refinement of incident HF risk prediction models, capturing diagnostic signs from available tests such as electrocardiograms, chest x-rays, or echocardiograms to identify structural/functional cardiac abnormalities suggestive of pre-HF (stage B HF), and interpretation of biomarkers and epigenetic data. Altogether, ML is able to expand the screening of individuals at risk for HF (stage A HF), identify populations with pre-HF (stage B HF), predict the risk of incident stage C HF events, and offer the ability to intervene early to prevent progression to or decline in stage C HF. In this narrative review, we discuss the methods by which ML is utilized in HF prevention, the benefits and pitfalls of ML in HF risk prediction, and the future directions. [ABSTRACT FROM AUTHOR]

Background: Hypertensive diseases in pregnancy have been associated with altered cardiac structure and function, yet these associations have not been systematically investigated in larger populations including African Americans. We evaluated the relationships between hypertensive diseases in pregnancy with cardiac structure and function later in life in the Genetic Epidemiology Network of Arteriopathy (GENOA) study.Methods: We investigated 1013 African American women sibships with echocardiographic measurements from the GENOA study (Phase II, 2000-05; Jackson, MS). Women were classified as self-reported nulliparous (n = 61), a history of normotensive pregnancies (n = 780), a history of a hypertensive pregnancies (n = 152), or a history of preeclampsia (n = 20). We compared adjusted associations among these 4 groups with echocardiographic measurements of cardiac structure and function using generalized estimating equations, accounting for familial clustering.Results: Among 1013 women with echocardiographic data (mean age 62 ± 9.5 years), women with a history of hypertensive pregnancy had lower left ventricular ejection fraction (LVEF) (P = 0.043) compared to nulliparous women and higher left atrial systolic dimension (LASD) compared to women with a history of normotensive pregnancies (P = 0.010), After adjusting for cardiovascular risk factors. There were no statistically significant differences in other echocardiographic parameters among these groups.Conclusions: A history of hypertension in pregnancy is associated with lower LVEF later in life, compared to nulliparous women and higher LASD compared to women with a history of normotensive pregnancies. However, given the multiple comparisons considered, this finding should be interpreted cautiously and requires further study. [ABSTRACT FROM AUTHOR]

Background: Preeclampsia (PE) is a disorder prevalent in 3-8% of pregnancies, characterized by hypertension, endothelial dysfunction and cardiac dysfunction, including hypertrophy and impaired global longitudinal strain (GLS), which indicates reduced contractility and tissue injury. Despite several clinical studies highlighting impaired cardiac function in these women, the underlying mechanisms have not been studied, in part, due to lack of an appropriate animal model. The Reduced Uterine Perfusion Pressure (RUPP) rat model produces a PE-like phenotype, including adverse cardiac remodeling. However, whether this translates to impaired cardiac function is not known. The aim of this study was to test the hypothesis that placental ischemia in the RUPP rat leads to impaired left ventricular (LV) systolic function and GLS.Study Design: RUPP (n = 10) rats underwent surgery to induce placental ischemia on gestational day (GD) 14. Sham (n = 10) and RUPP rats had indwelling carotid catheters placed on GD 18, and blood pressure and echocardiography measurements were made on GD 19.Results: The RUPP group exhibited increased mean arterial pressure compared to the Sham group (123 ± 3 vs. 97 ± 2 mmHg, P < 0.01). RUPP hearts exhibited impaired LV ejection fraction (60 ± 2 vs. 78 ± 2%, P < 0.01) and GLS (-17.89 ± 0.5 vs. -26.31 ± 2.7%, P = 0.02), in addition to cardiac hypertrophy (0.97 ± 0.04 vs. 0.91 ± 0.02 g, P = 0.02).Conclusions: Cardiac dysfunction and impaired strain are present in RUPP rats during pregnancy. These findings represent an animal model of PE that could be used to understand the mechanisms of cardiac dysfunction in this disease and ultimately, improve or prevent cardiac abnormalities in these patients. [ABSTRACT FROM AUTHOR]

Background Increased left ventricular (LV) myocardial stiffness may be associated with impaired LV hemodynamics and incident heart failure (HF). However, an indicator that estimates LV myocardial stiffness easily and non-invasively is lacking. The purpose of this study was to determine whether diastolic wall strain (DWS), an echocardiographic estimator of LV myocardial stiffness, is associated with incident HF in a middle-aged community-based cohort of African Americans. Methods and results We investigated associations between DWS and incident HF among 1528 African Americans (mean age 58.5 years, 66% women) with preserved LV ejection fraction (EF ≥50%) and without a history of cardiovascular disease in the Atherosclerosis Risk in Communities Study. Participants with the smallest DWS quintile (more LV myocardial stiffness) had a higher LV mass index, higher relative wall thickness, and lower arterial compliance than those in the larger four DWS quintiles ( p < 0.01 for all). Over a mean follow-up of 15.6 years, there were 251 incident HF events (incidence rate: 10.9 per 1000 person-years). After adjustment for traditional risk factors and incident coronary artery disease, both continuous and categorical DWS were independently associated with incident HF (HR 1.21, 95%CI 1.04–1.41 for 0.1 decrease in continuous DWS, p = 0.014, HR 1.40, 95%CI 1.05–1.87 for the smallest DWS quintile vs other combined quintiles, p = 0.022). Conclusions DWS was independently associated with an increased risk of incident HF in a community-based cohort of African Americans. DWS could be used as a qualitative estimator of LV myocardial stiffness. [ABSTRACT FROM AUTHOR]

Background: Clinical risk factors associated with heart failure (HF) symptoms in aortic stenosis (AS) patients with preserved ejection fraction (EF) have not been fully identified. We hypothesized that left ventricular (LV) diastolic stiffness is associated with HF symptoms in patients with AS.Methods and Results: We retrospectively evaluated 275 patients with at least moderate AS (aortic valve area <1.5 cm2) and preserved EF (≥50%). LV diastolic stiffness was evaluated with the use of echocardiographic parameters, diastolic wall strain (DWS, a measure of LV wall stiffness), and KLV (a marker of LV chamber stiffness). There were 69 patients with HF. Patients with HF were older, were more likely to be African American, had a higher body mass index, and had more hypertension and coronary artery disease (P < .05 for all). Aortic valve area index and mean pressure gradient across the aortic valve were not different between patients with and without HF. Despite similar echocardiographic parameters of AS severity, patients with HF had stiffer LV (DWS 0.21 ± 0.06 vs 0.25 ± 0.06 [P < .01], KLV 0.17 ± 0.11 vs 0.13 ± 0.08 [P < .01]). Logistic regression analyses revealed that after adjusting for age, race, body mass index, history of hypertension, and coronary artery disease, LV diastolic stiffness parameters remained significantly associated with HF symptoms.Conclusions: LV diastolic stiffness is independently associated with HF in AS patients with preserved EF. [ABSTRACT FROM AUTHOR]

Background--African Americans develop chronic kidney disease and pulmonary hypertension (PH) at disproportionately high rates. Little is known whether PH heightens the risk of heart failure (HF) admission or mortality among chronic kidney disease patients, including patients with non-end-stage renal disease. Methods and Results--We analyzed African Americans participants with chronic kidney disease (estimated glomerular filtration rate <60 mL/min per 1.73 m2 or urine albumin/creatinine >30 mg/g) and available echocardiogram-derived pulmonary artery systolic pressure (PASP) from the Jackson Heart Study (N=408). We used Cox models to assess whether PH (PASP>35 mm Hg) was associated with higher rates of HF hospitalization and mortality. In a secondary, cross-sectional analysis, we examined the relationship between cystatin C (a marker of renal function) and PASP and potential mediators, including BNP (B-type natriuretic peptide) and endothelin-1. In our cohort, the mean age was 63±13 years, 70% were female, 78% had hypertension, and 22% had PH. Eighty-five percent of the participants had an estimated glomerular filtration rate >30 mL/min per 1.73 m2. During follow-up, 13% were hospitalized for HF and 27% died. After adjusting for potential confounders, including BNP, PH was found to be associated with HF hospitalization (hazard ratio, 2.37; 95% confidence interval, 1.15-4.86) and the combined outcome of HF hospitalization or mortality (hazard ratio, 1.84; confidence interval, 1.09-3.10). Log cystatin C was directly associated with PASP (adjusted β =2.5 [95% confidence interval, 0.8-4.1] per standard deviation change in cystatin C). Mediation analysis showed that BNP and endothelin-1 explained 56% and 40%, respectively, of the indirect effects between cystatin C and PASP. Conclusions--Among African Americans with chronic kidney disease, PH, which is likely pulmonary venous hypertension, was associated with a higher risk of HF admission and mortality. [ABSTRACT FROM AUTHOR]

Background: Early-diastolic left ventricular (LV) longitudinal expansion is delayed with diastolic dysfunction. We hypothesized that, in patients with heart failure (HF), regardless of LV ejection fraction (EF), there is diastolic temporal nonuniformity with a delay of longitudinal relative to circumferential expansion.Methods and Results: Echocardiography was performed in 143 HF patients-50 with preserved EF (HFpEF) and 93 with reduced EF (HFrEF)-as well as 31 normal control subjects. The delay of early-diastolic mitral annular velocity from the mitral Doppler E (TE-e') was measured as a parameter of the longitudinal expansion delay. The delay of the longitudinal early-diastolic global strain rate (SRE) relative to circumferential SRE (DelayC-L) was calculated as a parameter of temporal nonuniformity. Intra-LV pressure difference (IVPD) was estimated with the use of color M-mode Doppler data as a parameter of LV diastolic suction. Although normal control subjects had symmetric LV expansion in early diastole, TE-e' and DelayC-L were significantly prolonged in HF regardless of EF (P < .01 vs control for all). Multivariate analysis revealed that DelayC-L was the independent determinant of IVPD among the parameters of LV geometry and contraction (β = -0.21; P < .05).Conclusion: An abnormal temporal nonuniformity of early-diastolic expansion is present in HF regardless of EF, which was associated with reduced LV suction. [ABSTRACT FROM AUTHOR]

In this study, we examined the combined effect of aging and myocardial infarction on left ventricular remodeling, focusing on matrix metalloproteinase (MMP)-9-dependent mechanisms. We enrolled 55 C57BL/6J wild type (WT) and 85 MMP-9 Null (Null) mice of both sexes at 11-36 months of age and evaluated their response at Day 7 post-myocardial infarction. Plasma MMP-9 levels positively linked to age in WT mice (r = .46, p = .001). MMP-9 deletion improved survival (76% for WT vs 88% for Null, p = .021). Post-myocardial infarction, there was a progressive increase in left ventricular dilation with age in WT but not in Null mice. By inflammatory gene array analysis, WT mice showed linear age-dependent increases in three different proinflammatory genes (C3, CCl4, and CX3CL1; all p < .05), whereas Null mice showed increases in three proinflammatory genes (CCL5, CCL9, and CXCL4; all p < .05) and seven anti-inflammatory genes (CCL1, CCL6, CCR1, IL11, IL1r2, IL8rb, and Mif; all p < .05). Compared with WT, macrophages isolated from Null left ventricle infarct demonstrated enhanced expression of anti-inflammatory M2 markers CD163, MRC1, TGF-β1, and YM1 (all p < .05), without affecting proinflammatory M1 markers. In conclusion, MMP-9 deletion stimulated anti-inflammatory polarization of macrophages to attenuate left ventricle dysfunction in the aging post-myocardial infarction. [ABSTRACT FROM AUTHOR]

Although disruption of leptin signaling is associated with obesity as well as cardiac lipid accumulation and dysfunction, it has been difficult to separate the direct effects of leptin on the heart from those associated with the effects of leptin on body weight and fat mass. Using Cre-loxP recombinase technology, we developed tamoxifen-inducible, cardiomyocyte-specific leptin receptor- deficient mice to assess the role of leptin in regulating cardiac function. Cre recombinase activation in the heart resulted in transient reduction in left ventricular systolic function which recovered to normal levels by day 10. However, when cardiomyocyte leptin receptors were deleted in the setting of Cre recombinase-induced left ventricular dysfunction, irreversible lethal heart failure was observed in less than 10 days in all mice. Heart failure after leptin receptor deletion was associated with marked decreases of cardiac mitochondrial ATP, phosphorylated mammalian target of rapamycin (mTOR), and AMP-activated kinase (pAMPK). Our results demonstrate that specific deletion of cardiomyocyte leptin receptors, in the presence of increased Cre recombinase expression, causes lethal heart failure associated with decreased cardiac energy production. These observations indicate that leptin plays an important role in regulating cardiac function in the setting of cardiac stress caused by Cre-recombinase expression, likely through actions on cardiomyocyte energy metabolism. [ABSTRACT FROM AUTHOR]

A new approach to calculating left ventricular (LV) early filling propagation velocity (VP) from color M-mode echocardiograms using wavelet analysis is described. Current methods for measuring VP do not account for the spatiotemporal variation in VP. They are confined by empirical assumptions and user inputs that hinder the accuracy of VP, limiting its clinical utility. We evaluated three methods for measuring LV early filling: conventional VP, the strength of propagation (VS) and wavelet propagation velocity (VW) determined from the most energetically significant wave (peak VW). Group A comprised 125 patients (n = 50 normal filling, n = 25 impaired relaxation, n = 25 pseudonormal filling and n = 25 restrictive filling), and group B comprised 69 patients (n = 32 normal, n = 15 dilated and n = 22 hypertrophic). Peak VW most accurately distinguished normal from diseased patients. For group A, the area under the receiver operating characteristic curve was 0.92 for peak VW versus 0.62 for VP, 0.63 for VS and 0.58 for intraventricular pressure difference. These correspond to a 50%-70% improvement in classification ability. Similar improvements were measured in group B. Peak VW may provide a more accurate evaluation of diastolic function than standard methods and enable better diagnostic classification of patients with diastolic dysfunction. [ABSTRACT FROM AUTHOR]