Kofo O. Ogunyankin

Right Ventricular Structure Is Associated With the Risk of Heart Failure and Cardiovascular Death The Multi-Ethnic Study of Atherosclerosis (MESA)-Right Ventricle Study

Background— Changes in right ventricular (RV) morphology are associated with morbidity and mortality in heart and lung disease. We examined the association of abnormal RV structure and function with the risk of heart failure or cardiovascular death in a population-based multiethnic sample free of clinical cardiovascular disease at baseline. Methods and Results— The Multi-Ethnic Study of Atherosclerosis (MESA) performed cardiac magnetic resonance imaging on 5098 participants between 2000 and 2002 with follow-up for incident heart failure and cardiovascular death (“death”) until January 2008. RV volumes and mass were available for 4204 participants. The study sample (n=4144) was 61.4±10.1 years old and 47.6% male. The presence of RV hypertrophy (increased RV mass) was associated with more than twice the risk of heart failure or death after adjustment for demographics, body mass index, education, C-reactive protein level, hypertension, and smoking status (hazard ratio, 2.52; 95% confidence interval, 1.55–4.10; P<0.001) and a doubling (or more) of risk with left ventricular mass at the mean value or lower (P for interaction=0.05). Conclusions— RV hypertrophy was associated with the risk of heart failure or death in a multiethnic population free of clinical cardiovascular disease at baseline.Background— Changes in right ventricular (RV) morphology are associated with morbidity and mortality in heart and lung disease. We examined the association of abnormal RV structure and function with the risk of heart failure or cardiovascular death in a population-based multiethnic sample free of clinical cardiovascular disease at baseline. Methods and Results— The Multi-Ethnic Study of Atherosclerosis (MESA) performed cardiac magnetic resonance imaging on 5098 participants between 2000 and 2002 with follow-up for incident heart failure and cardiovascular death (“death”) until January 2008. RV volumes and mass were available for 4204 participants. The study sample (n=4144) was 61.4±10.1 years old and 47.6% male. The presence of RV hypertrophy (increased RV mass) was associated with more than twice the risk of heart failure or death after adjustment for demographics, body mass index, education, C-reactive protein level, hypertension, and smoking status (hazard ratio, 2.52; 95% confidence interval, 1.55–4.10; P <0.001) and a doubling (or more) of risk with left ventricular mass at the mean value or lower ( P for interaction=0.05). Conclusions— RV hypertrophy was associated with the risk of heart failure or death in a multiethnic population free of clinical cardiovascular disease at baseline. # Clinical Perspective {#article-title-27}

Endothelial cysteinyl leukotriene 2 receptor expression mediates myocardial ischemia-reperfusion injury.

Cysteinyl leukotrienes (CysLTs) have been implicated as inflammatory mediators of cardiovascular disease. Three distinct CysLT receptor subtypes transduce the actions of CysLTs but the role of the endothelial CysLT2 receptor (CysLT2R) in cardiac function is unknown. Here, we investigated the role of CysLT2R in myocardial ischemia-reperfusion (I/R) injury using transgenic (tg) mice overexpressing human CysLT2R in vascular endothelium and nontransgenic (ntg) littermates. Infarction size in tg mice increased 114% compared with ntg mice 48 hours after I/R; this increase was blocked by the CysLT receptor antagonist BAY-u9773. Injection of 125 I-albumin into the systemic circulation revealed significantly enhanced extravasation of the label in tg mice, indicating increased leakage of the coronary endothelium, combined with increased incidence of hemorrhage and cardiomyocyte apoptosis. Expression of proinflammatory genes such as Egr-1, VCAM-1, and ICAM was significantly increased in tg mice relative to ntg controls. Echocardiographic assessment 2 weeks after I/R revealed decreased anterior wall thickness in tg mice. Furthermore, the postreperfusion time constant tau of isovolumic relaxation was significantly increased in tg animals, indicating diastolic dysfunction. These results reveal that endothelium-targeted overexpression of CysLT2R aggravates myocardial I/R injury by increasing endothelial permeability and exacerbating inflammatory gene expression, leading to accelerated left ventricular remodeling, induction of peri-infarct zone cellular apoptosis, and impaired cardiac performance.

Global longitudinal strain aids the detection of non-obstructive coronary artery disease in the resting echocardiogram.

AIMS To evaluate the diagnostic power of abnormal global longitudinal strain (GLS) to detect non-obstructive coronary artery disease (CAD) in the resting echocardiogram. GLS using two-dimensional speckle-tracking echocardiography (2D STE) is a powerful tool for detecting advanced CAD. However, the diagnostic power of 2D STE for detecting moderate, clinically unapparent CAD from images obtained at rest is unknown. METHODS AND RESULTS We retrospectively studied 2D STE characteristics in 123 consecutive patients who underwent stress echocardiography, and subsequently coronary angiography within 10 days. We compared the diagnostic power of GLS at rest to the conventional wall motion score index (WMSI) during stress for detecting stenosis ≥ 50% (CAD(>50)) in any major coronary artery. Studies with akinetic or dyskinetic segments and reduced left ventricular ejection fraction were excluded. In 56 patients with significant CAD(>50), GLS was -16.77 ± 3.18% compared with -19.05 ± 3.43% in the 67 patients without CAD(<50) (P = 0.0002). A GLS cutpoint of greater than -17.77% had the most optimal sensitivity and specificity (66/76%) for detecting CAD and was comparable to a WMSI ≥ 1.13 (68/70%) measured during stress. CONCLUSION Non-obstructive CAD was identified by a reduced GLS measured by 2D STE in rest images with similar accuracy to the traditional WMSI measured in stress echocardiography.

Genome-Wide Association Study of Cardiac Structure and Systolic Function in African Americans: The Candidate Gene Association Resource (CARe) Study

Background—Using data from 4 community-based cohorts of African Americans, we tested the association between genome-wide markers (single-nucleotide polymorphisms) and cardiac phenotypes in the Candidate-gene Association Resource study. Methods and Results—Among 6765 African Americans, we related age, sex, height, and weight-adjusted residuals for 9 cardiac phenotypes (assessed by echocardiogram or magnetic resonance imaging) to 2.5 million single-nucleotide polymorphisms genotyped using Genome-wide Affymetrix Human SNP Array 6.0 (Affy6.0) and the remainder imputed. Within the cohort, genome-wide association analysis was conducted, followed by meta-analysis across cohorts using inverse variance weights (genome-wide significance threshold=4.0 ×10−7). Supplementary pathway analysis was performed. We attempted replication in 3 smaller cohorts of African ancestry and tested lookups in 1 consortium of European ancestry (EchoGEN). Across the 9 phenotypes, variants in 4 genetic loci reached genome-wide significance: rs4552931 in UBE2V2 (P=1.43×10−7) for left ventricular mass, rs7213314 in WIPI1 (P=1.68×10−7) for left ventricular internal diastolic diameter, rs1571099 in PPAPDC1A (P=2.57×10−8) for interventricular septal wall thickness, and rs9530176 in KLF5 (P=4.02×10−7) for ejection fraction. Associated variants were enriched in 3 signaling pathways involved in cardiac remodeling. None of the 4 loci replicated in cohorts of African ancestry was confirmed in lookups in EchoGEN. Conclusions—In the largest genome-wide association study of cardiac structure and function to date in African Americans, we identified 4 genetic loci related to left ventricular mass, interventricular septal wall thickness, left ventricular internal diastolic diameter, and ejection fraction, which reached genome-wide significance. Replication results suggest that these loci may be unique to individuals of African ancestry. Additional large-scale studies are warranted for these complex phenotypes.

Prevalence, Prospective Risk Markers, and Prognosis Associated With the Presence of Left Ventricular Diastolic Dysfunction in Young Adults The Coronary Artery Risk Development in Young Adults Study

The authors sought to determine the prevalence, prospective risk markers, and prognosis associated with diastolic dysfunction in the Coronary Artery Risk Development in Young Adults (CARDIA) Study. The CARDIA Study cohort includes approximately equal proportions of white and black men and women. The authors collected data on risk markers at year 0 (1985-1986), and echocardiography was done at year 5 when the participants were 23-35 years of age. Participants were followed for 20 years (through 2010) for a composite endpoint of all-cause mortality, myocardial infarction, heart failure, and stroke. Diastolic function was defined according to a validated hierarchical classification algorithm. In the 2,952 participants included in the primary analysis, severe diastolic dysfunction was present in 1.1% and abnormal relaxation was present in 9.3%. Systolic blood pressure at year 0 was associated with both severe diastolic dysfunction and abnormal relaxation 5 years later, whereas exercise capacity and pulmonary function abnormalities were associated only with abnormal relaxation 5 years later. After multivariate adjustment, the hazard ratios for the composite endpoint in participants with severe diastolic dysfunction and abnormal relaxation were 4.3 (95% confidence interval: 2.0, 9.3) and 1.6 (95% confidence interval: 1.1, 2.5), respectively. Diastolic dysfunction in young adults is associated with increased morbidity and mortality, and the identification of prospective risk markers associated with diastolic dysfunction could allow for targeted primary prevention efforts.

Effect of cardiac resynchronization therapy on right ventricular function.

Purpose of review The focus only on the left ventricle (LV) for both evaluation of cardiac dyssynchrony and the efficacy of resynchronization therapy (CRT) is too limited to explain the nuances of clinical response to CRT. Right ventricular function, synchrony and remodeling are now commonly characterized noninvasively. This review presents new insights into the role of the right ventricle independently and in conjunction with the LV in determining the clinical efficacy of CRT. Recent findings There are patients with predominantly right ventricular dyssynchrony who respond to CRT without reverse remodeling of the LV. Studies of longitudinal axis function of the right ventricle show that contractile function improvement precedes right ventricular reverse remodeling in clinical responders to CRT. The discordance seen in some CRT responders between improvements in left ventricular and right ventricular morphology, function and markers of synchrony is best understood using multiple markers of cardiac longitudinal axis function and cardiac deformation analysis. Summary Advanced right ventricular dysfunction reduces the likelihood of clinical response to CRT. However, right ventricular contractile function may improve following CRT independent of changes in right ventricular size or volumetric measures of right ventricular function. The consequences of isolated improvements in right ventricular function on CRT-related prognosis deserve further study.

Racial Differences in Left Atrial Size: Results from the Coronary Artery Risk Development in Young Adults (CARDIA) Study

Whites have an increased risk of atrial fibrillation (AF) compared to Blacks. The mechanism underlying this association is unknown. Left atrial (LA) size is an important AF risk factor, and studies in older adults suggest Whites have larger LA diameters. However, because AF itself causes LA dilation, LA size differences may be due to greater subclinical AF among older Whites. We therefore assessed for racial differences in LA size among young adults at low AF risk. The Coronary Artery Risk Development in Young Adults (CARDIA) study enrolled White and Black participants between 18 and 30 years of age. LA diameter was measured in a subset of participants using echocardiography at Year 5 (n = 4,201) and Year 25 (n = 3,373) of follow up. LA volume was also assessed at Year 5 (n = 2,489). Multivariate linear regression models were used to determine the adjusted association between race and LA size. In unadjusted analyses, mean LA diameter was significantly larger among Blacks compared to Whites both at Year 5 (35.5 ± 4.8 mm versus 35.1 ± 4.5 mm, p = 0.01) and Year 25 (37.4 ± 5.1 mm versus 36.8 ± 4.9 mm, p = 0.002). After adjusting for demographics, comorbidities, and echocardiographic parameters, Whites demonstrated an increased LA diameter (0.7 mm larger at Year 5, 95% CI 0.3–1.1, p<0.001; 0.6 mm larger at Year 25, 95% CI 0.3–1.0, p<0.001). There was no significant association between race and adjusted Year 5 LA volume. In conclusion, in a young, well-characterized cohort, the larger adjusted LA diameter among White participants suggests inherent differences in atrial structure may partially explain the higher risk of AF in Whites. The incongruent associations between race, LA diameter, and LA volume suggest that LA geometry, rather than size alone, may have implications for AF risk.

Association of Aortic Root Dilation from Early Adulthood to Middle Age with Cardiac Structure and Function: The CARDIA Study

Background: The human aorta dilates with advancing age. However, the association between progressive aortic dilation with aging and cardiac remodeling has not been established in studies of community‐dwelling adults. The aim of this study was to test the hypothesis that there would be a relationship between aortic size increase over the early adult life span with left ventricular (LV) structural remodeling and subclinical LV dysfunction in middle age, even in the absence of overt cardiovascular and valvular disease. Methods: Included were Coronary Artery Risk Development in Young Adults study participants (N = 2,933) aged 23 to 35 years with available transthoracic echocardiographic measurements during 20 years of follow‐up. Multivariate linear regression models assessed sex‐specific associations between 20‐year change in aortic root diameter with LV structure and function. Results: Larger aortic root diameter at 20‐year follow‐up was associated with greater LV mass (2.77 vs 2.18 g/mm in men and women, respectively, P < .001). In longitudinal analyses, increase in aortic root diameter over 20‐year follow‐up was associated with a greater 20‐year increase in LV mass and ratio of LV mass to LV end‐diastolic volume ratio in both sexes. In women but not in men, increased aortic root diameter over 20 years was associated with increased left atrial dimension, impaired E/E′, and impaired early diastolic longitudinal and circumferential strain rates assessed by speckle‐tracking echocardiography. Conclusions: Progressive increase in aortic root diameter from early adulthood to middle age was associated with increased LV mass and LV concentric remodeling in both sexes and impaired diastolic function predominantly in women. HighlightsAortic root dilation over the early adult life‐cycle is associated with impaired diastolic function predominantly in women.Aortic root dilation from early adulthood to middle age is associated with increased left ventricular mass and left ventricular concentric remodeling in community‐dwelling individuals.Our study findings support the hypothesis that aortic root dilation is associated with adverse cardiac remodeling and underscore the potential importance of sex‐specific ventricular‐arterial interactions in the pathogenesis of heart failure. Abbreviations: AoD = Aortic root diameter; CARDIA = Coronary Artery Risk Development in Young Adults; LV = Left ventricular; LVM = Left ventricular mass; STE = Speckle‐tracking echocardiography.

Successful treatment of hypertension accounts for improvements in markers of diastolic function − a pilot study comparing hydrochlorothiazide-based and amlodipine-based treatment strategies

BACKGROUND There is controversy regarding whether blood pressure (BP) medications have relevant therapeutic benefits beyond those due to lowering of BP. OBJECTIVE To show that rapid successful treatment of hypertension leads to improvement in cardiac morphology and function regardless of the pharmacological agents used. METHODS Hypertension was defined as an average 24 h ambulatory BP of higher than 135/85 mmHg in 38 subjects with a mean (+/- SD) age of 54+/-7 years. Patients were randomly assigned to treatment with a diuretic based (n=20) or a calcium channel blocker (CCB)-based (n=18) medication. All subjects were followed every two weeks, and similar additional medications were added until the BP was lower than 125/80 mmHg, then followed monthly for a total of six months. Echocardiography with tissue Doppler imaging was performed, and was repeated after six months of aggressive pharmacotherapy and lifestyle management. RESULTS Baseline ambulatory BP monitoring and echocardiographic measures of diastolic function were similar between both treatment groups. Subjects received 3.5+/-1 pills and 11+/-2 follow-up visits. The average 24 h BP was reduced from 145/91 mmHg to 124/75 mmHg (P<0.001) in the CCB group. A greater lowering from 143/91 mmHg to 117/72 mmHg occurred in the diuretic group (P=0.02 for the difference between groups) at six months. There was significant improvement in tissue Doppler imaging diastolic function parameters in both groups, with a trend toward greater improvement in the diuretic group. The left ventricular mass/ height(2.7) index decreased from 40 g/m(2.7) to 37 g/m(2.7) in the diuretic group (P=0.02), whereas a nonsignificant change (41 g/m(2.7) to 42 g/m(2.7)) occurred in the CCB group. CONCLUSIONS Aggressive BP lowering is associated with improved left ventricular diastolic function and mass proportional to the extent of BP normalization.

Right Ventricular Structure is Associated with the Risk of Heart Failure and Cardiovascular Death: The MESA-Right Ventricle Study

Background— Changes in right ventricular (RV) morphology are associated with morbidity and mortality in heart and lung disease. We examined the association of abnormal RV structure and function with the risk of heart failure or cardiovascular death in a population-based multiethnic sample free of clinical cardiovascular disease at baseline. Methods and Results— The Multi-Ethnic Study of Atherosclerosis (MESA) performed cardiac magnetic resonance imaging on 5098 participants between 2000 and 2002 with follow-up for incident heart failure and cardiovascular death (“death”) until January 2008. RV volumes and mass were available for 4204 participants. The study sample (n=4144) was 61.4±10.1 years old and 47.6% male. The presence of RV hypertrophy (increased RV mass) was associated with more than twice the risk of heart failure or death after adjustment for demographics, body mass index, education, C-reactive protein level, hypertension, and smoking status (hazard ratio, 2.52; 95% confidence interval, 1.55–4.10; P<0.001) and a doubling (or more) of risk with left ventricular mass at the mean value or lower (P for interaction=0.05). Conclusions— RV hypertrophy was associated with the risk of heart failure or death in a multiethnic population free of clinical cardiovascular disease at baseline.Background— Changes in right ventricular (RV) morphology are associated with morbidity and mortality in heart and lung disease. We examined the association of abnormal RV structure and function with the risk of heart failure or cardiovascular death in a population-based multiethnic sample free of clinical cardiovascular disease at baseline. Methods and Results— The Multi-Ethnic Study of Atherosclerosis (MESA) performed cardiac magnetic resonance imaging on 5098 participants between 2000 and 2002 with follow-up for incident heart failure and cardiovascular death (“death”) until January 2008. RV volumes and mass were available for 4204 participants. The study sample (n=4144) was 61.4±10.1 years old and 47.6% male. The presence of RV hypertrophy (increased RV mass) was associated with more than twice the risk of heart failure or death after adjustment for demographics, body mass index, education, C-reactive protein level, hypertension, and smoking status (hazard ratio, 2.52; 95% confidence interval, 1.55–4.10; P <0.001) and a doubling (or more) of risk with left ventricular mass at the mean value or lower ( P for interaction=0.05). Conclusions— RV hypertrophy was associated with the risk of heart failure or death in a multiethnic population free of clinical cardiovascular disease at baseline. # Clinical Perspective {#article-title-27}