Daisuke Kamimura

Delayed Time to Peak Velocity Is Useful for Detecting Severe Aortic Stenosis

Background Time to peak velocity (TPV) is an echocardiographic variable that can be easily measured and reflects a late peaking murmur, a classic physical finding suggesting severe aortic stenosis (AS). The aim of this study was to investigate the usefulness of TPV to evaluate AS severity. Methods and Results This study included 700 AS patients, whose aortic valve area (AVA) was <1.5 cm2, and 200 control patients. The TPV was defined as the time from aortic valve opening to when the flow velocity across the aortic valve reaches its peak. AS severity was classified as follows: High gradient severe AS, mean pressure gradient ≥40 mm Hg and AVA index (AVAI) <0.6 cm2/m2; Low gradient severe AS, mean pressure gradient <40 mm Hg, AVAI <0.6 cm2/m2, and dimensionless index <0.25; moderate AS, mean pressure gradient <40 mm Hg, AVAI ≥0.6 cm2/m2. The area under the receiver operating characteristic curve of TPV to predict high gradient severe AS was 0.94 (95% CI: 0.92–0.97, P<0.001). TPV was significantly delayed in low gradient severe AS compared with moderate AS both in patients with preserved (102±13 ms versus 83±13 ms, P<0.001) and with reduced ejection fraction (110±18 ms versus 88±13 ms, P<0.001). Delayed TPV was associated with increased all‐cause mortality or need for aortic valve replacement after adjustment for confounders (hazard ratio for first quartile, reference is fourth quartile: 7.31, 95% CI 4.26–12.53, P<0.001). Conclusions TPV is useful to evaluate AS severity and predict poor prognosis of AS patients.

The association between cigarette smoking and inflammation: The Genetic Epidemiology Network of Arteriopathy (GENOA) study

To inform the study and regulation of emerging tobacco products, we sought to identify sensitive biomarkers of tobacco-induced subclinical cardiovascular damage by testing the cross-sectional associations of smoking with 17 biomarkers of inflammation in 2,702 GENOA study participants belonging to sibships ascertained on the basis of hypertension. Cigarette smoking was assessed by status, intensity (number of cigarettes per day), burden (pack-years of smoking), and time since quitting. We modeled biomarkers as geometric mean (GM) ratios using generalized estimating equations (GEE). The mean age of participants was 61 ±10 years; 64.5% were women and 54.4% African American. The prevalence of smoking was 12.2%. After adjusting for potential confounders, 6 of 17 biomarkers were significantly higher among current smokers at a Bonferroni adjusted p-value threshold (p<0.003). High sensitivity C-reactive protein was the most elevated biomarker among current smokers when compared to never smokers [GM ratio = 1.39 (95% CI: 1.23, 1.57); p <0.001]. Among former smokers, each pack-year of cigarettes smoked was associated with a 0.4% higher serum level of hsCRP [GM ratio = 1.004 (95% CI: 1.001, 1.006); p = 0.002] and each 5-year lapsed since quitting was associated with a 4% lower serum level of hsCRP [GM ratio = 0.96 (95% CI: 0.93, 0.99); p = 0.006]. However, we found no significant association of smoking intensity or burden with biomarkers of inflammation among current smokers. HsCRP appears to be the most sensitive biomarker of inflammation associated with cigarette smoking of those investigated, and could be a useful biomarker of smoking-related injury for the study and regulation of emerging tobacco products.

Physical Activity Is Associated With Reduced Left Ventricular Mass in Obese and Hypertensive African Americans

BACKGROUND Physical activity (PA) has been associated with decreased left ventricular (LV) hypertrophy in previous studies. However, little is known about the relationship between PA and LV structure and factors which influence this relationship among African Americans. METHODS We evaluated 1,300 African Americans with preserved LV ejection fraction (EF > 50%) from the Genetic Epidemiology Network of Arteriopathy (GENOA) Study (mean age 62.4 years, 73% women). PA index was calculated as 3 * heavy activity hours + 2 * moderate activity hours + slight activity hours/day. The relationship between PA index and LV structure was evaluated using generalized estimating equation. The association between PA index and LV mass index by age group, sex, body mass index (BMI), history of hypertension, diabetes or coronary heart disease, estimated glomerular filtration rate, and current smoking status were plotted. RESULTS After adjustment for these factors, higher PA index was independently associated with lower LV mass index (P < 0.05). There were significant interactions between PA index and obesity (BMI ≥ 30) and history of hypertension on LV mass index (P for interaction <0.05, for both). Higher PA index was associated with lower LV mass index more in obese or hypertensive participants compared with nonobese or nonhypertensive participants. CONCLUSIONS Higher PA index was associated with reduced LV hypertrophy in obese and hypertensive African Americans. Prospective studies aimed at assessing whether increasing PA prevents LV hypertrophy and potentially reduces the risk of heart failure in these at risk groups are warranted.

Left Ventricular False Tendons are Associated With Left Ventricular Dilation and Impaired Systolic and Diastolic Function

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 ± 23 mmHg, P = 0.76) or body mass index (BMI, 31 ± 8 versus 29 ± 10 kg/m2, 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.

Obesity and Metabolic Syndrome Hypertension

Obesity is a growing problem worldwide, and excess visceral adiposity is a major risk factor for many metabolic, kidney, and cardiovascular disorders including primary (essential) hypertension. The mechanisms by which obesity leads to hypertension and kidney dysfunction are not completely understood, but physical compression of the kidneys and activation of the renin-angiotensin-aldosterone and sympathetic nervous systems appear to initially increase renal sodium reabsorption, impair renal-pressure natriuresis, and ultimately raise blood pressure. Other factors such as lipotoxicity and endothelial and vascular dysfunction may accompany and/or exacerbate increased blood pressure as obesity is sustained. Concomitant vascular and metabolic derangements such as hyperglycemia and inflammation interact with increased blood pressure to cause kidney injury which exacerbates the hypertension, making it more difficult to control while causing further renal injury. Maintenance of a healthy weight is important for primary prevention of hypertension and kidney disease. Weight loss, if it can be achieved, appears to be effective in treating many patients with chronic hypertension and kidney disease. However, long-term weight management is challenging for many people, and more effective therapeutic options are needed.

Higher plasma leptin levels are associated with reduced left ventricular mass and left ventricular diastolic stiffness in black women: insights from the Genetic Epidemiology Network of Arteriopathy (GENOA) study

Our previous experimental animal data suggest a beneficial effect of leptin on LV structure and function. We hypothesized that leptin levels are associated with lower LV mass and myocardial stiffness which are important risk factors for the development of heart failure with preserved ejection fraction (HFpEF). We evaluated 1172 blacks, in which the prevalence of HFpEF is quite high, with preserved LV ejection fraction (EF > 50%) from the Genetic Epidemiology Network of Arteriopathy Study (mean age 62.9 years, 72% women), a community-based study to identify genes influencing blood pressure and target organ damage due to hypertension. Associations between leptin levels and indices of LV structure and function were evaluated using generalized estimating equations accounting for clustering in siblings. LV myocardial stiffness was evaluated using diastolic wall strain (DWS) measured by echocardiography. Analyses were stratified by sex because leptin levels were three times higher in women than men (p < 0.001). After adjustment for confounders, higher leptin levels were associated with lower LV mass (coefficient for 1 s.d. increase of leptin level: −5.825 g, 95% CI: −9.755 to −1.895 g, P = 0.004) and higher DWS (lower LV stiffness) (coefficient for 1 s.d. increase of leptin level: 0.009, 95% CI: 0.002–0.015, P = 0.007) in women. There were no statistically significant associations in men. In women, there were interactions between leptin levels and body mass index quartiles on LV mass and stiffness (p < 0.05 for both). Higher leptin levels were associated with lower LV mass and stiffness in obese but not lean black women.

Increased Proximal Aortic Diameter is Associated With Risk of Cardiovascular Events and All‐Cause Mortality in Blacks The Jackson Heart Study

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.

Elevated serum osteoprotegerin is associated with increased left ventricular mass index and myocardial stiffness

Aim Osteoprotegerin (OPG) is associated with a poor prognosis in patients with heart failure with preserved ejection fraction (HFpEF). OPG has also been associated with fibrosis and collagen cross-linking, which increase arterial and left ventricle (LV) myocardial stiffness. Little is known about the relation of OPG and LV structure and function in African-Americans who are disproportionately affected by HFpEF. Methods and results Our analysis included 1172 participants with preserved LV ejection fraction (>50%) from the African-American cohort in the Genetic Epidemiology Network of Arteriopathy Study (mean age 63 years, 72% female). We used diastolic wall strain indicator measured by echocardiography to assess LV myocardial stiffness. Diastolic wall strain was calculated as (LV posterior thickness at end-systole − LV posterior thickness at end-diastole)/LV posterior thickness at end-systole. Associations between OPG levels and indices of arterial and LV structure and function were evaluated by using generalized linear mixed models and adjusted for possible confounders. OPG levels were correlated with age, female sex, presence of hypertension and diabetes, and lower estimated glomerular filtration rate (P < 0.05 for all). Multivariable analysis revealed that higher OPG levels were associated with greater LV mass index, increased LV myocardial stiffness, and higher N-terminal prohormone brain natriuretic peptide levels (P < 0.05 for all). Conclusion In African-Americans, higher OPG levels were associated with characteristics common in patients with HFpEF and were significantly associated with known precursors to HFpEF. These findings indicate a potential role for OPG in the pathophysiology of HFpEF in African-Americans.

Diastolic wall strain is associated with incident heart failure in African Americans: Insights from the atherosclerosis risk in communities study

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.

Increased Left Ventricular Diastolic Stiffness Is Associated With Heart Failure Symptoms in Aortic Stenosis Patients With Preserved Ejection Fraction

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.