Boaz D. Rosen

Left Ventricular Concentric Remodeling Is Associated With Decreased Global and Regional Systolic Function The Multi-Ethnic Study of Atherosclerosis

Background—The transition from compensatory concentric remodeling to myocardial failure is not completely understood in humans. To investigate determinants of incipient myocardial dysfunction, we examined the association between concentric remodeling and regional LV function in asymptomatic participants of the Multi-Ethnic Study of Atherosclerosis (MESA). Methods and Results—Myocardial tagged MRI was performed. Regional myocardial function expressed as peak systolic midwall circumferential strain (Ecc) was analyzed in 441 consecutive studies by HARP (Harmonic Phase) tool. Peak Ecc was correlated with the extent of concentric remodeling determined by the ratio of left ventricular mass to end-diastolic volume (M/V ratio). In men, a gradual decline in peak global Ecc was seen with increasing M/V ratio (test for trend, P<0.001). Among women, however, Ecc tended to be lower only in the fifth compared with the first quintile of M/V ratio (P=0.1). The association of lower Ecc with increasing M/V ratio was regionally heterogeneous but was particularly prominent in the LAD region in men (test for trend, P<0.001) and in women (test for trend, P=0.02). In the right coronary and left circumflex artery territories, these associations were less marked in both genders. Conclusions—In this cross-sectional study of asymptomatic individuals, concentric left ventricular remodeling was related to decreased regional systolic function. The reduction in regional function, which was more pronounced in the left anterior descending coronary artery territory, may reflect the local transition from compensatory remodeling to myocardial dysfunction.

Quantitative assessment of regional myocardial function with MR-tagging in a multi-center study: interobserver and intraobserver agreement of fast strain analysis with Harmonic Phase (HARP) MRI

PURPOSE To assess the reproducibility of Harmonic Phase (HARP) analysis of myocardial MR tagged images acquired in the Multi-Center Study of Atherosclerosis (MESA). METHODS Using the HARP method, three independent observers performed two separate quantitative strain analyses of myocardial cine MR-tagging images blindly in 24 participants. The images were obtained in four different centers and analyzed at a single core lab. Each study comprised 3 short-axis slices subdivided in 12 segments (24 x 3 x 12 = 864 segments), each with three layers. Normal strains (circumferential [Ecc] and radial [Err]), principal strains (Lambda1, Lambda2), and the angle alpha (between Ecc-Lambda2) were calculated. Intraclass correlation coefficient (R) for peak systolic strains, and all pooled systolic and diastolic strain data were used to determine inter- and intraobserver agreement. Two observers also visually graded study quality. R values were related to the image quality in different myocardial regions and layers. RESULTS Overall, HARP yielded an excellent inter- and intraobserver agreement for peak systolic strain data (for Ecc, R = 0.84 and 0.89, respectively) and all systolic pooled data (for Ecc, interobserver R = 0.82, intraobserver R = 0.69-0.76). Both inter and intraobserver agreement were lower for diastolic pooled data (R = 0.69 and 0.58-0.62, respectively). There was a direct relationship between image quality and performance of the HARP analysis, with increasing inter- and intraobserver R values in studies with longer tag persistence. Both inter- and intraobserver agreement were better in the anterior and septal myocardial regions, and in the midwall layer. The intraobserver agreement was similar among the three observers. CONCLUSION Employing the HARP method for quantitative strain analysis of myocardial MR tagged images provides a high inter- and intraobserver agreement. These good results are obtained in case of good to excellent MR image quality.

Arterial Stiffness Is Associated With Regional Ventricular Systolic and Diastolic Dysfunction The Multi-Ethnic Study of Atherosclerosis

Objective—The pathophysiology of left ventricular (LV) dysfunction, particularly in the setting of a preserved ejection fraction (EF), remains unclear. Few studies have investigated the relationship between arterial compliance and LV function in humans, and none used cardiovascular MRI. Methods and Results—We sought to determine whether arterial compliance is related to regional myocardial function among participants of the Multi-Ethnic Study of Atherosclerosis (MESA). Arterial compliance was assessed using carotid ultrasound measurements to calculate the distensibility coefficient (DC) and Young’s modulus (YM). Circumferential systolic (SRS) and diastolic (SRE) strain rates were calculated by harmonic phase (HARP) from tagged MRI. Associations between arterial compliance and indices of ventricular function were adjusted for cardiovascular risk factors. We found a significant association between arterial compliance and SRS in all myocardial regions (P<0.05); arterial compliance was also associated with SRE in the lateral and septal wall regions (P<0.05). Multiple linear regression analyses demonstrated a direct linear relationship between the carotid artery DC and SRS across all LV segments and slices, even after adjustment for cardiovascular risk factors and LV mass. In regression analyses, a significant relationship between arterial compliance and SRE in the septal and antero-apical walls was also found and remained significant after multivariable adjustment. Conclusion—Arterial stiffness is associated with early and asymptomatic impairment of systolic as well as diastolic myocardial function. Further studies are needed to elucidate role of vascular compliance in the development of ventricular dysfunction and failure.

Expression of Opioid Receptors During Heart Ontogeny in Normotensive and Hypertensive Rats

BACKGROUND The opioidergic systems are involved in modulating nociceptive stimuli. In addition, the recent results suggest that endogenous and exogenous opioids could play a role in the modulation of blood pressure and cardiac functions. However, little is known regarding the expression and role of opioid-binding sites in the heart. The decreased sensitivity to noxious stimuli in hypertensive rats raises the possibility of different developmental pattern expression of opioid-binding sites in normotensive versus hypertensive rats. METHODS AND RESULTS Opioid receptor expression in hearts from hypertensive and normotensive rats was studied during heart development by binding assays. From P1 until P90, the development of the heart in the two rat strains was accompanied by a gradual increase in the density of kappa-opioid receptors. Hearts from hypertensive rats expressed significantly higher levels of kappa receptors compared with those of normotensive rats. At ages older than P7, mu-opioid receptors could not be detected in hearts of both strains, whereas delta-opioid-binding sites gradually increased until reaching adult levels. Seven-day-old cardiomyocyte cultures of both rat strains expressed similar densities of delta or kappa receptors to those observed in hearts from 7-day-old neonates. The mu-binding sites were not detected in cardiomyocytes cultures. Similar to the in vivo state, cultured myocytes from hypertensive rats had significantly higher levels of kappa-binding sites (1.5 fold) compared with those of normotensive rats. The kappa sites are pertussis toxin sensitive, and the state of coupling of the receptor to G protein is similar for the two rat strains. CONCLUSION The role of opioid-binding sites in the heart is not completely clear. Hypertensive rats are known to be less sensitive to noxious stimuli compared with normotensive rats. It is controversial whether the site if application of noxious stimuli plays an important role in the sensitivity to pain in hypertensive rats. We suggest that the opioidergic system could play a role in the modulation of blood pressure in addition to its known effect on nociception.

Left Ventricular Concentric Remodeling Is Associated With Decreased Global and Regional Systolic Function

Background— The transition from compensatory concentric remodeling to myocardial failure is not completely understood in humans. To investigate determinants of incipient myocardial dysfunction, we examined the association between concentric remodeling and regional LV function in asymptomatic participants of the Multi-Ethnic Study of Atherosclerosis (MESA). Methods and Results— Myocardial tagged MRI was performed. Regional myocardial function expressed as peak systolic midwall circumferential strain (Ecc) was analyzed in 441 consecutive studies by HARP (Harmonic Phase) tool. Peak Ecc was correlated with the extent of concentric remodeling determined by the ratio of left ventricular mass to end-diastolic volume (M/V ratio). In men, a gradual decline in peak global Ecc was seen with increasing M/V ratio (test for trend, P<0.001). Among women, however, Ecc tended to be lower only in the fifth compared with the first quintile of M/V ratio (P=0.1). The association of lower Ecc with increasing M/V ratio was regi...

Coronary Artery Atherosclerosis Is Related to Reduced Regional Left Ventricular Function in Individuals Without History of Clinical Cardiovascular Disease The Multiethnic Study of Atherosclerosis

Objective—We investigated whether regional coronary calcium score by computed tomography is related to regional left ventricular systolic function measured by MRI tagging in participants of the Multiethnic Study of Atherosclerosis. Methods and Results—The Multiethnic Study of Atherosclerosis is a prospective observational study of men and women without a history of previous heart disease from 4 ethnic groups. Calcium scores were measured separately for the left anterior descendent (LAD), left circumflex (LCX), and right (RCA) coronary arteries. Left ventricular strain and strain rate were determined by tagged MRI in the corresponding vascular territories of the coronary vessels in 509 participants. Greater coronary calcification in the LAD, LCX, and right RCA coronary arteries were related to worse function in their respective perfusion. Anterior wall strain rate was −1.37±0.41 when LAD calcium was zero versus −1.17±0.24 1/s in the highest quartile of calcium score (P<0.001). Similar relationships were evident in the LCX and RCA regions. Participants with 1- and 2-vessel coronary artery calcium had better myocardial function in the remote area compared with the territory supplied by the diseased artery. Conclusions—High-local calcium score is related to regional dysfunction in the corresponding coronary territory among individuals without a history of previous heart disease. These results indicate a link between atherosclerosis and subclinical regional left ventricular dysfunction.

Relationship between baseline coronary calcium score and demonstration of coronary artery stenoses during follow-up MESA (Multi-Ethnic Study of Atherosclerosis).

OBJECTIVES The MESA (Multi-Ethnic Study of Atherosclerosis) is a population-based study of 6,814 men and women. We sought to analyze the relationship between the extent of coronary artery calcium (CAC) at baseline and the severity of coronary stenoses in clinically indicated coronary angiography studies during follow-up. BACKGROUND CAC is an established predictor of major cardiovascular events. Yet, the relationship between CAC and the distribution and severity of coronary artery stenoses has not been widely explored. METHODS All MESA participants underwent noncontrast enhanced cardiac computed tomography during enrollment to determine baseline CAC. We analyzed 175 consecutive angiography reports from participants who underwent coronary catheterization for clinical indications during a median follow-up period of 18 months. The relationship between baseline CAC and the severity of coronary stenosis detected in coronary angiographies was determined. RESULTS Baseline Agatston score was 0 in only 7 of 175 (4%) MESA participants who underwent invasive angiography during follow-up. When coronary arteries were studied separately, 13% to 18% of coronary arteries with >or=75% stenosis had 0 calcium mass scores at baseline. There was close association between baseline calcium mass score and the severity of stenosis in each of the coronary arteries (test for trend, p < 0.001). For example, mean calcium mass scores for <50%, 50% to 74%, and >or=75% stenosis in the left anterior descending coronary artery were 105.1 mg, 157.2 mg, and 302.2 mg, respectively (p < 0.001). Finally, there was a direct relationship between the total Agatston Score at baseline and the number of diseased vessels (test for trend, p < 0.001). CONCLUSIONS The majority of patients with clinically indicated coronary angiography during follow-up had detectable coronary calcification at baseline. Although there is a significant relationship between the extent of calcification and mean degree of stenosis in individual coronary vessels, 16% of the coronary arteries with significant stenoses had no calcification at baseline.

Lower Myocardial Perfusion Reserve Is Associated With Decreased Regional Left Ventricular Function in Asymptomatic Participants of the Multi-Ethnic Study of Atherosclerosis

Background— Myocardial ischemia is an important determinant of regional left ventricular systolic function. Myocardial blood flow reserve may be impaired by cardiovascular disease before alterations of myocardial perfusion at rest become manifest. Nevertheless, the relation between flow reserve and regional myocardial function has not been studied in individuals without a history of clinical heart disease. Methods and Results— Seventy-four participants (66±9 years, mean±SD) of the Multi-Ethnic Study of Atherosclerosis (MESA) underwent myocardial magnetic resonance tagging and contrast-enhanced perfusion studies. Regional myocardial function was evaluated as peak systolic circumferential strain (Ecc) in the three main coronary territories (left anterior descending [LAD], left circumflex, and right coronary artery [RCA]). Myocardial blood flow at rest and during adenosine-induced hyperemia was quantified by contrast-enhanced magnetic resonance imaging, to study the relation between regional flow and function after multivariable adjustment for age, gender, body mass index, left ventricular mass, and traditional risk factors. Lower regional myocardial blood flow during hyperemia was associated with reduced regional left ventricular function expressed as lower Ecc in the RCA (P<0.01) and left circumflex regions (P<0.05) measured in the subendocardium, mid-wall, and subepicardium. In contrast, no significant association was seen in the LAD territory (P=0.16). In addition, segmental function in LAD and RCA regions was reduced when individuals in the lowest 10th percentile for regional myocardial flow reserve were compared with the other participants. Absolute decreases in mid-wall Ecc LAD and RCA and global Ecc were 3.0%, 3.4%, and 2.8%, respectively (P<0.05 for all regions). Conclusions— Lower myocardial flow reserve is related to reduced regional function in asymptomatic individuals.

Resting Heart Rate as Predictor for Left Ventricular Dysfunction and Heart Failure: MESA (Multi-Ethnic Study of Atherosclerosis)

OBJECTIVES The objective of this study was to investigate the relationship between baseline resting heart rate and incidence of heart failure (HF) and global and regional left ventricular (LV) dysfunction. BACKGROUND The association of resting heart rate to HF and LV function has not been well described in an asymptomatic multi-ethnic population. METHODS Resting heart rate was measured in participants in the MESA (Multi-Ethnic Study of Atherosclerosis) trial at inclusion. Incident HF was registered (n = 176) during follow-up (median 7 years) in those who underwent cardiac magnetic resonance imaging (n = 5,000). Changes in ejection fraction (ΔEF) and peak circumferential strain (Δεcc) were measured as markers of developing global and regional LV dysfunction in 1,056 participants imaged at baseline and 5 years later. Time to HF (Cox model) and Δεcc and ΔEF (multiple linear regression models) were adjusted for demographics, traditional cardiovascular risk factors, calcium score, LV end-diastolic volume, and mass in addition to resting heart rate. RESULTS Cox analysis demonstrated that for 1 beat/min increase in resting heart rate, there was a 4% greater adjusted relative risk for incident HF (hazard ratio: 1.04; 95% CI: 1.02 to 1.06; p < 0.001). Adjusted multiple regression models demonstrated that resting heart rate was positively associated with deteriorating εcc and decrease in EF, even when all coronary heart disease events were excluded from the model. CONCLUSIONS Elevated resting heart rate was associated with increased risk for incident HF in asymptomatic participants in the MESA trial. Higher heart rate was related to development of regional and global LV dysfunction independent of subclinical atherosclerosis and coronary heart disease. (Multi-Ethnic Study of Atherosclerosis [MESA]; NCT00005487).

Non-invasive half millimetre 32 detector row computed tomography angiography accurately excludes significant stenoses in patients with advanced coronary artery disease and high calcium scores

Objective: To show an overall diagnostic accuracy ⩾ 90% for detection of ⩾ 50% stenoses by coronary half millimetre 32 detector row computed tomography angiography (32 × 0.5-MDCTA) in patients with advanced coronary artery disease (CAD) and a high likelihood of raised calcium scores. Methods: ECG gated 32 × 0.5-MDCTA (32 × 0.5 mm cross sections, 0.35 × 0.35 × 0.35 mm3 isotropic voxels, 400 ms rotation) was performed after injection of iodixanol (120 ml, 320 mg/ml) in 30 consecutive patients (25 men, mean (SD) age 59 (13) years, body mass index 26.2 (4.9) kg/m2). Native arteries, including ⩾ 1.5 mm branches, and bypass grafts were screened for ⩾ 50% stenoses. Stents were excluded. Conventional coronary angiography (performed 18 (12) days before 32 × 0.5-MDCTA) was analysed by quantitative coronary angiography. Results: Median Agatston calcium score was 510 (range 3–5066). Sensitivity, specificity, and positive and negative predictive values for detection of ⩾ 50% stenoses in native arteries were 76% (29 of 38), 94% (190 of 202), 71% (29 of 41), and 96% (190 of 199), respectively. Overall diagnostic accuracy was 91% (219 of 240). Due to the following artefacts 20% (69 of 352) of the vessels were excluded: motion, noise, and low contrast enhancement isolated or in combination (45 of 69 (65%)); image distortion by implantable cardioverter-defibrillator or pacemaker leads (18 of 69 (26%)); and blooming secondary to severe calcification (6 of 69 (9%)). Conclusions: Coronary 32 × 0.5-MDCTA accurately excludes ⩾ 50% stenoses in patients with advanced CAD and high calcium scores with an overall diagnostic accuracy of 91%.