Carotid Plaque Score is Associated with 10-year Major Adverse Cardiovascular Events in Low-Intermediate Risk Patients Referred to a General Cardiology Community Clinic.

AIMS: Atherosclerotic carotid plaque assessments have not been integrated into routine clinical practice due to the time-consuming nature of both imaging and measurements. Plaque score, Rotterdam method, is simple, quick, and only requires 4-6 B-mode ultrasound images. The aim was to assess the benefit of plaque score in a community cardiology clinic to identify patients at risk for major adverse cardiovascular events (MACE). METHODS AND RESULTS: Patients ≥40 years presenting for risk assessment were given a carotid ultrasound. Exclusions included a history of vascular disease or MACE and being >75 years. Kaplan-Meier curves and hazard ratios were performed. The left and right common carotid artery (CCA), bulb, and internal carotid artery (ICA) were given 1 point per segment if plaque present (plaque score 0 to 6). Administrative data holdings at ICES were used for 10-year event follow-up. Of 8,472 patients, 60% were females (n = 5,121). Plaque was more prevalent in males (64% vs 53.9%; P <0.0001). The 10-year MACE cumulative incidence estimate was 6.37% with 276 events (males 6.9 % vs females 6.0%; P = 0.004). Having both maximal CCA IMT <1.00 mm and plaque score = 0, was associated with less events. A plaque score <2 was associated with a low 10-year event rate (4.1%) compared to 2-4 (8.7%) and 5-6 (20%). CONCLUSION: A plaque score ≥2 can re-stratify low-intermediate risk patients to a higher risk for events. Plaque score may be used as a quick assessment in a cardiology office to guide treatment management of patients.

The association of carotid plaque burden and composition and the coronary artery calcium score in intermediate cardiovascular risk patients.

Both the carotid ultrasound and coronary artery calcium (CAC) score quantify subclinical atherosclerosis and are associated with cardiovascular disease and events. This study investigated the association between CAC score and carotid plaque quantity and composition. Adult participants (n = 43) without history of cardiovascular disease were recruited to undergo a carotid ultrasound. Maximum plaque height (MPH), total plaque area (TPA), carotid intima-media thickness (CIMT), and plaque score were measured. Grayscale pixel distribution analysis of ultrasound images determined plaque tissue composition. Participants then underwent CT to determine CAC score, which were also categorized as absent (0), mild (1-99), moderate (100-399), and severe (400+). Spearman correlation coefficients between carotid variables and CAC scores were computed. The mean age of participants was 63 ± 11 years. CIMT, TPA, MPH, and plaque score were significantly associated with CAC score (ρ = 0.60, p < 0.0001; ρ = 0.54, p = 0.0002; ρ = 0.38, p = 0.01; and ρ = 0.49, p = 0.001). Echogenic composition features %Calcium and %Fibrous tissue were not correlated to a clinically relevant extent. There was a significant difference in the TPA, MPH, and plaque scores of those with a severe CAC score category compared to lesser categories. While carotid plaque burden was associated with CAC score, plaque composition was not. Though CAC score reliably measures calcification, carotid ultrasound gives information on both plaque burden and composition. Carotid ultrasound with assessment of plaque features used in conjunction with traditional risk factors may be an alternative or additive to CAC scoring and could improve the prediction of cardiovascular events in the intermediate risk population.

Progression of atherosclerosis with carnitine supplementation: a randomized controlled trial in the metabolic syndrome.

BACKGROUND: L-carnitine (L-C), a ubiquitous nutritional supplement, has been investigated as a potential therapy for cardiovascular disease, but its effects on human atherosclerosis are unknown. Clinical studies suggest improvement of some cardiovascular risk factors, whereas others show increased plasma levels of pro-atherogenic trimethylamine N-oxide. The primary aim was to determine whether L-C therapy led to progression or regression of carotid total plaque volume (TPV) in participants with metabolic syndrome (MetS). METHODS: This was a phase 2, prospective, double blinded, randomized, placebo-controlled, two-center trial. MetS was defined as ≥ 3/5 cardiac risk factors: elevated waist circumference; elevated triglycerides; reduced HDL-cholesterol; elevated blood pressure; elevated glucose or HbA1c; or on treatment. Participants with a baseline TPV ≥ 50 mm3 were randomized to placebo or 2 g L-C daily for 6 months. RESULTS: The primary outcome was the percent change in TPV over 6 months. In 157 participants (L-C N = 76, placebo N = 81), no difference in TPV change between arms was found. The L-C group had a greater increase in carotid atherosclerotic stenosis of 9.3% (p = 0.02) than the placebo group. There was a greater increase in total cholesterol and LDL-C levels in the L-C arm. CONCLUSIONS: Though total carotid plaque volume did not change in MetS participants taking L-C over 6-months, there was a concerning progression of carotid plaque stenosis. The potential harm of L-C in MetS and its association with pro-atherogenic metabolites raises concerns for its further use as a potential therapy and its widespread availability as a nutritional supplement. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02117661, Registered April 21, 2014, https://clinicaltrials.gov/ct2/show/NCT02117661 .

Speckle tracking carotid artery circumferential strain is a marker of arterial sclerosis but not coronary atherosis.

PURPOSE: Circumferential speckle tracking carotid artery strain is a novel method of quantifying vessel wall stiffness. We hypothesized that carotid wall stiffness would be associated with carotid intimal medial thickening (a medial process associated with risk factors), but not coronary artery disease (an intimal process). METHODS: Bilateral carotid artery ultrasound was conducted on outpatients who had previously undergone elective coronary angiography. Mean carotid artery far wall circumferential strain (FWCS) was assessed for correlations with coronary angiographic stenosis, cardiac risk factors, carotid intima-media thickness (CIMT), and carotid plaque. RESULTS: One hundred and sixty five (165) patients were studied. No significant association was found between the presence of coronary artery disease on angiography and mean FWCS. FWCS was higher in current tobacco smokers. In addition, carotid strain was found to decrease with increased age (r = -0.33, P < 0.001). When adjusted for pulse pressure (PP), FWCS/PP was negatively correlated with mean CIMT (r = -0.29, P = 0.002) and bulb maximum plaque height (r = -0.27, P = 0.004). Hypertension and diabetes were associated with decreased FWCS/PP (increased wall stiffness). CONCLUSIONS: While no clear relationship between carotid strain and coronary artery disease was observed, increased CIMT, carotid plaque, and cardiac risk factors were associated with decreased carotid strain. Further work is required to explore the relationship between carotid strain and cardiovascular events.

Predictors of an abnormal postexercise ankle brachial index: Importance of the lowest ankle pressure in calculating the resting ankle brachial index.

BACKGROUND: The postexercise ankle-brachial index (ABI) is useful in patients with suspected peripheral arterial disease (PAD) and a normal resting ABI. Our objective was to determine the independent predictors of an abnormal postexercise ABI. HYPOTHESIS: We hypothesized that the lowest ankle systolic pressure to calculate the resting ABI would be associated with an abnormal post-exercise ABI. METHODS: Among 619 consecutive patients referred for suspected PAD, we calculated the postexercise ABI in patients with a normal resting ABI. An ABI <0.90 at rest was considered abnormal. We investigated 3 definitions of an abnormal postexercise ABI, defined as either <0.90, or >5% or >20% reduction compared with rest. RESULTS: Using multivariate analysis, the lowest ABI (calculated using the lowest and not the highest ankle systolic pressure) was consistently the most powerful independent predictor of an abnormal postexercise ABI. Patients with an abnormal lowest resting ABI were significantly more likely to have an abnormal postexercise ABI, as well as a significantly greater reduction in the ABI compared with rest. The lowest ABI had a high specificity (95%) but low sensitivity (82%) for a postexercise ABI <0.90. CONCLUSIONS: An abnormal lowest ABI (calculated with the lowest ankle systolic pressure) is the most important independent predictor of an abnormal ABI response to exercise in patients with a conventionally normal ABI. All such patients should be exercised and their ABI measured postexercise.

Focused Vascular Ultrasound for the Assessment of Atherosclerosis: A Proof-of-Concept Study.

BACKGROUND: Current decisions to refer for angiographic coronary assessment are based on pain character, risk scores, stress testing, and occasionally calcium scoring. Carotid plaque has emerged as an effective vascular biomarker, but the cost and time of a full carotid ultrasound examination are disadvantageous. Focused vascular ultrasound (FOVUS) is a rapid limited assessment of carotid plaque that can be conducted by non-vascular-trained operators. The objective of the study was to determine the test characteristics of FOVUS for the assessment of significant coronary atherosclerosis in symptomatic patients referred for cardiac assessment. METHODS: In this prospective study, FOVUS was performed in 208 outpatients at low to intermediate risk undergoing same-day angiography. Carotid artery maximal plaque height was measured in each participant. A previously established receiver operating characteristic curve determined that a value of ≥1.5 mm was the threshold for significant angiographic coronary artery disease. FOVUS scan results, alone or combined with stress testing, were analyzed for the prediction of significant coronary artery disease. RESULTS: The negative predictive value and sensitivity of plaque height alone by FOVUS were found to be 77% and 93%, respectively. Adding the FOVUS scan result to stress testing significantly increased the negative predictive value and sensitivity of these traditional risk stratification tools. CONCLUSIONS: Rapid carotid plaque height measurement by FOVUS enhanced atherosclerosis risk prediction in patients referred for cardiac assessment. Rapid plaque quantification had good negative predictive value and high sensitivity alone or in combination with stress testing. FOVUS may serve as a potential point-of-care ultrasound tool in the integrated assessment of cardiac pain.

Carotid Ultrasound Maximum Plaque Height-A Sensitive Imaging Biomarker for the Assessment of Significant Coronary Artery Disease.

OBJECTIVES: We investigated the use of carotid intima-media thickness and carotid plaque in predicting significant angiographic coronary stenosis. METHODS: Three hundred eighteen consecutive outpatients underwent angiography and carotid ultrasound on the same day. The extent of coronary stenosis was determined using an established scoring system. Mean far distal carotid intima-media thickness of the common carotid artery, maximum plaque height, and total plaque area in the bulbs were measured by ultrasound. Cutoff values were identified using a receiver operating characteristic curve for predicting and ruling out coronary artery disease. RESULTS: The mean ± SD carotid intima-media thickness (≥50% stenosis = 0.91 ± 0.23 mm, <50% stenosis = 0.82 ± 0.18 mm), maximum plaque height (≥50% stenosis = 2.64 ± 0.85 mm, <50% stenosis = 1.72 ± 1.04 mm), and total plaque area (≥50% stenosis = 39.1 ± 27.7 mm(2) , <50% stenosis = 22.2 ± 23.4 mm(2) ) were significantly higher in patients with coronary artery disease (P ≤ 0.001 for all three comparisons). Increased CIMT, plaque height, and area correlated with increased number of affected vessels. Plaque height had the best negative likelihood ratio for ruling out disease (0.15). The optimal threshold values for predicting coronary disease were 0.82 mm for carotid intima-media thickness, 1.54 mm for plaque height, and 25.6 mm(2) for total plaque area. CONCLUSION: Increased carotid intima-media thickness and plaque measurements are indicative of the presence of epicardial coronary stenosis. Plaque burden is a more sensitive imaging biomarker for ruling out significant coronary artery disease, including in younger individuals.

ICEBERG: Intimal Carotid Evaluation Before Echocardiography Reveals Global Vascular Risk.

BACKGROUND: There is growing evidence that carotid ultrasonography provides important prognostic information about cardiovascular risk assessment. Our objective was to determine whether abbreviated rapid carotid ultrasonographic screening would reveal important global vascular risk information in statin-naive patients referred for routine transthoracic echocardiography (TTE). METHODS: Abbreviated carotid ultrasonographic imaging was performed in 560 consecutive patients undergoing TTE. The common carotid artery (CCA), the carotid bulb, and the internal carotid artery (ICA) were scanned. Maximal CCA intima-media thickness (IMT) was measured in the far wall. Carotid plaque was defined using the Atherosclerosis Risk in Communities (ARIC) study criteria. RESULTS: Of the 2283 patients who underwent TTE during a 1-year period, a total of 560 patients met inclusion criteria. There were 241 men, with a mean age of 63.2 ± 12.8 years and a mean CCA IMT of 1.11 ± 0.48 mm; 61% (147) had carotid plaque. The 319 women had a mean age of 66.3 ± 10.8 years and a mean CCA IMT of 1.03 ± 0.36 mm; 62.4% (199) had carotid plaque. All patients with plaque were considered to be at high risk. CONCLUSIONS: Of the 560 consecutive statin-naive patients referred for TTE with no history of vascular disease, a large proportion of both men (61%) and women (62.4%) had carotid plaque, indicating a high risk for vascular events according to the Canadian lipid guidelines. Although such patients are seen in the echocardiography laboratory, the addition of an abbreviated carotid ultrasonographic screening provides important information regarding risk stratification and the implementation of preventive therapy.

Gestational hypertension and the developmental origins of cardiac hypertrophy and diastolic dysfunction.

The developmental origins of health and disease refer to the theory that adverse maternal environments influence fetal development and the risk of cardiovascular disease in adulthood. We used the chronically hypertensive atrial natriuretic peptide knockout (ANP-/-) mouse as a model of gestational hypertension, and attempted to determine the effect of gestational hypertension on left ventricular (LV) structure and function in adult offspring. We crossed normotensive ANP+/+ females with ANP-/- males (yielding ANP+/-(WT) offspring) and hypertensive ANP-/- females with ANP+/+ males (yielding ANP+/-(KO) offspring). Cardiac gene expression was measured using real-time quantitative PCR. Cardiac function was assessed using echocardiography. Daily injections of isoproterenol (ISO) were used to induce cardiac stress. Collagen deposition was assessed using picrosirius red staining. All mice were 10 weeks of age. Gestational hypertension resulted in significant LV hypertrophy in offspring, with no change in LV function. Treatment with ISO resulted in significant LV diastolic dysfunction with a restrictive filling pattern (increased E/A ratio and E/e') and interstitial myocardial fibrosis only in ANP+/-(KO) and not ANP+/-(WT) offspring. Gestational hypertension programs adverse LV structural and functional remodeling in offspring. These data suggest that adverse maternal environments may increase the risk of heart failure in offspring later in life.

Gestational hypertension in atrial natriuretic peptide knockout mice and the developmental origins of salt-sensitivity and cardiac hypertrophy.

OBJECTIVE: To determine the effect of gestational hypertension on the developmental origins of blood pressure (BP), altered kidney gene expression, salt-sensitivity and cardiac hypertrophy (CH) in adult offspring. METHODS: Female mice lacking atrial natriuretic peptide (ANP-/-) were used as a model of gestational hypertension. Heterozygous ANP+/- offspring was bred from crossing either ANP+/+ females with ANP-/- males yielding ANP+/-(WT) offspring, or from ANP-/- females with ANP+/+ males yielding ANP+/-(KO) offspring. Maternal BP during pregnancy was measured using radiotelemetry. At 14weeks of age, offspring BP, gene and protein expression were measured in the kidney with real-time quantitative PCR, receptor binding assay and ELISA. RESULTS: ANP+/-(KO) offspring exhibited normal BP at 14weeks of age, but displayed significant CH (P<0.001) as compared to ANP+/-(WT) offspring. ANP+/-(KO) offspring exhibited significantly increased gene expression of natriuretic peptide receptor A (NPR-A) (P<0.001) and radioligand binding studies demonstrated significantly reduced NPR-C binding (P=0.01) in the kidney. Treatment with high salt diet increased BP (P<0.01) and caused LV hypertrophy (P<0.001) and interstitial myocardial fibrosis only in ANP+/-(WT) and not ANP+/-(KO) offspring, suggesting gestational hypertension programs the offspring to show resistance to salt-induced hypertension and LV remodeling. Our data demonstrate that altered maternal environments can determine the salt-sensitive phenotype of offspring.

The effect of the change in the Framingham Risk Score calculator between the 2006 and 2009 Canadian lipid guidelines.

BACKGROUND: Recent Canadian lipid guidelines changed the methodology used for calculating the Framingham Risk Score (FRS). We assessed the impact this would have on management when related to baseline lipid profiles and the possible need for statin drug therapy. METHODS: Patients with their FRS calculated between November 2006 and March 2010 were considered. There were 247 patients categorized as either low or intermediate risk. RESULTS: The study population consisted of 91 men and 156 women with a mean (SD) age of 52.7 ± 15.0 years. The average FRS was 5.6 ± 4.8 vs 11.5 ± 8.3 (2006 vs 2009) (P < .00010). The number of FRS patients categorized as low and intermediate risk requiring some form of lipid-lowering treatment increased from 35 (14.2%) to 81 (32.8%), a 2.3-fold increase. Of 41 high-risk patients, 40 had a baseline low-density lipoprotein cholesterol of ≥ 2.0 mmol/L and would qualify for not only health behaviour interventions but also statin drug treatment. CONCLUSIONS: The new FRS increases the number of 2006 patients with low and intermediate scores who move from low to high risk (n = 11, 5.9%), from low to intermediate risk (n = 50, 26.9%), and from intermediate to high risk (n = 30, 49.2%), leading to a 2.3-fold increase in the need for lipid-lowering treatment. Therapies intended to improve lipid profiles and potentially patient outcomes include both health behaviour interventions alone or in combination with lipid-lowering drug therapy. Given the relationship between low-density lipoprotein cholesterol and cardiovascular events is linear, treating more patients is likely to lead to a further reduction in cardiovascular events.

The accuracy of the physical examination for the detection of lower extremity peripheral arterial disease.

BACKGROUND: Peripheral arterial disease (PAD) is a major risk factor for adverse cardiovascular events. There has been a definite push for wider use of the ankle-brachial index (ABI) as a simple screening tool for PAD. Perhaps this has occurred to the detriment of a thorough physical examination. OBJECTIVE: To assess the accuracy of the physical examination to detect clinically significant PAD compared with the ABI. METHODS: PADfile, the PAD module of CARDIOfile (the Kingston Heart Clinic's cardiology database [Kingston, Ontario]), was searched for all patients who underwent peripheral arterial testing. Of 1619 patients, 1236 had all of the necessary data entered. Patients' lower limbs were divided into two groups: those with a normal ABI between 0.91 and 1.30, and those with an abnormal ABI of 0.90 or lower. Peripheral pulses were graded as either absent or present. Absent was graded as 0/3, present but reduced (1/3), normal (2/3) or bounding (3/3). Femoral bruits were graded as either present (1) or absent (0). Using the ABI as the gold standard, the sensitivity, specificity, negative predictive value (NPV), positive predictive value and overall accuracy were calculated for the dorsalis pedis pulse, the posterior tibial pulse, both pedal pulses, the presence or absence of a femoral bruit and, finally, for a combination of both pedal pulses and the presence or absence of a femoral bruit. RESULTS: In 1236 patients who underwent PAD testing and who underwent a complete peripheral vascular physical examination (all dorsalis pedis and posterior tibial pulses palpated and auscultation for a femoral bruit), the sensitivity, specificity, NPV, positive predictive value and accuracy for PAD were 58.2%, 98.3%, 94.9%, 81.1% and 93.8%, respectively. CONCLUSIONS: The clinical examination of the peripheral arterial foot pulses and the auscultation for a femoral bruit had a high degree of accuracy (93.8%) for the detection or exclusion of PAD compared with the ABI using the cut-off of 0.90 or lower. If both peripheral foot pulses are present in both lower limbs and there are no femoral bruits, the specificity and NPV of 98.3% and 94.9%, respectively, make the measurement of the ABI seem redundant. The emphasis in PAD detection should be redirected toward encouraging a thorough physical examination.

Factors influencing the echocardiographic estimate of right ventricular systolic pressure in normal patients and clinically relevant ranges according to age.

BACKGROUND: Previous studies have shown that in the absence of underlying cardiac pathology, the echocardiographic estimate of right ventricular systolic pressure (RVSP) increases progressively and normally with age. There are limited data in patients older than 60 years of age. OBJECTIVE: To define the ranges of RVSP according to age and to include more elderly patients than have previously been reported. METHODS: All patients undergoing echocardiography since May 26, 1999, at the Kingston Heart Clinic (Kingston, Ontario) have had their data entered into a locally designed cardiology database (CARDIOfile; Registered trademark, Kingston Heart Clinic). RVSP was calculated from the peak tricuspid regurgitant jet velocity (V) using the modified Bernoulli equation (RVSP = 4V2 + RAP), with the mean right atrial pressure (RAP) estimated to be 10 mmHg. Of the 22,628 patients who had undergone echocardiography, 10,905 had RVSP measured. All abnormal echocardiograms were excluded, leaving 1559 echocardiograms for analysis. RESULTS: Patient age ranged from 15 to 93 years. The mean age was 49 years. RVSP increased significantly only after the age of 50 years. The mean (+/- SD) RVSP for those younger than 50 years, 50 to 75 years, and older than 75 years of age was 27.3+/-5.7 mmHg, 30.2+/-7.6 mmHg and 34.8+/-8.7 mmHg, respectively (P<0.0001 among all age groups). The normal range (95% CI) of RVSP in those younger than 50 years, 50 to 75 years, and older than 75 years of age was 16 mmHg to 39 mmHg, 15 mmHg to 45 mmHg, and 17 mmHg to 52 mmHg, respectively. Multivariate analysis indicated that age, mitral diastolic early-to-late filling velocity ratio, ejection fraction, aortic size and early mitral filling velocity/ early diastolic mitral annular velocity were the only significant independent variables. There were significant changes in diastolic function with increasing age, which may have been responsible for the changes in RVSP. CONCLUSIONS: RVSP remains stable in both men and women until the age of 50 years. Thereafter, RVSP increases progressively in a linear manner with age and is significantly higher in patients older than 75 years of age. The changes may relate to changes in diastolic function. These ranges should be taken into account when using echocardiogram-derived RVSP for the diagnosis of pulmonary hypertension in the absence of cardiovascular disease.

Estimated right ventricular systolic pressure during exercise stress echocardiography in patients with suspected coronary artery disease.

OBJECTIVE: To determine the normal range of estimated right ventricular systolic pressure (RVSP) at peak exercise during exercise stress echocardiography (ExECHO) in a series of consecutive patients referred for the investigation of coronary artery disease. METHODS: Of 1057 ExECHO examinations over a span of 11 months, 807 met the study criteria. A total of 250 patients were excluded, 188 for missing rest or peak RVSP measurements, 16 for a resting RVSP above 50 mmHg, 16 for nondiagnostic echocardiographic images and the remaining 30 for missing data. The maximal tricuspid regurgitant jet was recorded at rest and following acquisition of the stress images (mean [+/- SD] time 103.1+/-35.2 s). A mean right atrial pressure of 10 mmHg was used in the calculation of RVSP. All data were entered into a cardiology database (CARDIOfile; Registered trademark, Kingston Heart Clinic) for later retrieval and analysis. RESULTS: There were 206 male (58.9+/-12.0 years of age) and 601 female patients (57.4+/-12.0 years of age). Patient age ranged from 18 to 90 years. The mean resting and peak exercise RVSP was 27.8+/-7.8 mmHg and 34.8+/-11.3 mmHg in men, and 27.8+/-7.7 mmHg and 34.6+/-11.7 mmHg in women, respectively. The mean increase in RVSP was 7.0+/-8.8 mmHg in men and 6.7+/-8.9 mmHg in women. The 95% CI for peak RVSP was 12.2 mmHg to 57.4 mmHg in men, and 11.2 mmHg to 58.0 mmHg in women. There was no significant difference in peak RVSP for a normal ExECHO compared with an abnormal ExECHO. RVSP at rest and at peak exercise increased with both age and left atrial size. CONCLUSIONS: In individual patients, the RVSP should not increase above the resting value by more than 24.6 mmHg in men and 24.5 mmHg in women. This value was calculated as the increase in RVSP plus 2xSD of the RVSP. Peak RVSP should not exceed 57.4 mmHg in men and 58.0 mmHg in women. If either of these criteria is exceeded, the response of RVSP to exercise should be considered abnormal.