High Lipoprotein(a) May Explain One-Quarter of Clinical Familial Hypercholesterolemia Diagnoses in Danish Lipid Clinics.

CONTEXT: Cholesterol carried in lipoprotein(a) adds to measured low-density lipoprotein cholesterol (LDL-C) and may therefore drive some diagnoses of clinical familial hypercholesterolemia (FH). OBJECTIVE: We investigated plasma lipoprotein(a) in individuals referred to Danish lipid clinics and evaluated the effect of plasma lipoprotein(a) on a diagnosis of FH. METHODS: Individuals referred to 15 Danish lipid clinics who were suspected of having FH according to nationwide referral criteria were recruited between September 1, 2020 and November 30, 2021. All individuals were classified according to the Dutch Lipid Clinical Network criteria for FH before and after LDL-C was adjusted for 30% cholesterol content in lipoprotein(a). We calculated the fraction of individuals fulfilling a clinical diagnosis of FH partly due to elevated lipoprotein(a). RESULTS: We included a total of 1166 individuals for analysis, of whom 206 fulfilled a clinical diagnosis of FH. Median lipoprotein(a) was 15 mg/dL (29 nmol/L) in those referred and 28% had lipoprotein(a) greater than or equal to 50 mg/dL (105 nmol/L), while 2% had levels greater than or equal to 180 mg/dL (389 nmol/L). We found that in 27% (55/206) of those fulfilling a clinical diagnosis of FH, this was partly due to high lipoprotein(a). CONCLUSION: Elevated lipoprotein(a) was common in individuals referred to Danish lipid clinics and in one-quarter of individuals who fulfilled a clinical diagnosis of FH, this was partly due to elevated lipoprotein(a). These findings support the notion that the LPA gene should be considered an important causative gene in patients with clinical FH and further support the importance of measuring lipoprotein(a) when diagnosing FH as well as for stratification of cardiovascular risk.

Prognostic implications of left ventricular asymmetry in patients with asymptomatic aortic valve stenosis.

Aims: Left ventricular (LV) regional hypertrophy in the form of LV asymmetry is a common finding in patients with aortic valve stenosis. The aim of this study was to test the hypothesis that LV asymmetry predicts future symptomatic status and indication for aortic valve replacement (AVR) in patients with asymptomatic aortic valve stenosis. Methods and results: In total, 114 patients with asymptomatic aortic valve stenosis (peak velocity > 2.5 m/s assessed by echocardiographic screening and LV ejection fraction > 50%) were enrolled in the study. LV asymmetry and LV geometry was assessed by multi-detector computed tomography according to previous definitions. Follow-up was conducted using electronic health records. Event-free survival was assessed using Cox proportional hazards models. Patients were followed for a median of 2.2 years (interquartile range 1.6-3.6). Indication for AVR occurred in 46 patients (40%). Patients with LV asymmetry had more than 3 times the risk of AVR (hazard ratio: 3.16; 95% CI: 1.77-5.66; P < 0.001) compared with patients with no LV asymmetry. Multivariate Cox analysis revealed that LV asymmetry was a predictor of future need of AVR (hazard ratio: 3.10; 95% CI: 1.44-6.65; P = 0.004), independent of LV geometry, jet velocity, valvular calcification, and pro-BNP. Conclusions: LV asymmetry is an independent predictor of future need for AVR in patients with asymptomatic aortic valve stenosis. It has incremental prognostic value to LV geometry and may provide a useful method of risk stratification.

Six-minute walking test and long term prognosis in patients with asymptomatic aortic valve stenosis.

BACKGROUND: Management of asymptomatic patients with aortic valve stenosis is challenging due to the elusive relationship between symptomatic status and hemodynamic parameters in addition to the occurrence of cardiovascular death. The 6-minute walking test (6MWT) reflects overall hemodynamic function and could contribute to risk assessment in such patients. METHODS AND RESULTS: One hundred sixteen asymptomatic patients (peak velocity>2.5m/s and left ventricular ejection fraction >50% assessed by echocardiographic screening; 85 males; aged 72±8years) underwent clinical workup, transthoracic echocardiography and a 6MWT. The mean distance covered by patients able to perform the 6MWT (n=107) was 422±90m. Patients were grouped in tertiles according to distance covered in the 6MWT: Short, intermediate and long distance patients. During a median follow-up of 5.5years (IQR 4.5-6.3), 29 (25%) patients died, 10 (9%) from cardiovascular causes. Multivariate analysis revealed that short distance patients (≤390m) were at higher risk of all-cause mortality (HR: 2.44; 95% CI: 1.05-5.67; p=0.04) and cardiovascular mortality (HR: 6.12; 95% CI: 1.18-31.83; p=0.03). For every 100m covered, the risk of all-cause mortality decreased by 35% (HR: 0.65; 95% CI: 0.43-0.99; p=0.04). Long distance patients (>465m) did not experience cardiovascular deaths during follow-up. CONCLUSIONS: In asymptomatic patients with aortic valve stenosis, the 6MWT is an independent predictor of all-cause and cardiovascular mortality. It is of incremental value to the echocardiographic evaluation, suggesting that the 6MWT might be useful to guide clinical follow-up intervals and treatment strategy.

Basal longitudinal strain predicts future aortic valve replacement in asymptomatic patients with aortic stenosis.

AIMS: To evaluate the prognostic value of global longitudinal strain (GLS) and basal longitudinal strain (BLS) with the knowledge of coexisting coronary pathology evaluated by multi-detector computed tomography (MDCT) coronary angiography. BACKGROUND: GLS and BLS are both sensitive markers of myocardial dysfunction and predictors of outcome in asymptomatic aortic stenosis. Aortic stenosis and ischaemic heart disease share risk factors and longitudinal function can be severely reduced in both conditions, why some of the previous findings of impaired regional longitudinal function in asymptomatic aortic stenosis could in fact be explained by silent ischaemic heart disease. METHODS AND RESULTS: Prospective follow-up of 104 asymptomatic patients with moderate-severe aortic stenosis defined as an aortic valve area <1.5 cm(2). Patients underwent a thorough clinical work-up, advanced echocardiographic analysis and coronary angiography by MDCT. The combined endpoint was indication for aortic valve replacement (AVR) and sudden cardiac death. During a median follow-up of 2.3 years (interquartile range 1.7-3.6) 43 patients (41%) met the endpoint of indication for AVR. The basal (13.4 ± 3.1% vs. 15.7 ± 3.1%) and mid-ventricular segments (14.9 ± 2.7% vs. 16.2 ± 2.9%) were significantly reduced, but with sparing of the apical segments, in patients who later underwent AVR. In various multivariable Cox regression models, including only BLS, but not GLS, remained an independent predictor of AVR. CONCLUSION: In contrast to GLS, reduced BLS is a significant predictor of future AVR in asymptomatic patients with aortic stenosis, independently of clinical characteristics, conventional echocardiographic measures, and coronary pathology.

Prognostic value of multi-detector computed tomography in asymptomatic aortic valve stenosis.

BACKGROUND: Multi-Detector Computed Tomography (MDCT) is a high-resolution imaging technique with potential additive value in the evaluation of patients with aortic valve stenosis (AS). We aimed to assess the prognostic value of MDCT in asymptomatic patients with AS compared to conventional transthoracic echocardiography (TTE). METHODS: 116 patients with asymptomatic AS (Vmax>2.5m/s assessed by clinical screening TTE, LVEF>50%) were examined with TTE (Vivid e9) and MDCT (Aquilion 320) on the same day. The treating physician was blinded for research protocol defined imaging results. Outcome was defined as indication for aortic valve replacement (AVR) determined by the treating physician or sudden cardiac death. RESULTS: The mean age was 72 (8) years, 27% were women, mean AVA by TTE was 1.01 (0.30) cm(2). Median follow up time was 27 (IQR 19-44) months. Forty seven patients (41%) developed indication for AVR. No patients suffered a sudden cardiac death. AVA and aortic valve calcification were significant univariable predictors of AVR when measured by both TTE and MDCT, whereas left ventricular mass was only significant measured by MDCT. Significant coronary artery disease by MDCT tended to predict future indication for AVR, but this did not reach statistical significance (HR: 1.79 (95% CI 0.96-3.44), p=0.08). CONCLUSION: MDCT derived AVA can be of use as an alternative to TTE derived AVA in patients with asymptomatic AS to predict future clinical indication for AVR.

Association of ischemic heart disease to global and regional longitudinal strain in asymptomatic aortic stenosis.

Longitudinal deformation has been shown to deteriorate with progressive aortic stenosis as well as ischemic heart disease. Despite that both conditions share risk factors and are often coexisting, studies have not assessed the influence on longitudinal deformation for both conditions simultaneously. Thus the purpose of this study was to evaluate the association between subclinical ischemic heart disease and global and regional longitudinal strain in asymptomatic patients with significant aortic stenosis. Prevalent patients with a diagnosis of aortic stenosis at six hospitals in the Greater Copenhagen area were screened for inclusion. A total of 104 asymptomatic patients with moderate-severe aortic stenosis (aortic valve area ≤1.5 cm(2)) fulfilled study criteria and underwent advanced echocardiographic analysis and coronary angiography by multi-detector computed tomography. Angiography revealed coronary stenosis >50% in 31% (n = 32). All regional longitudinal strain measures (apical, mid and basal longitudinal strain) were significant predictors of significant coronary stenosis (>70% stenosis), but only apical and mid longitudinal strain were significant predictors in multivariable analyses independent of aortic valve area, stroke volume index, pro-BNP, valvulo-arterial impedance, body mass index and heart rate. In linear regression models with both aortic valve area and significant coronary stenosis, apical (p < 0.001) and mid (p < 0.01) longitudinal strain were associated to significant coronary stenosis but not aortic valve area. Conversely, basal longitudinal strain was significantly associated to aortic valve area (p = 0.001), but not to significant coronary stenosis. Subclinical coronary artery disease is frequent in moderate and severe aortic stenosis, and should be suspected when regional longitudinal dysfunction is predominant in the apical and mid ventricular segments.

Aortic root, not valve, calcification correlates with coronary artery calcification in patients with severe aortic stenosis: A two-center study.

BACKGROUND: The underlying pathology in aortic stenosis (AS) and coronary artery stenosis (CAS) is similar including atherosclerosis and calcification. We hypothesize that coronary artery calcification (CAC) is likely to correlate with aortic root calcification (ARC) rather than with aortic valve calcification (AVC), due to tissue similarity between the two types of vessel rather than with the valve leaflet tissue. MATERIAL AND METHODS: We studied 212 consecutive patients (age 72.5 ± 7.9 years, 91 females) with AS requiring aortic valve replacement (AVR) in two Heart Centers, who underwent multidetector cardiac CT preoperatively. CAC, AVC and ARC were quantified using Agatston scoring. Correlations were tested by Spearman's test and Mann-Whitney U-test was used for comparing different subgroups; bicuspid (BAV) vs tricuspid (TAV) aortic valve. RESULTS: CAC was present in 92%, AVC in 100% and ARC in 82% of patients. CAC correlated with ARC (rho = 0.51, p < 0.001) but not with AVC. The number of calcified coronary arteries correlated with ARC (rho = 0.45, p < 0.001) but not with AVC. 29/152 patients had echocardiographic evidence of BAV and 123 TAV, who were older (p < 0.001) but CAC was associated with TAV even after adjusting for age (p = 0.01). AVC score was associated with BAV after adjusting for age (p = 0.03) but ARC was not. Of the total cohort, 82 patients (39%) had significant coronary stenosis (>50%), but these were not different in the pattern of calcification from those without CAS. CAC was consistently higher in patients with risk factors for atherosclerosis compared to those without. CONCLUSION: The observed relationship between coronary and aortic root calcification suggests a diffuse arterial disease. The lack of relationship between coronary and aortic valve calcification suggests a different pathology.

Tissue Velocities and Myocardial Deformation in Asymptomatic and Symptomatic Aortic Stenosis.

BACKGROUND: Assessment of myocardial longitudinal function has proved to be a sensitive marker of deteriorating myocardial function in aortic stenosis, demonstrated by both color Doppler tissue imaging and recently by two-dimensional speckle-tracking echocardiography. The aim of this study was to compare velocity (color Doppler tissue imaging) and deformation (two-dimensional speckle-tracking echocardiography) in relation to global and regional longitudinal function in asymptomatic and severe symptomatic aortic stenosis. METHODS: In a cross-sectional design, 231 patients with aortic stenosis were divided into four groups: asymptomatic moderate aortic stenosis (aortic valve area, 1.0-1.5 cm(2); n = 38), asymptomatic severe aortic stenosis (aortic valve area < 1.0 cm(2); n = 66), and symptomatic severe aortic stenosis with preserved (n = 68) and reduced (<50%) left ventricular ejection fraction (n = 59). RESULTS: Among all global (peak systolic s', diastolic e' and a', longitudinal displacement, and global longitudinal strain and strain rate) and regional longitudinal (basal, middle, and apical longitudinal strain and strain rate) parameters, only diastolic e', longitudinal displacement, and basal longitudinal strain (BLS) remained significantly associated with symptomatic status, independent of age, gender, heart rate, aortic valve area, stroke volume index, left ventricular mass index, left atrial volume index, and tricuspid annular systolic plane excursion. Furthermore, in a model with the aforementioned parameters, including e', longitudinal displacement, and BLS, only BLS remained significantly associated with symptomatic status in the entire study population (BLS per one-unit decrease: odds ratio, 1.23; 95% CI, 1.04-1.46; P = .017). Furthermore, patients with BLS < 13% were more likely to be symptomatic (odds ratio, 4.97; 95% CI, 2.6-9.4; P < .001), and no patients with asymptomatic severe aortic stenosis with BLS ≥ 13% were admitted with myocardial infarction or heart failure during follow-up of 1,462 days. CONCLUSIONS: Among the many echocardiographic measures of longitudinal velocity and deformation, BLS has the strongest association with symptomatic status in aortic stenosis, and BLS < 13% is related to adverse outcomes in severe asymptomatic aortic stenosis.

Aortic valve area assessed with 320-detector computed tomography: comparison with transthoracic echocardiography.

To evaluate the diagnostic accuracy of aortic valve area (AVA) assessment with 320-detector Computed Tomography (MDCT) compared to transthoracic echocardiography (TTE) in a population with mild to severe aortic valve stenosis. AVA was estimated in 169 patients by planimetry on MDCT images (AVA(MDCT)) and by the continuity equation with TTE (AVA(TTE)). To generate a reference AVA (AVA(REF)) we used the stroke volume from MDCT divided by the velocity time integral from CW Doppler by TTE (according to the continuity equation: stroke volume in LVOT = stroke volume passing the aortic valve). AVA(REF) was used as the reference to compare both measures against, since it bypasses the assumption of LVOT being circular in the continuity equation and the potential placement error of PW Doppler in the LVOT. The mean (±SD) age of the patients was 71 (±9) years, 113 (67%) were males. Mean AVA(TTE) was 0.93 (±0.33) cm(2), mean AVA(MDCT) was 0.99 (±0.36) cm(2) and mean AVA(REF) was 1.00 (±0.39) cm(2). The mean difference between AVA(TTE) and AVA(MDCT) was -0.06 cm(2), p = 0.001, mean difference between AVA(TTE) and AVA(REF) was -0.06 cm(2), p < 0.001, and mean difference between AVA(MDCT) and AVA(REF) was -0.01 cm(2), p = 0.60. Calcification of the aortic valve quantified by Agatston score, significantly decreased the correlation between AVA(MDCT) and AVA(REF), (r low Agatston = 0.90, r high Agatston = 0.57). MDCT measured AVA is slightly larger than AVA measured by TTE (0.06 cm(2)). The accuracy and precision errors on AVA measurements are comparable for MDCT and TTE. Valvular calcification may primarily affect the accuracy of AVA(MDCT).