bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 2521: A Multicentre Randomized Study comparing Efficacy Of Telmisartan versus Carvedilol In Preventing Atrial Fibrillation Recurrence In Hypertensive Patients.
Authors: Galzerano Domenico , Conforti Gabriele , Breglio Roberto , Caselli Salvatore , Saetta Gabriele , Carbone Giuseppe , Tuccillo Bernardino , Lama Diana , Tammaro Paolo , Capogrosso Paolo
Published: July 2021

Background
: The possibility of addressing blood pressure(BP) control and lower incidence of atrial fibrillation(AF) should be a suitable pharmacological goal in antihypertensive therapy. The renin-angiotensin-aldosterone system (RAAS) play an important role as a mediator of atrial remodeling in AF

AIM:
this prospective , randomized, multicentre study sought to assess the effect of an antihypertensive treatment with Telmisartan (Telm) and Carvedilol (Carv) in preventing the recurrence of AF in hypertensive pts with a history of recent atrial fibrillation.

Methods and Results
: We studied 154 mild hypertensive (SBP>130<160 mmHg and\or DBP>80<100 mmHg) out patients. All pts were in sinus rhytm but with at least from one to four Ecg documented episodes of AF in the previous six months. The two groups didn’t differ dealing with left ventricular(LV) mass, LV Ejection fraction and left atrial diameter. After one week placebo period, they were randomized to telmisartan 80mg once day(od) or to Carv 25 mg od and followed for one year period. BP and 24 hour EKG was monthly recorded. Every pt was asked to report any episode of symptomatic AF and to perform an Ekg as early as possible . 132 pts completed the study ,70 in Telm group and 62 in Carv group.After 12 months the BP mean values were significantly reduced in both group without any difference between the two group. (Telm : 154\97 to 123\75 mmHg P<0.001; Carv Group: 153\94 to 125\78 , p<0,001) Left atrial diameter as assessed by echocardiography was lower in Telm group but didn’t differ statistically significant with Carv Group (Telm: 3,4±2,3 cm ; Carv: 3,6 ±2,4 cm). In 10\70(14,2 %) pts in the Telm group and in 23±62(37,09%) pts in Carv group an episode (symptomatic or asymptomatic )was reported (P<0,005, χ
2
test).

Conclusion:
Telm seems to be more effective than Carv in preventing new episodes of AF in hyp with recurrent AF .
Our
results suggest that the angiotensin II receptor blockers (ARBs), also target the RAAS by binding to angiotensin type 1 (AT
1
) receptors could be favourably interfere the electrical and structural atrial remodeling in hyp pts suggesting an own effect on this phenomen.
Abstract 364: Ottawa Heart Genomic Study: Discovery Of Novel Genes For Coronary Artery Disease By Genome-wide Association Utilizing The 500k SNP Array
Authors: Stewart Alexandre F , McPherson Ruth , Williams Kathryn , Kavaslar Nihan , Rutberg Julie , Doelle Heather , Ewart Gwen , Wells George , Roberts Robert
Published: July 2021

Purpose: To identify genes predisposing to Coronary Artery Disease (CAD). Methods: We selected the unbiased approach of using the genome wide scan association case control method. Using the Affymetrix 500K SNP array that that average a marker every 6,000 base pairs, we estimated that to detect a Minor Allele Frequency (MAF) of ≥ 10%, an odds ratio for risk of > 1.3 with 90% power would require 14,000 subjects (9,000 cases and 5,000 controls). Phase I consists of genotyping of 1,000 cases of early onset CAD and 1,000 asymptomatic older controls. Phase II will determine whether SNPs showing an association in Phase 1 are replicated in 8,000 cases and 4,000 controls. The phenotype is confirmed or excluded by coronary arteriograms obtained by catheterization or multi-slice CT. Cases with diabetes mellitus are excluded.

Results: Initiated in 2005, over one billion genotypes have been performed and analyzed for 1,054 controls and 997 cases completing Phase I. Starting with data on 500,668 SNPs, control genotypes that were monoallelelic (21,668 SNPs) or not in Hardy Weinberg equilibrium were excluded using a false discovery rate (FDR) Q value <0.001 (1,473 SNPs). Individual SNPs with call rates <95% (30,826 SNPs) in cases and controls were excluded, leaving 446,701 SNPs. Fisher’s exact test was used to compare genotypes between cases and controls (FDR Q value <0.05), identifying 2,819 significant SNPs. SNPs with a MAF < 0.01 in both cases and controls (598 SNPs) were removed leaving 2,221 significant SNPs. 14 SNPs in exons were non-synonymous, i.e. cause amino acid substitutions. 53 clusters of SNPs (defined as ≥3 SNPs) within genes and 45 between genes were identified, including one at 9p21.3 that was replicated in multiple independent populations (McPherson et al., Science Express 2007 - in press). In addition, 13 SNPs were identified on the X chromosome. There was no evidence of stratification in our population. SNPs showing significant association with CAD are being assessed in an independent population during Phase II.

Conclusions: This is the first genome wide scan for CAD genes utilizing 500,668 markers. Phase I has identified many genes not previously known to be associated with CAD.
Abstract 365: Genetic Variants in ALOX5 and ALOX5AP are Associated with Reduced Response to Aspirin in African American Families with Premature Coronary Artery Disease
Authors: Herrera-Galeano J. E , Faraday Nauder , Yanek Lisa R , Moy Taryn F , Becker Diane M , Becker Lewis C
Published: July 2021

Background:

ALOX5 (arachidonate 5-lipoxygenase) and ALOX5AP (arachidonate 5-lipoxygenase activating protein) are involved in the production of leukotrienes, which may interact with cyclo-oxygenase to alter the formation of thromboxane. Reduced suppression of thromboxane production by aspirin (ASA) was associated with worse cardiovascular outcomes in the HOPE study. We therefore examined whether genetic variants in ALOX5 or ALOX5AP could modify the effect of ASA on thromboxane production.

Methods:

We measured urinary 11-dehydro-thromboxane B2 (UTX) levels after 2 weeks of ASA, 81 mg/day, in 1546 healthy individuals from 2-generational families with premature coronary heart disease (CHD) (n=573 African Americans from 120 families; n = 973 whites from 202 families). We genotyped 18 SNPs in ALOX5 and 10 SNPs in ALOX5AP with about 4 kb density. FBAT software was used to determine whether any SNPs were associated with the upper quartile of UTX (the least ASA suppression). The analysis was adjusted for known risk factors such as smoking, high blood pressure, sex, age, obesity, fibrinogen, diabetes and cholesterol.

Results:

We obtained significant associations between SNPs in both genes and the upper quartile of UTX in African Americans, but not in whites (Table

). The SNPs were not in linkage disequilibrium except for rs7896431 and
rs901681
(r
2
=0.80) in African Americans.

Conclusion:

Both the ALOX5 and ALOX5AP genes have polymorphisms associated in African Americans with less suppression of UTX by ASA. The response to ASA may be affected by an interaction between the leukotriene and thromboxane pathways.

Association of SNPs and the upper quartile of UTX
Abstract 2539: Relationship of Aortic Wall Thickness and Distensibility with Subclinical Measures of Cardiovascular Disease: The Multi-Ethnic Study of Atherosclerosis
Authors: Bahrami Hossein , Lima Joao A , Polak Joseph F , Pearson Gregory D , Liu Kiang , Bluemke David A
Published: July 2021

Background:
While increased carotid intima-media thickness (IMT) is considered an independent risk factor for cardiovascular disease (CVD), little is known about the relationship of aortic thickness (AWT) and aortic distensibility (AD) with CVD risk factors. We studied the association of these aortic parameters with other measures of subclinical CVD.

Methods:
The Multi-Ethnic Study of Atherosclerosis (MESA) includes 6,814 participants, aged 45– 85 years; white, African-American, Hispanic, and Chinese. AD and AWT were measured by MRI. Average and maximum AWT of the proximal descending thoracic aorta were used as two measures of AWT. AD was calculated as the difference in aortic cross-sectional area indexed by diastolic cross-sectional area and average pulse pressure. IMT of the common and internal carotid arteries were determined by high-resolution B-mode ultrasonography and LV mass was determined by MRI. Phantom-adjusted Agatston calcium score from CT images was used to define coronary artery calcification (CAC).

Results:
In univariable analyses, higher carotid IMT, ankle-brachial index (ABI) <0.9, CAC score, LV mass, and presence of coronary calcium were associated with lower AD and higher AWT (table

). However, in multivariable analyses, the only measures of subclinical CVD that had significant associations with both AD and AWT were LV mass and carotid IMT, while ABI was associated with only AWT. After adding age to the models, CAC score was no longer associated with either AD or AWT. The relationship between CAC score and AD varied by ethnicity; higher CAC score was associated with higher AD only in African Americans.

Conclusions:
AD and AWT are related to carotid IMT and LV mass, even after controlling for traditional risk factors. The associations of AD and AWT with CAC appears to be mainly due to their relationship with conventional risk factors, particularly age. Overall, AWT and AD may have closer relationship with LV mass than with subclinical atherosclerosis.
Abstract 2564: Predictors of Early Stent Thrombosis in Patients with Acute Coronary Syndromes in the Drug-Eluting Stent Era: Analysis from the ACUITY trial
Authors: Aoki Jiro , Stone Gregg W , Mehran Roxana , Moses Jeffery , Bertrand Michel E , Lincoff A. Michael , Ohman E. Magnus , White Harvey D , Parise Helen , Leon Martin B , Lansky Alexandra J
Published: July 2021

Objectives.
The purpose of this study was to evaluate the incidence and predictors of early (<30days) stent thrombosis (ST) in pts with acute coronary syndromes (ACS) in the drug-eluting stent (DES) era.

Background.
Predictors of ST, including detailed quantitative coronary angiographic (QCA) analysis parameters have not been carefully investigated in pts with ACS.

Methods.
In the prospective, multicenter ACUITY trial, a total of 7,179 pts with moderate and high risk ACS were treated with stents (66.4% of whom received at least 1 DES). Among these pts, core lab QCA was performed in 3,518 (49.0%) pts.

Results.
Within 30 days, 101 pts (1.4%) suffered definite or probable ST by the Academic Research Consortium (ARC) definition. Pts with ST were older and had a higher prevalence of diabetes mellitus, prior MI and renal insufficiency, higher TIMI risk scores and ST segment deviation compared to those without ST. By core lab QCA pts with ST were more likely to have greater overall coronary artery disease burden, procedural angiographic complications, suboptimal final angiographic results, implantation of ≥2 stents, and use of aspirin <50% of time within 30 days. A final stent diameter stenosis >20% and implantation of ≥2 stents were the strongest independent predictors of early ST (Table

). DES use was not significantly different between pts with and without ST (62.4% vs. 66.5%, P=0.40).

Conclusions.
Early ST in pts with ACS is frequent with both BMS and DES, and is predicted by use of multiple stents and suboptimal angiographic results. Avoiding multiple stents and improving operator technique and antiplatelet compliance may minimize the risk of early ST in ACS.

Multivariate predictors of early ST
Abstract 371: Prevalence and Spectrum of Thin Filament Mutations in 1025 Patients with Hypertrophic Cardiomyopathy
Authors: Will Melissa L , Landstrom Andrew P , Bos J. Martijn , Gersh Bernard J , Ommen Steve R , Ackerman Michael J
Published: July 2021

Background
Recently, genetic testing for sarcomeric hypertrophic cardiomyopathy (HCM) became a commercially available diagnostic test involving analysis of 8 HCM-associated myofilament genes, four of which encode thin filament proteins -
TNNT2-
encoded cardiac troponin T,
TPM1
-encoded alpha tropomyosin,
TNNI3-
encoded cardiac troponin I, and
ACTC-
encoded cardiac actin. Compared to the two most common subtypes of sarcomeric HCM, much less is known about the prevalence and spectrum of thin filament HCM.

Methods
Comprehensive open reading frame/splice site mutational analysis of these 4 thin filament-encoding genes was performed, using polymerase chain reaction, denaturing high performance liquid chromatography, and direct DNA sequencing, on the largest assembled cohort of unrelated patients (N = 1025, 61% male, 49 ± 18 years at diagnosis, maximal left ventricular wall thickness, LVWT, 22.3 ± 7 mm) with clinically diagnosed HCM that were seen at the Mayo Clinic.

Results
Nineteen distinct missense mutations, involving conserved residues and absent in 600 reference alleles, were identified in 36 of 1025 patients (3.5%) including TNNT2 (16 patients), TNNI3 (12), TPM1 (7) and ACTC (1). Among these 36 patients with thin filament-HCM, their average age at diagnosis was 33.2 ± 16 years and the average LVWT was 21 ± 8 mm. Eighteen patients (50%) had evidence for familial HCM and 13% had a positive history for sudden cardiac death. Only 13 patients (36%) had a reverse septal curvature by echocardiography. Instead, 12 patients (34%) had either sigmoidal or neutral septal contours and 9 patients (25%) had apical variant-HCM.

Conclusion
Here, we present the largest cohort analysis of thin filament HCM to date and detail the prevalence and spectrum of HCM-associated mutations in these 4 genes. Compared to the strong association between reverse septal curvature and thick filament HCM, the septal morphology associated with thin filament HCM was quite varied. Contrary to published estimates of the frequency of troponin T-HCM (5 – 10%) and the other subtypes of thin filament HCM, the prevalence of thin filament HCM was very low in this cohort. If confirmed in other cohorts, a revised cascade for HCM genetic testing should be considered.
Abstract 2575: Abnormal Regional Right Ventricular Mechanics In Acute Myocardial Infarction Without Evidence Right Ventricular Involvement by Wall Motion Analysis or Electrocardiography
Authors: Pinheiro Aurelio C , Liang Hsin-Yueh , Dimaano Veronica L , Eulitt Patrick , Corretti Mary , Schulman Steven , Abraham Theodore P
Published: July 2021

Background:
Right ventricular (RV) involvement portends a worse prognosis in acute myocardial infarction (AMI). Tissue Doppler strain echocardiography (TDSE) allows accurate, sensitive quantitation of RV mechanics. We compared TDSE to echocardiographic wall motion abnormality (WMA) and electrocardiography (EKG) in detecting RV dysfunction in AMI.

Methods and Results:
We prospectively imaged 55 subjects (40 consecutive patients with AMI and 15 healthy controls). All patients had troponin profiles, coronary angiography, and echocardiography and TDSE. Coronary artery stenosis >70% was considered significant. We excluded 7 AMI with multiple vessel disease. We separated the rest into those with left anterior descending related AMI (LAMI) and right coronary artery related AMI (RAMI). EKG revealed RV AMI in 1 patient. None had RV WMA. RV free wall base and mid-apical segments were analyzed separately. Systolic strain (sS) and systolic (SRs) and early diastolic (SRe) strain rates were lower in RAMI compared to controls with the predominant abnormality in the basal RV with preserved mid-apical mechanics. LAMI mechanics were similar to controls except for lower SRe.

Conclusions:
TDSE reveals significantly abnormal RV mechanics in RAMI in the absence of WMA or RV related EKG abnormality. TDSE offers a superior alternative to EKG and conventional echocardiography for RV evaluation in AMI.
Abstract 2603: Gender Is An Important Determinate For The Predictive Value Of NT-proBNP In Patients Presenting With An Acute Coronary Syndrome
Authors: Weber Michael W , Keil Eva , Stanisch Michael , Nef Holger , Moellmann Helge , Kleine Christian , Dippel Bianca , Elsaesser Albrecht , Hamm Christian
Published: July 2021

Background
BNP und NT-proBNP provide prognostic information in patients with acute coronary syndromes (ACS). Even though it is generally accepted, that gender, age and atrial fibrillation are important determinants for BNP respectively NT-proBNP values, there is no data available evaluating the impact of those factors on the predictive value of those biomarkers. Therefore it was our aim to evaluate the predictive value of NT-proBNP for mortality after an ACS in association to gender, age and rhythm

Methods and results
We included 1123 consecutive patients (age 64±12 years; 342 females) with an ACS within the last 48 hours. Follow up data after median of 204 days were available for 1115 (99%) patients. During the follow up 77 (6.8%) patients died. NT-proBNP values on admission were higher in patients who deceased compared to those who survived (2047 (576 –5624) pg/ml vs. 465 (127–1519) pg/ml; p<0,001). The AUC of the ROC curve for NT-proBNP as a predictor for mortality was 0.714 (p<0.001) and an optimised cut-off value of 1815 pg/ml could be calculated. Patients with NT-proBNP above this cut-off had a significantly higher mortality rate (16% vs. 4%; p<0,001; Log Rank 48; p<0,001)). Even though patients with AF had higher NT-proBNP values as those patients with SR (1952 (770 – 4070) pg/ml vs. 452 (121–1492) pg/ml) NT-proBNP at the same cut-off value of 1815 pg/ml was highly discriminative for mortality (27.9% vs. 7.5%; p<0.022; Log Rank 5.7; p=0,017). Patients with an age above 65 years had higher NT-proBNP values as compared to patients younger than 65 years (894 (255–2642) pg/ml vs. 279 (75–945) pg/ml; p<0,001). However the predictive value of NT-proBNP in both age groups was comparable. Women had higher NT-proBNP values as compared to men (966 (237–2549) pg/ml vs. 407 (102–1273) pg/ml; p<0,001). But in dissimilarity, in women NT-proBNP values above 1815 pg/ml were not associated with a higher mortality and thus were without predictive value (10,6% vs. 6,8%; p<0,304; Log Rank 1,556; p<0,212).

Conclusion
Gender, age and rhythm are important determinants for NT-proBNP values of patients presenting with an ACS. However, only gender had impact on the predictive value of NT-proBNP for mortality. In women cut-off values need to be adopted.
Abstract 2640: Clinical Characteristics and Risk Stratification in Symptomatic and Asymptomatic Patients with Brugada Syndrome - Multi-center Study in Japan-
Authors: Takagi Masahiko , Yokoyama Yasuhiro , Aonuma Kazutaka , Aihara Naohiko , Hiraoka Masayasu
Published: July 2021

Background Neither the clinical characteristics nor risk stratification of symptomatic and asymptomatic patients with Brugada syndrome have been clearly determined. We compared clinical and ECG characteristics of symptomatic and asymptomatic patients with Brugada syndrome to identify new markers for distinguishing high- from low-risk patients.

Methods A total of 216 consecutive individuals with Brugada syndrome (mean age 52±14 years, 197 males) were enrolled in the Japan Idiopathic Ventricular Fibrillation Study (J-IVFS). Clinical and ECG characteristics were compared among 3 groups of patients: VF group; patients with aborted sudden death and documented VF (N=34), Syncope (Sy) group; patients with syncope without documented VF (N=70), and Asymptomatic (As) group; subjects without symptoms (N=112). Comparisons were made among the 3 groups as well as between the symptomatic (VF/Sy) and asymptomatic (As) groups. Short-term prognosis was also compared among the 3 groups, and between the VF/Sy and As groups.

Results 1) Clinical characteristics: incidence of past history of AF was significantly higher in the VF and Sy groups than in the AS group (26, 26, and 12 %, respectively; [p=0.04]), though no other clinical parameters differed among the groups. 2) On resting 12-lead ECG, r-J interval (interval from QRS onset to J point) in lead V2 and QRS duration in lead V6 were highest in the VF group (104, 98, and 92 msec in V2 [p<0.001]; 106, 103, and 94 msec in V6 [p<0.0001], respectively, VF vs. Sy vs. As). 3) Positive late potential and inducibility of VF by EPS did not differ in incidence among the 3 groups. 4) Clinical follow-up: during a mean follow-up of 36±16 months, incidence of cardiac events (sudden death and/or VF) was higher in the VF/Sy groups than in the As group (29, 8, and 0 %, respectively [p<0.001]). Multivariate analysis showed that the frequencies of r-J interval ≥ 90 msec in lead V2 and QRS duration ≥ 90 msec in lead V6 were significantly higher in patients with cardiac events (p=0.02, 0.02, respectively).

Conclusions In symptomatic patients, prolonged ventricular depolarization in precordial leads of the ECG was prominent in the VF group, and this sign can be used to distinguish high- from low-risk patients with Brugada syndrome.
Abstract 2655: Correlates Of Aortic Valve Calcification In Aortic Stenosis: Insights From The Astronomer Study
Authors: Chan Kwan , Tam James , Sochowski Randall , Dumesnil Jean , Giannoccaro Peter , Jue John , Pandey Shekhar , Joyner Cam , Teo Koon
Published: July 2021

Aortic valve calcification (AVC), a common finding in aortic stenosis (AS), is a predictor of rapid AS progression and increased risk of cardiac events. We evaluated clinical, echocardiographic and biochemical correlates of AVC to gain insight into pathogenesis and to identify potential targets for intervention.

Methods: The ASTRONOMER study (Aortic Stenosis Progression

Observation: Measuring Effects of Rosuvastatin) is a randomized trial to assess cholesterol lowering using rosuvastatin on AS progression in mild to moderate AS. Patients with indication for cholesterol lowering were excluded. Severity of AVC was classified as none, mild, moderate and severe according to published criteria.

Results: 272 patients (167 men, 105 women; mean age 58.1±13.6 years) have been enrolled with peak and mean AV gradients 41±11 and 23±8 mmHg respectively. Patients with none or mild AVC were compared with patients with moderate or severe AVC (Table

). ACE-I= angiotensin converting enzyme inhibitor, BAV=bicuspid aortic valve, BP=blood pressure, HDL-C=high-density lipoprotein cholesterol, LDL-C= low-density lipoprotein cholesterol, MAC=mitral annular calcification. Regression analysis showed that AVC was associated with age (p<0.001), male sex (p=0.01), systolic BP (p=0.002), LDL-C (p=0.05), MAC (p=0.01) and tricuspid AV (p=0.001). With adjustment for age, correlates of AVC were male sex with odds ratio (OD) 2.04, p<0.01, systolic BP (OD=1.02, p=0.096), and LDL-C (OD 1.44, p=0.077).

Conclusions: In patients with AS, age and male sex are the main correlates of AVC. After adjusting for age, AVC is not associated with AV morphology but appears to be related to male sex, BP and LDL-C. Thus BP and LDL-C are promising modifiable targets to prevent AVC which in turn should reduce AS progression.
Abstract 376: A Potential Role for TRAIL in the Pathogenesis of Pulmonary Arterial Hypertension
Authors: Lawrie Allan , Southwood Mark , Suntharalingam Jay , Francis Sheila E , Crossman David C , Morrell Nicholas W , Newman Christopher M
Published: July 2021

Pulmonary arterial hypertension (PAH) is a life threatening disease characterised by the narrowing and occlusion of small pulmonary arteries. Endothelial cell (EC) loss, and increased proliferation and migration of pulmonary artery smooth muscle cells (PA-SMC) are strongly implicated in disease pathogenesis. Tumor necrosis factor (TNF)-Related Apoptosis-Inducing Ligand (TRAIL) induces EC apoptosis and SMC migration, consistent with an important role in vascular biology. TRAIL is a type II TNF family transmembrane protein, whose extracellular domain can be proteolytically cleaved from the cell surface to act as a soluble cytokine (sTRAIL) capable of binding to five TRAIL receptors, (TRAIL-R1– 4) and osteoprotegerin (OPG). We hypothesised that TRAIL expression is increased in PAH and that this contributes to the excessive migration of PA-SMC that characterises this condition. TRAIL gene expression was studied in microarrays of PA-SMC RNA isolated from idiopathic PAH (IPAH) patients, and from the lungs of monocrotaline-treated (Mct) rats. Immunohistochemistry was performed to localise TRAIL in both human and rat lung sections. To investigate the functional effects of TRAIL in PA-SMC, human PA-SMC were incubated with recombinant human TRAIL (1–50 ng/ml) for 5h and migration assessed by transwell assay. TRAIL gene expression was 10-fold higher in PA-SMC from IPAH patients compared to controls. Moreover, strong TRAIL immunoreactivity was observed in pulmonary vascular lesions from IPAH patients but not in vessels from patients undergoing lobectomy for lung carcinoma. In the Mct-rat model of PAH we found a 20-fold increase in TRAIL gene expression and a 2-fold increase in protein from whole lung extracts. Immunohistochemistry revealed strong TRAIL immunoreactivity within the muscularised pulmonary arteries of Mct-treated but not saline-treated control rats. Recombinant TRAIL was found to induce a dose dependent (maximum 3 fold) increase in migration of human PA-SMC compared with cells incubated with 0.1% serum alone. These data suggest that TRAIL may be an important molecule in the pathogenesis of PAH. Further studies to elucidate the regulation and function of this molecule in PAH are warranted.
Abstract 2681: Mutations in Smooth Muscle-Specific Contractile Proteins Cause Familial Thoracic Aortic Aneurysms and Dissections and Lead to Increased IGF-1 Expression
Authors: Papke Christina L , Pannu Hariyadarshi , Guo Dong-Chuan , Avidan Nili , Tran-Fadulu Van , Presley Caroline A , Milewicz Dianna M
Published: July 2021

Aortic aneurysms and dissections are the most common disorders affecting the aorta, and are a major cause of morbidity and mortality in the United States. Familial thoracic aortic aneurysms and dissections (FTAAD) are inherited in an autosomal dominant manner with variable expression and decreased penetrance. The disorder is genetically heterogeneous with four loci and three genes identified. Mutations in either
TGFBR2
, encoding the transforming growth factor β (TGF-β) type II receptor, or
MYH11
, encoding the smooth muscle cell (SMC)-specific β-myosin heavy chain, were previously found to cause FTAAD. Recently, positional cloning identified smooth muscle α-actin (
ACTA2
) mutations as a novel cause in 10% of FTAAD. Mutations in
ACTC
and
MYH7
cause hypertrophic cardiomyopathy (HCM), characterized by myocyte disarray and upregulation of mitotic and trophic factors. Histologic examination of aortic tissue from patients with
ACTA2
(n = 6) and
MYH11
(n = 2) mutations revealed SMC disarray in the aortic media similar to that seen in HCM. Furthermore, we hypothesized that mutations in
ACTA2
and
MYH11
cause a similar increase of mitotic and trophic factors in SMCs. The expression of two factors known to be increased in HCM, TGF-β1 and insulin-like growth factor 1 (IGF-1), were analyzed in patients’ aortic SMCs and dermal myofibroblasts. No changes in TGF-β1 were found; however, both mRNA, as measured by Q-PCR (p<0.05), and protein levels, as assessed by immunostaining, of IGF-1 were markedly increased in
MYH11
and two
ACTA2
mutant SMCs and aortic tissue compared with control SMCs and tissue. Differentiation of dermal fibroblasts into myofibroblasts was accomplished using TGF-β1 treatment; myofibroblast differentiation was confirmed by assessing α-actin mRNA and protein levels in untreated vs. TGF-β1-treated fibroblasts. Upon differentiation, patients’ myofibroblasts (n = 3) demonstrated increased IGF-1 expression compared with controls (p<0.05), similar to the increased IGF-1 expression by SMCs. In conclusion, IGF-1 secretion is increased in response to defects in SMC contractile proteins in SMCs and myofibroblasts. Future studies will clarify the role of IGF-1 in FTAAD and identify the pathways leading to increased IGF-1 expression.
Abstract 2703: Clinical and neurohormonal correlates and prognostic value of Kansas City Cardiomyopathy Questionnaire in patients with chronic heart failure
Authors: Nikolaou Maria , Parissis John , Farmakis Dimitrios , Bistola Vasiliki , Venetsanou Koula , Kourea Kallirhoe , Filippatos Gerasimos , Kremastinos Dimitrios
Published: July 2021

Chronic heart failure (CHF) is characterized by limited exercise activity, enhanced immune activation, and increased morbidity and mortality. Although quality of life and physical activity assessed by Kansas City Cardiomyopathy Questionnaire (KCCQ functional and overall) have been used for the clinical evaluation of CHF patients, the prognostic value as well as the relationship of this questionnaire with neurohormonal/immune activation remain uknown.

Methods:
One hundred thirty seven consecutive stable CHF patients (aged 64 ± 12 yrs, mean NYHA class: 2.9 ± 0.6, mean left ventricular ejection fraction: 26±7% ) were evaluated by the above questionnaire, Zung 20-item self rating and Beck Depression Inventory (BDI) scales, Duke physical activity score, plasma BNP, plasma cytokines (IL-6, IL-10 and TNF-a) and 6-min walking test. Patients were monitored for a 8-month follow-up period for disease progression defined as death and/or hospitalization.

Results:
The mean KCCQ functional and overall scores were 44±20% and 33±19%, respectively. Patients (n=41) with KCCQ overall score <50% had significantly higher Zung (46±10 vs 34±9, p<0.01) and BDI (18±10 vs 8±6, p<0.01) scales, plasma BNP (900±801 vs 543±374 pg/ml, p<0.05) and plasma IL-6 (12.7±7 pg/ml vs 8.5±6.4 pg/ml, p<0.05) as well as lower DUKE score (15±10 vs 28±13, p<0.01), 6-min walking distance (259±200 vs 363±113 m, p<0.001) and plasma anti-inflammatory cytokine IL-10 (6.1±3.2 pg/ml vs 9.4±5.4 pg/ml, p <0.05) as compared to those (n=96) with score >50%. KCCQ overall score was significantly corellated with plasma BNP levels (r=-0.42, p<0.01), 6-min walking distance (r=0.47, p<0.01) and BDI scale (r=-0.61, p<0.001). Finally, patients with KCCQ overall score >50% had longer event-free survival (182±13 vs 122±15 days, p<0.05) than those with score <50%.

Conclusion:
KCCQ is a valuable tool for the evaluation of severity of clinical and emotional symptoms of CHF patients, closely related with their neurohormonal/immune activation and seems to have important prognostic value in CHF.
Abstract 2713: Comparison of MRI Myocardial Tissue Tagging and Tissue Doppler Imaging for Assessment of Mechanical Dyssynchrony
Authors: Bilchick Kenneth C , Helm Robert H , Kessler Kristy L , Hefter Gail , Capriotti Anne R , Judge Daniel P , Russell Stuart , Osman Nael F , Abraham Theodore , Lardo Albert C
Published: July 2021

Background:
Echocardiographic (EC) indices of mechanical dyssynchrony (MD) are based largely upon longitudinal strain, whereas magnetic resonance imaging myocardial tissue tagging (MRI-MT) assessment is based on circumferential strain, the latter being the primary direction of myocardial contraction.

Methods:
We sought to compare cardiac MRI studies with an EC protocol using 2D imaging, tissue Doppler imaging (TDI), and M-mode in 32 subjects. Absolute strain, time to peak strain in 6 segments, TDI septal-to-lateral delay (SLD; MD if ≥ 70 ms), and M-mode septal-to-posterior wall motion delay (SPWMD; MD if ≥ 130 ms) were measured and compared to the MRI-MT-based CURE (circumferential uniformity ratio estimate, CURE; 0 –1, 0 = asynchrony, 1 = perfect synchrony; MD if < 0.75), which recently has been shown to predict clinical CRT response.

Results:
The 8 control subjects (normal QRSd; CURE 0.975 ± 0.01; SLD 26 ± 27 ms) had less MD by MRI-MT (p = 0.0001) and TDI (p = 0.04) as compared to 24 subjects with ejection fraction ≤ 35% (QRSd 135 ≤ 35 ms; CURE 0.695 ± 0.17; SLD 59 ± 39 ms). There was a moderate correlation between TDI and MRI-MT (R = 0.62), with a discordance rate of 22% overall and 25% in cardiomyopathy subjects, in some cases due to abnormal CURE with normal SLD and, in others, normal CURE with abnormal SLD. The M-mode assay (SPWMD) could not be assessed in 10 patients with septal akinesis (AK), although there was MD by TDI and MRI-MT in most of these subjects. In the patients without AK, the discordance rate between TDI and M-mode was 33%.

Conclusions:
MRI-MT assessment of circumferential strain and MD is complementary to TDI with a good correlation, but also a significant discordance rate.
Abstract 2719: Left Ventricular Dyssynchrony Is A Strong Independent Predictor Of Response To Cardiac Resynchronization Therapy
Authors: van Bommel Rutger J , Ypenburg Claudia , Bleeker Gabe B , van der Wall Ernst E , Schalij Martin J , Bax Jeroen J
Published: July 2021

Background
Recent studies have demonstrated that response to cardiac resynchronization therapy (CRT) is related to the presence of left ventricular (LV) dyssynchrony before implantation. A cutoff-value for LV dyssynchrony of 65 ms has been proposed, but this value has not been tested in prospective cohorts.

Methods
Two hundred and twenty consecutive patients (172 male, 60% ischemic cardiomyopathy) undergoing CRT were included. Clinical and echocardiographic parameters were assessed at baseline and after 6 months of CRT. Clinical improvement was defined as an improvement in 1 or more NYHA class and increase ≥ 25% in walking distance. Echocardiographic response was defined as a decrease in LV end-systolic volume ≥ 15%. LV dyssynchrony was assessed with tissue Doppler imaging (TDI) and calculated as the maximum time delay between the peak systolic velocities of 4 opposing basal walls.

Results
At 6 months follow-up, 143 patients (65%) showed clinical response to CRT. Responders and non-responders had comparable baseline characteristics, except for more LV dyssynchrony (93 ± 49 ms vs. 57 ± 43 ms), longer QRS duration (159 ± 31 ms vs. 142 ± 30 ms), larger LV volumes and lower LV ejection fraction (24 ± 7% vs. 26 ± 7%, all p < 0.05) in responders. Multivariate analyses showed that LV dyssynchrony was the only independent predictor for clinical response to CRT (Table

). LV dyssynchrony of ≥ 65 ms predicted clinical response to CRT with a sensitivity of 90% and a specificity of 74%. Furthermore, LV dyssynchrony of ≥ 65 ms predicted echocardiographic response at 6 months with a sensitivity of 76% and a specificity of 64%.

Conclusion
LV dyssynchrony ≥ 65 ms, as assessed with TDI, is a strong predictor of clinical and echocardiographic response to CRT in patients with moderate to severe heart failure.

Multivariate analysis predicting clinical response to CRT
Abstract 2721: Linkage of Left Ventricular Outflow Tract Obstruction to Xq28 in 3 French-Canadian Pedigrees
Authors: Provost Sylvie , Chetaille Philippe , Siles Ana , Thibeault Maryse , Bureau Nathalie , Riopel Kathleen , Mercier Jocelyne , Poisson Virginie , Leclerc Séverine , Jaeggi Michelle , Houde Christine , Miro Joaquim , Bigras Jean-Luc , Dubé Marie-Pierre , Richter Andrea , Andelfinger Gregor
Published: July 2021

BACKGROUND: Statistical genetic analysis of cohorts with left ventricular outflow tract obstruction (LVOTO) shows high heritability of such lesions. We have identified three X-linked French-Canadian pedigrees with a total of 54 family members with multiple cases of LVOTO and septal defects.

AIMS: The aim of this study was to evaluate the three pedigrees with LVOTO and septal defects for genetic linkage to the X chromosome.

METHODS: Detailed family history, physical exam, ECG, echocardiography and chart review was performed. Informed consent was obtained from all participants. Genomic DNA was isolated from peripheral blood samples. Twenty-four STR markers from the X chromosome were genotyped. We used a dominant genetic model with the following penetrances: 0.99 for homozygous women, 0.75 for heterozygous women, 0.99 for hemizygous men. Phenocopy rate was set to 0.01 and disease allele frequency to 0.001. Reference allele frequencies from the Quebec population were used. Analyses were performed with MLINK and MERLIN.

RESULTS: Sixteen family members were affected (13 males, 3 females). Predominant lesions were atrial (n = 5) and ventricular (n = 6) septal defects, coarctation (n = 4) and aortic lesions (stenosis (n = 4), bicuspid/abnormal aortic valve (n = 6)), as well as mitral valve lesions (n = 4). Males had a high incidence of supraventricular arrhythmias postoperatively (4 with atrial flutter/fibrillation, one with ICD implantation). LOD scores above 2 were obtained in parametric two-point linkage analysis for 3 markers in the Xq28 region. Multipoint non-parametric linkage analysis confirmed these results with a NPL score of 9.1 (P < .00001) over a STR marker in intron 13 of the F8C gene. Haplotype analysis allowed the definition of a candidate interval flanked by marker DXS8069 spanning to the telomeric end of Xq.

CONCLUSIONS: By analysing 3 multi-generation French-Canadian pedigrees, we mapped a syndrome of LVOTO and septal defects to the Xq28 region. Further work will refine our candidate region with dense SNP coverage to search for a shared haplotype identical by descent between the three French Canadian families, to complete the sequencing of candidate genes including FLNA, and to search for a possible founder effect in our population.
Abstract 2736: Mutations In The Nonpore Region of The HERG Gene Are at Risk of Acquired Long QT Syndrome
Authors: Sakamoto Yuichiro , Ino Hidekazu , Fujino Noboru , Uchiyama Katsuharu , Hayashi Kenshi , Sakata Kenji , Masuta Eiichi , Funada Akira , Tsubokawa Toshinari , Nakasima Keisuke , Higasida Haruhiro , Yamagishi Masakazu
Published: July 2021

Introduction
: Mutations involving the
KCNH2
gene in HERG channel are responsible for type2 LQTS. Previous study showed patients with mutations in the pore region of the HERG gene are markedly increased risk for arrhythmia-related cardiac events compared with patients with nonpore mutations. However, a few data exist regarding mode of onset and frequency in arrhythmic events of mutations in the nonpore regions of the HERG channel.

Hypothesis
:We hypothesized that patients with mutations in the nonpore regions of the HERG gene increase risk for cardiac events under a specific condition.

Methods:
We examined 104 unrelated subjects with LQTS. Genetic analysis of
KCNH2
gene was performed using standard genetic tests for probands and families of genotyped ones.Between subjects with and without pore mutations,difference in clinical characteristics such as QTc intervals, LQT score and major cardiac events are evaluated by standard statistical methods.

Result:
We identified 7 LQT2 patients with 3 pore mutations and 17 patients with 7 nonpore mutation, and evaluated clinical characteristics and characterized the electrophysiological properties of these mutations. The baseline QTc intervals were significantly longer with pore than with nonpore mutations (513 ± 60ms vs. 479 ± 21ms, p<0.01). The LQTS scores determined by Schwartz’s criteria were also significantly higher with pore mutations (4.5 ± 1.2 vs. 2.9 ± 1.2, p<0.01). However the frequency of LQTS-related cardiac events with nonpore mutaion was as high as with pore mutations (57 % vs. 30 %, N.S). Significantly 4 of 5 cardiac events with nonpore mutations occurred under medications (Probucol) or conditions (Hypokalemia) known to favor QT prolongation, although only 1 of 4 cardiac events with pore mutations did. Electrophysiological study revealed that the tail current amplitude through one nonpore mutant channel(M124T)was significantly decreased as compared that of WT HERG channel and Probucol significantly inhibited M124T HERG channels.

Conclusions:
These data demonstrate that LQT2 patients with nonpore mutations are also at high risk of arrhythmia-related events in the presence of drugs or other environmental stressors.
Abstract 2741: Paradoxical Reduction in Pulse Wave Reflection Following Maximal Exercise in Patients with Type 2 Diabetes Mellitus: Association with Exercise Central Blood Pressure
Authors: Sacre Julian W , Holland David , Sharman James E
Published: July 2021

Background:
Patients with type 2 diabetes mellitus (T2DM) have increased large artery stiffness and exaggerated brachial and central systolic blood pressure (SBP) responses to exercise. Elevations in exercise central SBP may be a result of increased arterial wave reflections and this study aimed to test this hypothesis.

Methods:
Maximal exercise stress tests were conducted in 50 T2DM patients (55 ± 8y, 70% males) and 50 controls (56 ± 8y, 70% males) matched by age, gender, maximal exercise brachial SBP and heart rate. Brachial and central BP were measured at rest and immediately post-exercise. Augmentation index (AIx), augmented pressure (AP; markers of wave reflection) and central SBP were recorded by radial tonometry.

Results:
Despite no significant differences between groups in maximal exercise brachial or central SBP, AIx and AP were significantly lower in T2DM patients (Table

). Exercise central SBP was inversely and independently associated with exercise AIx in the T2DM patients (β= -0.32; p=0.05) but not controls (β= -0.10; p=0.49). The presence of T2DM was also identified as a weak but significant independent determinant of exercise AIx (β= -0.19) and central SBP (β= 0.10; p<0.05 both).

Conclusions:
Patients with T2DM have 1) a paradoxical reduction in wave reflection at maximal exercise and 2) a significant inverse association between wave reflection and exercise central SBP that is not observed in controls. The reduced reflected pressure waves may indicate an increase in peripheral vasodilation to offset high exercise central BP.

Exercise hemodynamics in T2DM patients and controls
Abstract 2744: The 24-hour Blood Pressure Profile of Naproxcinod, a First-in-Class Cyclooxygenase Inhibiting Nitric Oxide Donator, Compared with Naproxen in Stable Hypertensive Subjects
Authors: Townsend Raymond , Bittar Neville , Rosen Jeffrey , Smith William , Ramsay Andrea , Chrysant Steven , Weiss Robert , Frayssinet Hayet , Duquesroix Brigitte
Published: July 2021

Background
: Naproxcinod is a first-in-class Cyclooxygenase Inhibiting Nitric Oxide Donator (CINOD) with anti-inflammatory and analgesic properties. Naproxcinod inhibits both COX-1 and COX-2 enzymes. It is well recognized that NSAIDs and coxibs may elevate blood pressure (BP) and antagonize the lowering effect of anti-hypertensive medications to an extent that may increase hypertension-related morbidity. Nitric oxide donation by naproxcinod may improve the BP profile of this novel compound. The objective of this Ambulatory Blood Pressure Monitoring (ABPM) study was to compare naproxcinod and naproxen.

Methods
: We performed an 8-week, double-blind, randomized, cross-over study. Eligible subjects were between 50 and 75 years of age, had stable hypertension (≤2 different antihypertensive drug classes) and were not currently taking NSAIDs. Subjects randomly received either naproxcinod 750 mg bid or naproxen 500 mg bid for 2 weeks, with 2 weeks of placebo before and in between the active treatment periods. A 24-hour ABPM was performed at the start and end of each of the two active treatment periods, in total 4 ABPMs per subject.

Results
: A total of 131 subjects were enrolled at 15 US sites and 120 were included in the modified ITT analysis. A difference of 1.9 mm Hg between the observed least square (LS) mean changes from baseline in both average 24-hour SBP (SE=1.14; p=0.101) and DBP (SE=0.69; p=0.007) in favor of naproxcinod as compared to naproxen was observed. The hourly SBP and DBP values with naproxcinod were consistently below those observed in the naproxen group with the exception of two time points which were similar in the two groups. No carry-over effect was detected between the two active treatment periods. Both treatments were well tolerated.

Conclusions
: This exploratory 24-hour ABPM study in stable hypertensive subjects demonstrated a differentiated BP profile in favor of naproxcinod 750 mg bid, when compared to naproxen 500 mg bid, which may represent a reduction of one of the key CV risk factors when long-term naproxcinod use is considered.
Abstract 2763: A Novel Method of Expressing Left Ventricular Mass Relative to Body Size in Children
Authors: Foster Bethany , Mackie Andrew , Mitsnefes Mark , Ali Huma , Mamber Silvia , Colan Steven
Published: July 2021

The presence of left ventricular hypertrophy (LVH) is a common outcome measure in studies of cardiovascular health in children. A widely used definition of pediatric LVH is a LV mass index (LVMI, g/m
2.7
)> 95
th
percentile for healthy children – determined to be 38.6 in a single pediatric reference population. However, LVMI increases with decreasing height in young children; it is therefore a suboptimal method of normalizing LV mass for body size and of defining LVH. The 95
th
%ile LVMI in any reference population will depend heavily on the height and age distribution of the population. The objective of this study was to compare the performance of a novel method of expressing LV mass relative to body size (centile curves) to the LVMI method. LV mass was estimated using 2D-guided M-mode echocardiography in 440 healthy, non-obese (BMI< 95
th
%ile) reference children (birth to 21 y) and 239 children at risk for LVH (hypertension, chronic kidney disease); the LVMI was calculated for all children. Three samples of 270 children, each with different age distributions, were drawn from the reference population, and a sample-specific 95
th
%ile LVMI was determined for each sample and for the whole reference group. At risk children were classified as having LVH or not based on each sample-specific 95
th
%ile. Then four sets of LV mass-for-height centile curves were constructed using Cole’s Lambda-Mu-Sigma method and data from each reference sample. At risk children were each assigned a LV mass-for-height %ile using these curves, and were re-classified as having LVH if the LV mass-for-height was >95
th
%ile. Table 1

provides results. The centile method provided a stable estimate of the proportion of at risk children with LVH regardless of reference group, whereas proportion estimates varied widely, and significantly, depending on reference population when the LVMI method was used. LV mass-for-height centile curves are superior to LVMI as a method for normalizing LV mass to body size in children.

Table 1
Abstract 2770: Neointimal Hyperplasia Patterns Among 3 Drug-Eluting Stents: A Comparative Intravascular Ultrasound Analysis of Everolimus-, Sirolimus-, and Paclitaxel-Eluting Stents
Authors: Sakurai Ryota , Courtney Brian K , Yamasaki Masao , Tsujino Ichizo , Waseda Katsuhisa , Hasegawa Takao , Shimohama Takao , Ako Junya , Hongo Yoichiro , Morino Yoshihiro , Miyazawa Akiyoshi , Hur Seung-Ho , Koizumi Tomomi , Honda Yasuhiro , Yock Paul G , Lansky Alexandra J , Sudhir Krishnankutty , Stone Gregg W , Fitzgerald Peter J
Published: July 2021

Background
The amount of neointimal hyperplasia as well as the percentage of neointimal stent surface coverage may be different among various types of drug-eluting stents (DES).

Methods
From the Stanford University Intravascular Ultrasound (IVUS) Core Laboratory database, this study consisted of the patients enrolled in prospective, multicenter clinical trials with DES deployment for
de novo
coronary lesions and 3-D IVUS at 8- to 9-month follow-up as part of their study protocol. In these cases, 155 single DES: (1) an 18-mm everolimus-eluting (EES, 52 stents in 50 patients); (2) an 18-mm sirolimus-eluting (SES, 51 stents); or (3) a 16-mm paclitaxel-eluting (PES, 52 stents) stent in 153 patients were investigated. Using Simpson’s rule, %neointimal volume was defined as neointimal volume / stent volume × 100. Circumferential stent length covered with neointima (L
N
) and stent perimeter (L
S
) were also measured at every 1-mm cross section throughout the stent. Then, %neointimal coverage was defined as total L
N
/ total L
S ×
100.

Results
EES had comparable %neointimal volume to SES, but less %neointimal volume than PES (5.2±5.3 vs 2.6±4.0 vs 9.2±8.7%,
P<
0.0001), whereas EES had greater %neointimal coverage than SES, but comparable %neointimal coverage to PES (25.7±19.9 vs 9.1±14.6 vs 29.3±23.5%,
P<
0.0001).

Conclusions
Compared to SES, EES had comparable neointimal hyperplasia, but greater neointimal stent coverage by IVUS. Compared to PES, EES had less neointimal hyperplasia, but comparable neointimal stent coverage by IVUS. This unique pattern of neointimal hyperplasia with these platforms may be important to the balance of the short-term efficacy and the long-term safety.