bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 2621: C-type Natriuretic Peptide Attenuates Vascular Remodeling In Severe Pulmonary Hypertension
Authors: Mazer Jeffrey M , Casserly Brian , Rounds Sharon , Choudhary Gaurav
Published: July 2021

Pulmonary vascular remodeling and endothelial proliferation are important pathophysiological processes contributing to increased vascular resistance seen with pulmonary hypertension (PH). C-type natriuretic peptide (CNP) is an endothelium derived natriuretic peptide that has been shown to have anti-inflammatory, anti-mitogenic and anti-proliferative actions. However, its role in modulating severe PH is not known. We hypothesized that CNP will attenuate severe PH through its effect on pulmonary vascular remodeling. In order to test our hypothesis we chose to study the effect of continuous infusion of CNP, delivered by an osmotic pump, in a rat model of severe PH. This model combines the use of a VEGF receptor blocker, SU5416 (SU), and hypoxia to induce severe PH and plexiform lesions. Adult male Sprague Dawley rats were implanted with osmotic pumps to deliver CNP or vehicle for three weeks. Subsequently they received a single dose of SU or diluant and were placed in either normoxic or hypoxic (10% FiO
2
) environment for 3 wks. the animals then underwent echocardiogram, right heart catheterization, and carotid catheterization to evaluate right ventricle (RV) function, RV mass, and RV pressure (RVP). The lungs were fixed and evaluated for vascular remodeling using H&E staining and immunohistochemistry. Rats exposed to hypoxia alone developed moderate PH, while animals given SU and exposed to hypoxia developed severe PH (RVP (mmHg)- Normoxia: 27±1; Hypoxia: 79±6; Hypoxia+SU: 92±3). RV hypertrophic response mirrored the RVP in each group. Animals with severe PH receiving low dose CNP (0.75μg/hr) had increased RV mass and RVP, similar to vehicle treated animals, but demonstrated a 19% reduction in the microvascular wall thickness (p<0.05 compared to vehicle). Upon treatment with a higher dose of CNP (2.25μg/hr), animals demonstrated a significant reduction in RVP in the severe PH group (76±5 mmHg), as compared to vehicle treated animals (95±6 mmHg, p<0.05). CNP attenuates severe pulmonary hypertension likely via its effects on microvascular remodeling.
Abstract 2646: Aortic Arch Plaques and Risk of Vascular Events in Subjects Without Prior Stroke
Authors: Russo Cesare , Jin Zhezhen , Sacco Ralph L , Homma Shunichi , Rundek Tatjana , Di Tullio Marco R
Published: July 2021

BACKGROUND: Aortic arch plaques (AAP) are a risk factor for cardiovascular embolic events. However, the risk of vascular events associated with AAP in the general population is unclear.

AIM: To assess whether AAP detected by transesophageal echocardiography (TEE) are associated with an increased risk of vascular events in a stroke-free cohort.

METHODS: The study cohort consisted of stroke-free subjects over age 50 from the Aortic Plaques and Risk of Ischemic Stroke (APRIS) study. AAP were assessed by multiplane TEE, and considered large if ≥ 4 mm in thickness. Vascular events including myocardial infarction, ischemic stroke and vascular death were recorded during the follow-up. The association between AAP and outcomes was assessed by univariate and multivariate Cox proportional hazards models.

RESULTS: A group of 209 subjects was studied (mean age 67±9 years; 45% women; 14% whites, 30% blacks, 56% Hispanics). AAP of any size were present in 130 subjects (62%); large AAP in 50 (24%). Subjects with AAP were older (69±8 vs. 63±7 years), had higher systolic BP (146±21 vs.139±20 mmHg), were more often white (19% vs. 8%), smokers (20% vs. 9%) and more frequently had a history of coronary artery disease (26% vs. 14%) than those without AAP (all p<0.05). Lipid parameters, prevalence of atrial fibrillation and diabetes mellitus were not significantly different between the two groups. During the follow up (94±29 months) 30 events occurred (13 myocardial infarctions, 11 ischemic strokes, 6 vascular deaths). After adjustment for other risk factors, AAP of any size were not associated with an increased risk of combined vascular events (HR 1.07, 95% CI 0.44 to 2.56). The same result was observed for large AAP (HR 0.94, CI 0.34 to 2.64). Age (HR 1.05, CI 1.01 to 1.10), body mass index (HR 1.08, CI 1.01 to 1.15) and atrial fibrillation (HR 3.52, CI 1.07 to 11.61) showed independent association with vascular events. In a sub-analysis with ischemic stroke as outcome, neither AAP of any size nor large AAP were associated with an increased risk.

CONCLUSIONS: In this cohort without prior stroke, the incidental detection of AAP was not associated with an increased risk of future vascular events. Associated co-factors may affect the AAP-related risk of vascular events reported in previous studies.
Abstract 2659: Increased Cystatin C Serum Levels Improve Risk Stratification in Patients with Acute Coronary Syndrome and Normal Glomerular Filtration Rate
Authors: Garcia-Acuna Jose , Garcia-Babarro Eva , Gutierrez Mario , Gonzalez-Juanatey Jose Ramon
Published: July 2021

Use of Cystatin C serum levels (CC) is a more sensible marker of renal function than serum Creatinine levels (Cr) and Glomerular Filtration Rate (GFR). Previous studies have shown that increased serum CC levels with normal GFR in a population with cardiovascular risks factors but without any cardiovascular disease is associated with increased cardiovascular events but this was not analyzed in ischemic heart disease patients. We prospectively studied 203 patients hospitalized with Acute Coronary Syndrome (ACS). Serum CC levels were determined in the first 24 hours of hospitalization in all cases and two groups were identified (>and< 0.95 mg/L). GFR was calculated by MDRD formulation using the first serum Cr determination in all patients and were established two groups (> and < 60 ml/min/1.73m2). Coronariography was performed in all patients. During 13 months follow-up period we analyzed Mayor Adverse Coronary Events (MACE) and Mortality. Patients with serum CC levels >0.95 were older, with higher hypertension prevalence, prior stroke, high frequency of renal disease and greater severity of coronary artery disease (42% patients with three-vessel coronary artery disease, p=0.05). During the follow-up these patients showed a significantly higher risk of heart failure new-onset (62% p=0.001) and mortality (14 %, p=0.001). Patients with GFR >60 and serum CC levels <0.95 presented significantly higher values of MACE (61%; p=0.001) and mortality (8%; p=0.001) in opposition to 18% and 3% respectively in the group of patients with GFR 3 60 and serum CC levels 30.95. Nevertheless significant prognostic differences between GFR >60 and serum CC levels <0.95 group and GFR >60 and serum CC levels >0.95 group were observed. In the multivariate analysis was observed than serum CC levels was an independent predictor to develop of new-onset heart failure (RR: 3.9 CI 95% 1.5–9.9; p=0.002), and mortality (RR: 2. CI 95% 1.2–3.6, p=0.001) during the follow-up. Serum CC levels are a powerful both mortality and heart failure predictor in patients with high risk ACS. High serum CC levels in patients with ACS and normal renal function identify a higher risk group. Serum CC determination may be include in the risk evaluation of patients with ACS.
Abstract 2733: Association of Psychological Disorders and Structural Coronary Arterial Disease
Authors: Grant Nakash , Choe David , Khandhar Sumit , Ahmadi Naser , Foster Gary P
Published: July 2021

Background
: Growing numbers of American Veterans are diagnosed with psychological disorders and myocardial infarctions without known preexisting cardiac risk factors. Confronted with this information, we studied the association between psychological disorders and the presence of coronary artery calcium. High risk coronary calcification [Agatston method coronary artery calcium score (CAC) >100] is associated with a striking increase in cardiovascular events (hazard ratio>10) making it an excellent surrogate marker.

Methods
: From a database of VA patients who have undergone cardiac computed tomography, 483 were studied (age 59±12 years, 86% male). Regression analysis was utilized for comparison of CAC score for individuals with depression, anxiety, post-traumatic stress disorder (PTSD) and substance abuse..

Results
: After adjustment for age, gender and cardiac risk factors, the odds ratio of CAC≥100 vs. CAC=0 was 1.24 (95% CI 1.02–2.08, p=0.044) for depression, 2.04 (95% CI 1.11– 6.17, p=0.027) for anxiety, 2.28 (95% CI 1.15–5.76, p=0.026) for PTSD and 2.61 (95% CI 1.14 – 6.03, p=0.022) for substance abuse as compared to normal cohort.

Conclusion
: Veterans with psychological disorders were found to have a significantly higher coronary artery calcification score than those without such disorders. These findings are independent of age, gender and other traditional cardiac risk factors.
Abstract 2752: Pulmonary Vein Isolation With And Without Additional Ablation Of Complex Fractionated Electrograms In Paroxysmal Atrial Fibrillation: Long-term Results Of A Prospective Randomized Study
Authors: Deisenhofer Isabel , Reents Tilko , Estner Heidi L , Fichtner Stephanie , von Bary Christian , Uecer Ekrem , Schmitt Claus , Luik Armin , Karlsruhe Klinikum , Karch Martin R , Hessling Gabriele
Published: July 2021

Introduction: Segmental pulmonary vein isolation (PVI) leads to elimination of paroxysmal atrial fibrillation (AF) in approximately 75% of patients. Ablation of complex fractionated atrial electrograms (CFAE) is an alternative ablation strategy. In this prospective randomized study the long-term effect of PVI alone is compared to the effect of combined PVI and CFAE ablation in paroxysmal AF.

Methods: 98 patients with paroxysmal AF (57±10 years, 74 male) were randomly assigned to PVI (48 patients) or PVI+CFAE ablation (50 patients). Additional CFAE ablation was performed in the PVI+CFAE group if AF was still inducible after PVI. Follow-up results were assessed with repetitive 7 days Holter ECG and clinical evaluation including repeat ablations.

Results: Additional CFAE ablation was performed in 30/50 (60%) patients of the PVI+CFAE group with still inducible AF after PVI. In each group, 2 patients were lost to long term follow-up. In the intention-to-treat analysis at 3 months and after 19±8 months, there was no significant difference between both groups (36/48 [75%] and 34/46 [74%] patients in the PVI and 37/50 [73%] and 40/48 [83%] of patients in the PVI+CFAE ablation group in sinus rhythm [p=0.32]). In subgroup analysis, patients actually treated with the combined PVI+CFAE ablation approach had a significantly better long-term success (25/28; 89%) than patients with still inducible AF who underwent PVI only (22/30;73%; p=0.02). In both groups repeat ablations were performed in 31% (PVI group; 15/48 patients) and 35% (PVI+CFAE group; 17/48 patients) (p=n.s). After 9 months, significantly more patients in the PVI+CFAE group experienced sustained regular atrial tachycardia than in the PVI group (6/44 versus 1/39 patients, P=0.02).

Conclusion: The combination of PVI and CFAE ablation was equally effective than PVI alone in reaching freedom of AF in the intention-to-treat analysis. During long-term follow-up, patients actually treated with combined PVI+CFAE ablation had a significantly better outcome (89% vs. 73%). However, the rate of ablation-induced regular atrial tachycardias is inreased.
Abstract 2753: The Relationship Between Pulmonary Vein Antrum Scarring Following Atrial Fibrillation Ablation and Procedural Success: Does Pulmonary Vein Isolation Matter?
Authors: Badger Troy J , Oakes Robert S , Shabaan Akram , Akoum Nazem W , Segerson Nathan M , Fish Eric N , Rao Swati N , Burgon Nathan S , Adjei-Poku Yaw , Kholmovski Eugene G , Vijayakumar Sathya , DiBella Edward V , MacLeod Rob S , Marrouche Nassir F
Published: July 2021

Background.
A mechanism of atrial fibrillation (AF) recurrence following ablation may be incomplete pulmonary vein antrum (PVA) scarring that allows for conduction between the pulmonary veins (PV) and the left atrium (LA). We report the relationship between circumferential PV scarring detected by delayed enhancement MRI (DE-MRI) and AF recurrence following PVAI.

Methods.
Eighty-six patients presenting for PVAI underwent DE-MRI 3 months post ablation. Circumferential ablation with posterior wall debulking was performed in all patients. PV ostia were marked on 3D images generated from the MRI data and assessed by consensus of two independent reviewers for the extent of scarring. Complete PVA scarring was defined as a continuous ring of enhancement surrounding the PVA. For patients with incomplete scarring, the degree of scarring was estimated.

Results.
The figure shows two patients from the cohort, Patient 1 exhibits successful scarring of all PVA. Patient 2 shows scarring of 1 PVA. At three months post ablation, complete circumferential lesion was seen on 131/335 PVA (39.1%). Complete scarring of 4 PVA was seen in 9 patients (10.5%), scarring of 3 PVA in 11 patients (12.8%) and scarring of 2 PVA was seen in 17 patients (19.8). Twenty-nine patients (33.7%) exhibited complete scarring in 1 PVA while 20 patients (23.3%) exhibited scarring in 0 PVA. Kaplan Meier analysis (Figure [E]

), suggests that PVA isolation may be important for long-term procedural success.

Conclusion:
Complete pulmonary vein antrum scarring exists in a very limited number of patients, despite its apparent importance for long-term procedural success.
Abstract 2754: Pulmonary Vein Isolation Using Irrigated vs. Conventional 4-mm Tip Catheters- Do Short and Long-Term Outcomes Differ?
Authors: Kamath Ganesh S , Makani Harikrishna , Enciso Jorge Silva , Kumar Sunil , Mittal Suneet , Steinberg Jonathan S
Published: July 2021

Open saline-irrigated tip ablation catheters have largely supplanted standard 4 mm tip ablation catheters for pulmonary vein isolation (PVI) of atrial fibrillation (AF), based on the assumption that the procedure is safer and more efficacious. However, outcomes after procedures that use identical techniques but different radiofrequency ablation catheters have not been compared. We studied 432 consecutive patients (age 57 ± 11 yrs) with AF (duration 7.9 ± 6.1 yrs) who underwent PVI; 320 (74 %) using a conventional 4 mm catheter and 112 (26 %) using an open irrigated tip catheter. Segmental PVI targeting the earliest LA-PV activation for all PVs in each patient was used for all patients regardless of catheter for the entire study cohort. Radiofrequency energy was delivered for ≥60 secs at each target site. The pts in the 2 groups were similar with respect to age, gender and duration of AF. All 432 pts had successful complete PVI. There was no significant difference in the total number of lesions delivered per PV in the conventional 4 mm group and the irrigated tip group (Table

) at the initial procedure. Following a single procedure, 227/ 320 (71%) patients in the conventional 4 mm and 75/112 (67%) in the irrigated group were AF-free on no antiarrhythmic drug at 12 mos (p=0.43). The number of patients who required repeat procedures was similar in the conventional group (57/320, 18%) and the irrigated tip group (22/112, 20%) (p=0.66). Serious complications were also similar (2.2% vs. 1.0 %, p=0.21) Contrary to conventional wisdom, the safety and 12 month efficacy of PVI for management of AF was similar for the two types of ablation catheters. These data suggest that PVI cohorts derived from differing ablation techniques can be combined for purposes of clinical investigation. Longer term outcomes may differ and should be studied as well.
Abstract 2765: Natural History and Genetic Features of Short QT Syndrome
Authors: Monteforte Nicola , Memmi Mirella , Bloise Raffaella , Ronchetti Elena , Napolitano Carlo , Priori Silvia G
Published: July 2021

Short QT syndrome (SQTS) is a rare genetic disorder characterized by abnormally short QT interval and high risk of sudden cardiac death (SCD). This study addresses the issue of natural history, genetics and electrocardiographic features in the largest prospective SQTS cohort (47 individuals in 24 families). Diagnosis was made in the presence of QTc interval ≤ 350 ms w./out history of cardiac arrest (CA) or SCD without structural abnormalities. Median age at diagnosis was 27 years (range 4–56); mean QTc was 323±17 ms, 22/36 (61%) pts had abnormal T wave (n=17) and/or J point elevation (n=8) and/or QRS slurring (n=3); at a mean observation time of 30±14 years, 22 (47%) pts had cardiac events: 11 SCD, 4 resuscitated CA and 7 syncopal episodes. Median age at SCD or CA was 19 (range 0 – 48) years (4 death/CA occurred in the first year of life). The Kaplan Meyer curve shows survival-free interval before drugs. Triggers for the 15 death/CA were exercise (44%) and rest (56%). Eight pts were treated with quinidine (250 mg bid) that prolonged QTc: from 320±18 ms to 380±18 ms (p<0.005). Genetic screening on
KCNH2, KCNQ1
and
KCNJ2
genes was positive in 3/24 probands and 3 family members. Interestingly, genotyped pts (n=6) presented significantly shorter QTc than non-genotyped pts (303±13 ms vs. 328±14 ms, p<0.001). In summary our data show that SQTS is a severe disorder with high risk of cardiac arrest occurring from infancy to adulthood. The yield of genetic testing is low (13%) suggesting genetic heterogeneity, but patients harboring a genetic mutation have more severe phenotype. The use of quinidine can help to normalize the QTc although its effect on cardiac events remains to be assessed.
Abstract 2800: Assessment of Computational Fluid Dynamics to Calculate Individual Coronary Wall Shear Stress In-Vivo
Authors: Rieber Johannes , Redel Thomas , Hetterich Holger , Potzger Tobias , Nikolaou Konstantin , Rist Carsten , Klauss Volker
Published: July 2021

Beyond classic risk parameters non physiologic or oscillating wall shear stress (WSS) has been proven to act as a local factor for initiation and progression of atherosclerosis as well as for plaque rupture. Direct measurement of WSS in-vivo is difficult and restricted to animal models. Computational fluid dynamics (CFD) is a validated tool to compute flow parameters and WSS. For this purpose an exact model of the underlying patient specific geometry of the coronary tree is a prerequisite. Using 3D-IVUS or modern multislice computed tomographic coronary angiography (CTA) with submilimeter resolution these data can be provided. The aim of this study was to 1.) demonstrate feasibility of in-vivo CFD calculation of human coronaries based on CTA and 2.) to correlate the findings with radio frequency tissue information derived by intravascular ultrasound. We prospectively included 10 patients with suspected coronary artery disease who received CTA (Dual source 64 slice CT) and invasive conventional coronary angiography. Intravascular ultrasound and ECG-triggered radio frequency analysis (VH) was attempted in all three epicardial vessels. In the CTA-dataset the coronaries were segmented and a mesh model for CFD was generated. CFD calculations were performed using a commercial available software package with laminar flow and blood as a Newtonian fluid as boundary conditions. Coronary models were stationary with rigid vessel walls, while the pulsatile inflow characteristics was derived from invasive Doppler velocity measurement. Flow pattern calculations, vessel wall shear stress and IVUS analysis were successfully performed in 24/30 and 17/30 coronary arteries. The presence of high shear stress and non turbulent flow was inversely correlated with the presence of plaque as determined by intravascular ultrasound. No correlation of any CFD parameter with the radio frequency tissue information could yet be observed. The findings of the present study demonstrate the feasibility of assessing fluid tissue interactions in human coronary arteries using CTA and its correlation to invasive findings. The possible impact of CFD parameters on risk- and treatment stratification has to be determined in a large scale prospective trial.
Abstract 2808: Combination of Adenosine Stress Perfusion and Late Enhancement Cardiac Magnetic Resonance Imaging in Patients with Suspected Coronary Artery Disease, Percutaneous Coronary Intervention and Coronary Bypass Graft -A Multi-Center Study
Authors: Bernhardt Peter , Pilz Guenter , Spiess Jochen , Hoefling Berthold , Hombach Vinzenz , Strohm Oliver
Published: July 2021

The combination of stress perfusion and late Gadolinium enhancement (LGE) cardiac magnetic resonance imaging (CMR) has been established for diagnosis of myocardial ischemia. However, little is known about this helpful clinical examination tool in patients who were treated by percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG). Aim of our study was to compare the diagnostic accuracy of stress perfusion and LGE in patients with suspected coronary artery disease (CAD), with PCI and with CABG in a multi-center trial. 477 patients with suspected CAD, 209 with PCI and 110 with CABG were included to the study and underwent adenosine stress perfusion and LGE 10 min. after a second bolus of contrast agent. CMR images were assessed visually using the 16-segments model. Myocardial ischemia was defined as resgional hypoenhancement in stress perfusion with absent LGE. All patients underwent coronary angiography. A significant stenosis was defined by QCA in case of ≥70% of coronary artery or bypass graft narrowing in vessels ≥2 mm diameter. A relevant vessel stenosis or occlusion was present in 173 (36%) patients with susptectd CAD, 69 (29%) PCI and 71 (65%) CABG patients. PCI was performed 314±231 and CABG 423±275 days before CMR examination. Sensitivity, specificity and overall accuracy per patient are given in table 1

CMR is feasible and suitable for detecting relevant vessel stenosis in patients who previously were treated by PCI or CABG. Diagnostic accuracy is reduced in patients with CABG. This could be due to different flow and perfusion kinetic. Furthermore, presented evaluation method may be inadequate, since collaterals and different perfusion territories are not taken into consideration. CMR yields similar diagnostic accuracy in patients with suspected CAD and those who previously were treated by PCI.
Abstract 2817: Degree of Left Ventricular Dyssynchrony in Heart Failure Patients Is Related to QRS Width
Authors: Hara Hideyuki , Tanaka Hidekazu , Oyenuga Olusegun , Kim Han-Na , Schwartzman David , Gorcsan John
Published: July 2021

Background
Recent narrow QRS cardiac resynchronization therapy (CRT) trials using tissue Doppler imaging (TDI) dyssynchrony criteria have not successfully predicted response. Our objective was to test the hypothesis that differences in degree and pattern of dyssynchony exist in narrow QRS vs. wide QRS pts.

Methods
We studied 277 heart failure (HF) pts with ejection fraction EF ≤ 35% referred for device therapy: 152 had QRS ≥ 120 ms for CRT and 125 with QRS <120 ms for defibrilator therapy. Ninety % had Class III HF, 59 % had ischemic disease. Dyssychrony was assessed by TDI longitudinal velocity opposing wall delay from 12 sites using 3 apical views and speckle tracking radial strain from 6 mid-ventricular sites using short axis views to assess regional time activation.

Results
Overall, radial mechanical activation was early in the anteroseptum and late in the posterolateral segments in all pts groups. Anteroseptal activation was significantly earlier (254±116ms*) in pts. with QRS >140 compared to those with QRS 120–140 ms (303±98ms) or QRS < 120ms (329±96ms), *p<0.05 vs other groups. Posteriolateral delay was also significantly later (474±89ms*) in pts. with QRS >140 compared to those with QRS 120–140 ms (449±66ms) or QRS < 120ms (440±75ms), *p<0.05 vs other groups. TDI, however, was just delayed in wide QRS patients.

Conclusions
The degree of radial dyssynchrony was related to QRS width, although the pattern of early septal and late posterolateral activation was preserved across groups. These findings may explain differences in response to CRT in narrow vs. wide QRS patients and impact future CRT considerations.
Abstract 2833: Magnetic Resonance Imaging Characterization of Peri-Infarct Zone Remodeling following Reperfused Myocardial Infarction
Authors: Schuleri Karl H , Centola Marco , Evers Kris S , Evers Robert , Hare Joshua M , Lardo Albert C
Published: July 2021

Background:
Clinical studies using delayed enhanced magnetic resonance imaging (de-MRI) suggest the peri-infarct zone (PIZ) contains a mixture of viable and non-viable myocytes and is associated with greater susceptibility to ventricular tachycardia induction and adverse cardiac outcomes. However, data characterizing the temporal formation and remodeling characteristics of the PIZ do not exist. We hypothesized that the PIZ undergoes spatial/temporal changes in parallel with structural ventricular remodeling following reperfused myocardial infarction (MI).

Methods:
Ten mini-pigs underwent coronary occlusion followed by reperfusion. Functional and de-MRI studies were performed prior and at five time points after MI induction. Custom signal density threshold algorithms based on the remote myocardium were applied to define the infarct core and PIZ region.

Results:
LVEDV increased from 34.7. ± 2.2 ml to 47.8± 3.0 ml (day 3 and week 12, respectively; p<0.001). The size of infarct scar expanded by 14% and thinned by 56% from day3 to 12 weeks (
p
=0.004 and
p
<0.001, respectively). Though, there was no change in total scar volume (11.0±0.8 ml and 9.2±1.2 ml, day 3 and week 12, respectively;
p
=NS), the PIZ volume showed significant changes over 12 weeks (figure

) parallel to the structural remodeling of the left ventricle. After the initial post-MI edema subsided the PIZ decreased further by 54% from day 10 to week 12 (
p
=0.04)

Conclusions
: The PIZ is dynamic and decreases in volume following reperfused MI. Remodeling characteristics of the PIZ may provide mechanistic insights into the development of life-threatening arrhythmias and sudden cardiac death post-MI.
Abstract 2882: Directed Evolution of Cardiac Specific Adeno-Associated Vector Variants
Authors: Hajjar Roger J , Chen Jiqiu , Kawase Yoshiaki , McPhee Scott , Samulski Jade , Samulski R. J
Published: July 2021

Adeno-associated vectors (AAV) have gained popularity in cardiovascular gene transfer because of their distinct characteristics: long-term expression, minimal immune response and strong tropism to cardiac tissue for specific serotypes (such as AAV9). However AAVs have certain limitations: Neutralizing antibodies in 40% of humans for each AAV serotype and non-specificity of the AAV serotypes to various organs. Chimeric viruses composed of capsid proteins of different serotypes, show distinct transduction profiles. To identify hybrid viruses that can selectively transduce cardiomyocytes in vivo, we generated a library of diverse AAV variants, obtained by DNA shuffling, with an enrichment of cardiotropic AAV variants, called biological nanoparticles (BNPs). We selected five BNPs from these experiments: BNP 108, 109, 111, 689, and 693. We then injected these different BNPs using GFP as a marker gene under the control of CMV along with AAV9 into rats (3 in each group and each time point) through their tail vein at a concentration of 1011 vg (viral genomes). We sacrificed the animals at one and four weeks and examined expression in the heart, liver, lung, kidneys, and aorta. We found that at 1 week, BNP 108 and 109 had the best expression in the heart (61±12% of the myocytes with green fluorescence) while BNP 111 and AAV9 had strong cardiac expression at 4 weeks (93±11% and 79±12% of the myocytes with green fluorescence). None of the BNPs showed expression in the liver, lung, kidneys, and aorta, while AAV9 demonstrated widespread expression in all these tissues. Transcoronary injection of BNP111 at a concentration of 1012 vg demonstrated the efficiency of BNP in transducing myocardium of large animals. We also found that all the BNPs are resistant to preexisting neutralizing antibodies against parent serotypes. These results show that directed evolution of AAV variants can yield BNPs that are highly cardiotropic and highly efficient of transducing cardiac tissue without infecting other organs and having resistance to preexisting neutralizing antibodies against parent serotypes. These BNPs may become very useful for clinical applications.
Abstract 2883: Retroinfusion-facilitated Inotropic AAV9-S100A1 Gene Therapy Restores Global Cardiac Function In A Clinically Relevant Pig Heart Failure Model
Authors: Pleger Sven T , Shan Changguang , Kziencek Jan , Mueller Oliver , Bekeredjian Raffi , Remppis Andrew B , Koch Walter J , Katus Hugo A , Most Patrick
Published: July 2021

Background:

Cardiac expression of the Ca-dependent inotropic protein S100A1 is decreased in human end-stage heart failure (HF) and cardiomyocyte-targeted viral-based S100A1 gene transfer rescued failing myocardium in small animal models
in vivo
and
in vitro
via improved systolic and diastolic sarcoplasmic reticulum Ca-handling. We therefore hypothesized that cardioselective AAV9-S100A1 gene therapy will improve cardiac performance in a large animal experimental HF model under clinical conditions.

Methods and Results:

Left ventricular (LV) posterolateral myocardial infarction (MI) was induced in pigs by occlusion of the left coronary circumflex artery and resulted in LV failure (HF) 2 weeks post-MI reflected by a 40% and 27% reduction in LV +dp/dt max. and EF, respectively, as assessed by LV catheterization and echocardiography. Post-MI HF pigs were then randomized for retroinfusion of AAV9-luciferase (luc; n=6, 1.5×10
13
total viral particles, tvp) and AAV9-S100A1 (S100A1; n=6, 1.5×10
13
tvp) driven by a cardioselective promoter via the anterior cardiac vein while the left anterior descending artery was temporarily occluded. 14 weeks after cardiac gene transfer, the S100A1-treated HF group showed significantly enhanced S100A1 protein expression (+46.7±17.9%, P<0.05 vs. control groups) in targeted remote LV myocardium and improved indices of cardiac function and remodeling (luc vs. S100A1: +dp/dtmax: 983±81 vs. 1526±83 mmHg/s, EF: 39±2.1 vs. 61±3.7 %, P<0.05 S100A1 vs. luc, LV endsystolic diameter: luc 4.45±0.1 vs. S100A1 3.43 ±0.1 cm, P<0.05 S100A1 vs. luc, HR: 72±4 vs. 69±2, beats/min, P=n.s. S100A1 vs. luc). Importantly, analyses of renal, hepatic and hematopoetic function showed no alteration as assessed by unchanged transaminases, retention values and white blood cell counts compared to sham pigs.

Conclusions:

Our translational study provides proof of concept that AAV9-S100A1 based HF gene therapy is feasible and restores cardiac function in a large animal HF model under clinical conditions. Next, certified toxicological analysis and different AAV9-S100A1 dosage protocols will be assessed to eventually advance to first phase I/II clinical studies determining therapeutic efficiency of cardiac S100A1 gene therapy in HF patients.
Abstract 2937: Association Of Low Body Mass Index And Weight Loss With Increased Mortality In 14,065 Transplant-wait-listed Hemodialysis Patients
Authors: Kalantar-Zadeh Kamyar , Streja Elani , Jing Jennie , Kovesdy Csaba P , Van Wyck David , Danovitch Gabriel M , Danovitch Gabriel M , Bunnapradis Suphamai
Published: July 2021

Obese individuals with terminal heart failure (HF) or end-stage renal disease (ESRD) are often asked to lose weight prior to heart or kidney transplantation despite recent findings of “obesity paradox” or “reverse epidemiology” indicating survival advantages of obesity in HF and ESRD. We hypothesized that lower BMI and weight loss over time in transplant-waitlisted hemodialysis (HD) patients (pts) is associated with increased death risk during the waiting period. By linking the 5-yr (7/2001– 6/2006) national database of a large dialysis organization (DaVita) to the
Scientific Registry of Transplant Recipients
, we identified 14,065 HD pts, who were transplant-waitlisted but who did not receive any kidney transplantation over the 5-yr period. Time-dependent survival models examined associations of calendar-quarterly measured BMI (using 13-wk averaged post-HD dry weight) and the percentage of change in weight over 6 mo with survival adjusted for case-mix and time-varying surrogates of malnutrition-inflammation complex syndrome (MICS). The 14,065 HD pts were 59.7±15.4 yrs old and included 47% women and 39% diabetics. The 13-wk averaged BMI was 26.4±6.7 kg/m
2
. Unadjusted and adjusted survival analyses showed progressively greater survival with higher BMI>23 kg/m
2
and higher death risk across weight loss increments: Obese transplant-waitlisted HD pts appear to have greater survival that is incrementally associated with higher height-adjusted-weight, whereas weight loss over time appears associated with increased death risk. These findings may question the benefit of recommending weight reduction during the pre-transplant waiting period in obese MHD pts.

This research has received full or partial funding support from the American Heart Association, AHA Western States Affiliate (California, Nevada & Utah).
Abstract 2945: Normalization of Beta Adrenergic Receptor Signaling Improves Left Ventricular Myocyte Function with Urotensin II Receptor Blockade in Murine Heart Failure
Authors: Cheng Heng-Jie , Zhou Peng , Cross Michael , Callahan Michael F , Little William C , Cheng Che-Ping
Published: July 2021

Background.
Urotensin II (UII), the most potent vasoconstrictor and its receptors (UT) are upregulated in heart failure (HF). Although the role of UII in cardiac regulation is not fully understood, increasing evidence suggests that in the failing myocardium, UII may exert an enhanced negative modulation on cardiac contractile performance and cardiac β-AR regulation, thus providing a potential mechanism for progressive deterioration in cardiac function in HF. We assessed the hypothesis that blocking UII may prevent HF-induced alterations in cardiac β-adrenergic receptor (AR) expression, restore normal β-adrenergic regulation, and improve left ventricular (LV) myocyte functional performance.

Methods.
We compared β
1
- and β
3
-AR expression and responses to β- and β
3
-AR stimulation in freshly isolated LV myocytes obtained from 3 groups of mice (6/group): 1) HF-2 months after receiving isoproterenol (ISO, 170 mg/kg, sq, for 2 days); 2) HF/UIIBK-one month after receiving ISO, then urantide, a potent UIIBK (10
−5
M/kg/day via sq implanted osmotic minipump) initiated after the onset of HF and given for 1 month; and 3) Controls.

Results.
Compared with controls, ISO-treated mice had established HF. Isolated cardiomyocyte studies showed about 42% reductions in cell contraction (dL/dt
max
, 78 vs 134 μm/s) and relaxation (dR/dt
max
, 69 vs 120 μm/s) with a much less increase in dL/dt
max
(29 vs 68%) and dR/dt
max
(31 vs 62%) in response to superfusion of ISO (10
−8
M). These changes were associated with significantly decreased β
1
-AR mRNA (40%, 0.57 vs 0.95), but increased β
3
-AR mRNA (54%, 0.43 vs 0.28) expression. Treatment with UII BK prevented HF-induced contrast changes of β
1
- and β
3
-AR mRNA expression. The signal ratios of β
1
-AR mRNA (0.85) and β
3
-AR mRNA (0.34) remained close to control levels. Basal and ISO-stimulated adenylate cyclase activity were normal, and ISO-induced increase in dL/dt
max
(61%) and dR/dt
max
(58%) were significantly augmented.

Conclusion.
In a murine model of progressive HF, chronic UIIBK prevents HF-induced contrast alterations of LV β
1
- and β
3
-AR expression, restores normal responsiveness of myocyte to β-AR stimulation, and improves LV myocyte function. Thus, UIIBK may provide a new therapeutic strategy for the treatment of HF.
Abstract 3002: Long Term Oral Contraceptive Use is an Independent Risk Factor for Arterial Stiffening
Authors: Rietzschel Ernst , De Buyzere Marc , Segers Patrick , Bekaert Sofie , De Bacquer Dirk , De Backer Guy , Gillebert Thierry
Published: July 2021

Oral contraceptives (OC) are among the most frequently used drugs in the world with approximately 100 million women worldwide taking OC. In contrast to the active controversy surrounding hormone replacement therapy, little attention has been focused on OC, a drug therapy taken by far more women for far longer time periods. We describe the population effects of current and long-term OC exposure on a prognostically well validated marker of arterial stiffness: carotid-femoral pulse wave velocity (PWV). The Asklepios study is a representative sample (2524 apparently healthy M/F volunteers, aged 35–55 years, 1301 women) from the Belgian general population, free from overt cardiovascular disease. The subjects were extensively screened (biochemistry, lifestyle, cardiac and vascular echography, arterial tonometry). PWV was measured from flow patterns registered by Doppler echography in the femoral and carotid arteries. Of 1301 women (median age 45.7 y), 27.4% were actively taking OC. In contrast past use of OC is far more prevalent with 81% of women having taken OC for at least 1 year. The median duration of exposition in these women was 13 years. Age-adjusted PWV was higher in women currently taking OC: 6.75 versus 6.55 m/s (difference 0.19 ± 0.09 m/s; p = 0.034). However, current OC users also had higher blood pressures (BP): systolic BP (+4.4 ± 0.9 mmHg; p < 0.001), diastolic BP (+2.3 ± 0.6 mmHg; p < 0.001). After adjustement for BP, the difference in PWV between current OC users and non-users became non-significant: 6.60 versus 6.62 m/s (difference 0.02 ± 0.09 m/s; p = 0.814). In contrast, duration of OC use is a significant determinant of PWV, even after adjustement for age, BP, lipid levels, body size, heart rate, drug therapy (lipid-lowering, antihypertensive), glycemic status and smoking: F = 6.1; p = 0.013. Per 10 years of OC exposure PWV increased by 0.1 m/s (0.02– 0.18; p = 0.013). Use of OC is associated with increased vascular stiffness in women. Current use is associated with increased PWV because OC’s increase blood pressure, long-term use (probably through structural remodelling of the vessels) is an independent determinant of PWV, increasing PWV by 0.10 m/s per 10 years exposure.
Abstract 3044: Transcatheter Aortic Valve Implantation in 168 High-Risk Patients with Symptomatic Severe Aortic Stenosis - Single Centre Experience
Authors: Boone Robert H , Altwegg Lukas A , Masson Jean-Bernard , Al Ali Abullah , Bugami Saad Al , Pasupati Sanjeevan , May Lee , Carere Ronald G , Moss Robert R , Munt Brad , Anson Cheung , Ye Jian , Thompson Christopher R , Lichtenstein Samuel V , Webb John G
Published: July 2021

Objectives:
We describe the outcome of 168 patients with severe symptomatic aortic stenosis treated with transcatheter aortic valve implantation (TAVI). This cohort includes the first in man transarterial and off-pump transapical patients.

Methods:
The balloon-expandable aortic prosthesis was implanted via the femoral artery or left ventricular apex in 113 and 58 patients respectively. Data are described as 1–57, 58 –114 femoral and 1–58 apical procedures, respectively. Clinical and echocardiographic follow-up occurred at 1, 6, 12, and 24 months. Unsuccessful cases were censored at 30 days.

Results:
Mean age was 82.5 years (range 50 –97) with 57% males. Procedural success was 94.2% [88%, 96%, & 98%] with no unsuccessful procedures in the last 46 cases. One patient had a successful transfemoral procedure after a prior failure, and 3 patients had successful transapical procedures following failed transfemoral attempts. Logistic EuroSCORE and STS predicted 30-day surgical mortality was 31% [28.4%, 29.1% & 36%], and 10.4% [8.9%, 9.6% & 12.6%] respectively. Observed 30-day mortality was 10.5% [10.5%, 3.5%, & 17.2%], and 0% in the last 39 trans-femoral cases. Intra-procedural mortality was 1.1% [1.8%, 0% & 1.7%]. Peri-procedural stroke occurred in 4% [3.5%, 7%, & 1.7%]. Median hospital stay was 5 days [4, 5, & 7]. Survival at 1, 6, 12 and 24 months was 88%, 80%, 74% [73.9%, 84%, & 65.6%] and 61%. AVA, MG, LVEF and MR significantly improved post TAVI (Table 1

), and MR, EF, and NYHA class significantly improved during follow-up. MG did not increase during follow-up, but AVA decreased slightly at 1 year (mean difference: 0.2±0.54cm
2
, p=0.04). Mild paravalvular AR was common but severe AR was not observed post-implant or at follow-up.

Conclusion:
TAVI provides sustained clinical benefit for up to 2 years in patients with symptomatic severe AS and high operative risk. Procedural outcome continues to improve with experience and device development.

Table 1:

Echocardiographic follow-up
Abstract 3085: Pre-stenting with a Bare Metal Stent before Percutaneous Pulmonary Valve Implantation Reduces the Risk of Stent Fractures
Authors: Nordmeyer Johannes , Lurz Philipp , Jones Alexander , Khambadkone Sachin , Taylor Andrew M , Bonhoeffer Philipp
Published: July 2021

Background:
Stent fractures are the most common complication after percutaneous pulmonary valve implantation (PPVI), with an incidence of 20%. In a third of these cases, stent fractures lead to recurrent right ventricular outflow tract (RVOT) obstruction and required re-intervention. A previous risk factor analysis indicated that a more rigid implantation site prevented this complication. We sought to analyze, whether pre-stenting with a bare metal stent (BMS) could reduce the incidence of stent fractures after PPVI.

Methods:
Between September 2005 and June 2008, we studied 108 consecutive PPVI patients (PPVI only: n=54; BMS + PPVI: n=54). All patients underwent biplane chest X-ray, echocardiography and clinical evaluation during protocolized follow-up (1, 3, 6 and 12 months post procedure and yearly thereafter). The primary endpoint was PPVI stent fracture of any type. Data on the previously identified risk factors for stent fractures were collected in all patients. Hazard ratios (HR) were calculated from a multivariate Cox regression analysis. Subsequently, probabilities for the primary endpoint were obtained from a logistic regression model.

Results:
In this series, the overall incidence of stent fractures was 14/108 (13%). Two factors were associated with a lower incidence of stent fractures: pre-stenting with BMS (HR 0.22,
P
=0.03) and calcifications along the implantation site (HR 0.19,
P
<0.01); one factor was associated with a higher incidence of stent fractures: recoil of PPV during balloon deflation (HR 16.3,
P
<0.01). According to these factors, performing pre-stenting with BMS could reduce the probability of developing stent fractures after PPVI in all patients, with the effect size depending on the individual risk profile. In the group with the lowest risk (i.e. presence of RVOT calcifications and no PPV recoil), the risk could be reduced by 6% (from 7% to 1%), in the low-risk group by 24% (from 31% to 7%), in the medium-risk group by 40% (from 65% to 25%) and in the group with the highest risk (i.e. no RVOT calcifications and PPVI recoil) by 26% (from 91% to 65%).

Conclusions:
Pre-stenting with BMS is associated with a lower incidence of stent fractures after PPVI and may represent a clinically applicable strategy to improve patient outcome.
Abstract 3090: Missense Mutations in SNTA1-Encoded Syntrophin Alpha and Sudden Infant Death Syndrome
Authors: Van Norstrand David W , Medeiros-Domingo Argelia , Tester David J , Cheng Jianding , Valdivia Carmen R , Makielski Jonathan C , Ackerman Michael J
Published: July 2021

An estimated 10–15% of sudden infant death syndrome (SIDS) may be channelopathic with approximately half of the SIDS-associated channel mutations involving the sodium channel (NaV1.5) macromolecular complex. Recently, SNTA1, which encodes the sodium channel interacting protein (ChIP), syntrophin alpha, was discovered to be a novel long QT syndrome (LQTS) susceptibility gene (LQT12) with mutations causing increased late sodium current secondary to increased s-nitrosylation of the sodium channel’s alpha subunit. Therefore, SNTA1 is a plausible candidate gene for SIDS. In this IRB-approved study, mutational analysis of SNTA1’s eight translated exons was performed using PCR, DHPLC, and direct DNA sequencing of DNA derived from 286 SIDS cases (112 females, 197 white, average age 2.9 ± 1.9 months, range 3 days -12 months). The anonymized study design precluded a determination of mutation status as familial or sporadic. Overall, 8/286 cases of SIDS harbored missense mutations in SNTA1 that were absent in 800 reference alleles. Six distinct, rare SNTA1 missense mutations were detected in 7/112 (6.25%) female infants but only 1/174 (0.6%) male infants (p < 0.01). Comprehensive open reading frame analysis of all 800 reference alleles also revealed rare genetic variants in 1% of the control subjects. A common pair of non-synonymous single nucleotide polymorphisms (P74L/A257G), with a heterozygous frequency of 1%, was identified similarly in both cases and controls. This study provides the first molecular evidence implicating mutations in SNTA1 as a novel pathogenic substrate for channelopathic SIDS. However, given the ~1% background rate of rare variants in controls, mechanistic studies of each putative SIDS-associated SNTA1 mutation will be necessary to confirm that the mutant ChIP yields a functionally perturbed NaV1.5 macromolecular complex akin to the investigations that established SNTA1 as a novel LQTS-susceptibility gene.
Abstract 3091: The Clinical and Electrocardiographic Phenotype of Unrelated Patients with Genotype-Negative Long QT Syndrome
Authors: El Yaman Malek M , Tester David J , Domingo Argelia Medeiros , Haglund Carla M , Ackerman Michael J
Published: July 2021

Long QT syndrome (LQTS) is a heterogeneous group of channelopathies characterized by increased risk of potentially lethal ventricular arrhythmias. LQT1, LQT2, and LQT3 comprise 95% of genetically proven cases and exhibit a number of established genotype-phenotype correlations. The study aimed at examining the phenotypes of genotype-negative LQTS, accounting for ~25% of LQTS cases. An IRB-approved retrospective analysis was conducted on 56 patients (39 female, 25 ± 17 years) who, after genetic testing either in our sudden death genomics laboratory or with the commercially available Familion test, were negative for mutations in the 3 principal LQTS-susceptibility genes (
KCNQ1, KCNH2,
and
SCN5A),
and the minor genes underlying LQT5 and LQT6. All had been diagnosed with LQTS, with a clinical diagnostic score of ≥ 3.5 or QTc ≥ 480 ms. The mean diagnostic score was 4.4 (95% CI 4.2 – 4.7); mean QTc was 525 ms (95% CI 508 – 543 ms). Two-thirds were symptomatic (syncope, cardiac arrest, and/or seizures) with exercise-triggered events in 10 (26%). Twenty-one (38%) had a family history of sudden cardiac arrest. ECG showed a T wave pattern suggestive of LQT1 in 32%, LQT2 in 43%, and LQT3 in 18%. In those with exercise-induced symptoms, the ECG was LQT2-like in 50% and LQT1-like in 30%. One patient had post-partum syncope with an LQT2-like ECG. None had an auditory trigger, but 3 patients, all with an LQT2-like ECG, had a family history of auditory-triggered events. One-third of the patients had received an ICD, 58% as secondary prevention. Over 2/3 were on beta-blockers. Among the 45 patients so far tested for mutations in minor LQTS-susceptibility genes, 2 had LQTS-causing mutations in
ANKB
(LQT4), 1 in
SCN4B
(LQT10), 1 in
AKAP9
(LQT11) and 2 in
SNTA1
(LQT12). Genotype-negative patients with a firm LQTS diagnosis show marked phenotypic heterogeneity, suggesting multiple underlying pathogenic pathways. Only a few patients have LQTS-causing mutations in minor genes after complete LQT1–12 genetic testing. Classifying genotype negative patients into LQT1-, LQT2-, or LQT3-like profiles may guide the discovery of novel genes encoding channel interacting proteins corresponding to those specific signaling pathways.