bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 14302: One-Year Survival in Heart Failure Patients With Preserved Ejection Fraction and Isolated Post-Capillary or Combined Post- and Pre-Capillary Pulmonary Hypertension
Authors: Nichols Elizabeth L , Rezaee Michael E , Brown Jeremiah R
Published: April 2024

Introduction:
Patients with combined post- and pre-capillary pulmonary hypertension (CpcPH) or isolated post-capillary pulmonary hypertension (PH) have been understudied due to limited hemodynamic information from right heart catheterization (RHC), which is not routinely performed in heart failure patients. This study compared the characteristics and outcomes of stable heart failure patients with no PH, isolated PH, and CpcPH determined by diastolic pulmonary gradient.

Hypothesis:
We hypothesized CpcPH would have lower 1-year survival compared to no PH or isolated PH patients undergoing RHC.

Methods:
We used the Dartmouth Dynamic Registry to identify patients with heart failure and preserved ejection fraction that underwent RHC at Dartmouth Hitchcock Medical Center between 1994 and 2012. CpcPH was defined by a diastolic pulmonary gradient >7mmHg. We obtained mortality data from the National Death Index. We compared demographic, clinical, laboratory, and hemodynamic characteristics of patients with no PH, isolated PH, and CpcPH. We used Kaplan-Meier statistics and multivariable Cox proportional hazards models to compare hazard for 1-year mortality for patients with no PH, isolated PH, and CpcPH adjusted for age, sex, diabetes, chronic kidney disease, and atrial fibrillation.

Results:
We identified 724 patients, of which 29% had no PH, 63% had isolated PH, and 7% had CpcPH. Mean follow up time was 341.8 days with a total of 676.1 person-years. There was a significant difference in crude one-year mortality; 4.0 for no PH, 8.4 for isolated PH and 21.0 (per 100 person-years) for CpcPH (log rank p =0.001). Adjusted Cox proportional hazard ratios compared to patients with no PH were 1.6 (95%CI: 0.1, 3.4) for isolated PH and 5.3 (95%CI: 2.1, 13.9) for CpcPH.

Conclusions:
Patients with CpcPH had worse survival than patients with isolated or no PH. Diastolic pulmonary gradient should be measured as a risk marker for identifying patients at high-risk of 1-year mortality.
Abstract 14304: The Role of Foxc1 During the Differentiation of Embryonic Stem Cells Into Functional Cardiomyocytes
Authors: Lambers Erin , Arnone Baron , Fatima Anees , Wasserstrom John A , Qin Gangjian , Kume Tsutomu
Published: April 2024

Background:
Embryonic Stem Cells (ESCs) hold great potential for regeneration of damaged myocardium, however the molecular circuitry that guides ESC differentiation into cardiac lineages remains poorly understood. This is exemplified by the elusive role of the developmental transcription factor, Foxc1, during cardiac development. When one human FoxC1 allele is mutated it causes Axenfeld-Rieger syndrome characterized by ocular defects and often heart defects. Foxc1 homozygous null mice are either embryonic lethal or die soon after birth with the majority of these mice containing severe heart malformations. The only known Foxc1 target during heart development is Tbx1, a transcription factor necessary for the proper alignment of the outflow tract. Because Foxc1 null mice contain heart defects that are far more severe than Tbx1 null mice, it is likely that foxc1 has additional regulatory roles in heart development. It is unknown in which specific cell types of the heart Foxc1 functions.

Hypothesis:
Foxc1 is critical for ESC differentiation into functional cardiomyocytes through the regulation of a downstream regulatory transcription network.

Methods and Results:
Using a murine Nkx2.5-GFP reporter ESC line, we show that Foxc1 knockdown (KD) reduces the number of Nkx2.5+ cells upon differentiation. Foxc1 KD also reduces a panel of cardiomyocyte marker transcripts as well as inhibits the beating of embryoid bodies (EBs). On the other hand, using an inducible Foxc1 overexpression (OE) ESC line, we show that Foxc1 OE increases a panel of cardiomyocyte transcripts and enhances the number beating of EBs. Additionally, Foxc1 OE beating EBs have an enhanced spontaneous beat rate and possess functional electrophysiological properties, beating in synchrony with surrounding cardiomyocytes upon electrical stimulation. RNA-sequencing results identify over 3,000 differentially regulated transcripts after Foxc1 OE during cardiomyogenesis.

Conclusion:
Both molecular and functional analyses reveal a positive correlation between Foxc1 expression level and cardiomyogenesis. Currently chromatin-immunoprecipitation sequencing is being performed to determine the direct downstream regulatory network of Foxc1 during cardiomyogenesis.
Abstract 14338: Fast Degrading Tissue-Engineered Vascular Graft With High Cellular Infiltration Inhibits Calcification of the Graft
Authors: Sugiura Tadahisa , Tara Shuhei , Nakayama Hidetaka , Yi Tai , Lee Yong-Ung , Miyachi Hideki , Fukunishi Takuma , Breuer Christopher K , Shinoka Toshiharu
Published: April 2024

Introduction:
Tissue-engineered vascular grafts (TEVGs) are biologically active grafts which are entirely reconstituted by host-derived cells over an inflammation-mediated degradation process. Calcification of the graft is a detrimental condition that can severely impact graft performance. Therefore, preventing graft calcification is of great importance to success of arterial TEVGs.

Hypothesis:
We assessed the hypothesis that the fast degrading TEVGs with high cellular infiltration into the scaffold could inhibit calcification of the grafts.

Methods:
We created two versions of aortic TEVGs: 1) Slow Degrading (SD) group and 2) Fast Degrading (FD) group. Both groups had the same inner layer composed of a 50:50 poly (l-lactic-co-
ε
-caprolactone) copolymer (PLCL) scaffold. However, the outer layer of the SD group was composed of a poly (l-lactic acid) (PLA) nano-fiber whereas the outer layer of the FD group was composed of a combination of PLA and polyglycolic acid (PGA) nano-fiber. The PGA in the outer layer of the FD group will degrade around 2-4 weeks after implantation, which will let more inflammatory cells infiltrate the scaffold than in the SD group. Both TEVGs were implanted in 8-10 week old female mice (n = 10 in each group) as infra-renal aortic interposition conduits. Animals were followed for 8 weeks.

Results:
In the SD group, acute thrombosis occurred in two mice. Von Kossa staining showed calcification of the scaffold in 6 out of 8 grafts in the SD group, but none in the FD group (Fig. A). The cell number in the outer layer of the FD group was significantly higher than in the SD group (2.65 ± 1.91 x 10
3
/mm
2
vs. 0.87 ± 0.65 x 10
3
/mm
2
, FD group and SD group, respectively,
p
=0.02); no significant difference was observed in the inner layer (1.80 ± 0.53 x 10
3
/mm
2
vs. 1.75 ± 0.60 x 10
3
/mm
2
, FD group and SD group, respectively,
p
=0.85) (Fig. A, B).

Conclusions:
In conclusion the fast degrading TEVG with high cellular infiltration inhibited calcification of the grafts.
Abstract 14379: Variation of Percutaneous Coronary Intervention in Patients Resuscitated From Out-of-Hospital Cardiac Arrest- A Statewide Evaluation
Authors: Swor Robert , Qu Lihua , Sawyer Kelly N , Putman Kevin , Fales William
Published: April 2024

Our primary objective is to describe the use of percutaneous coronary intervention (PCI) in patients resuscitated from OHCA using a probabilistic linked statewide EMS and hospital dataset. A secondary objective was to compare variations of care rendered by hospitals across Michigan.

We performed a retrospective study to describe PCI use in Adult (>18 years) OHCA patients resuscitated and transported to Michigan hospitals July 1, 2010 to June 30, 2013. We linked two databases , the Michigan EMS Information System (MI_EMSIS) and the Michigan Inpatient Database (MIDB), using a previously validated methodology to create our dataset. Inter-hospital transfers, duplicate cases, and cases with missing arrest rhythms were excluded. This dataset was queried for patient demographics, EMS cardiac arrest variables, provision of PCI, clinical characteristics(VF, cardiogenic shock (Cshock)), hospital diagnosis (AMI) and outcome. Rates of procedure are reported in aggregate and stratified by clinical characteristics, and, to assess the impact of geography on emergency care by the eight Michigan Emergency Care regions.

During the study period there were 2,855 matched EMS and MHA records, of which 32.1% survived to hospital discharge. PCI was almost exclusively performed in patients with AMI (38.7% vs 1.6%, (OR=39.0, 95% CI 26.7, 56.8). Clinical factors associated with PCI included initial VF (21.6% vs 9.5%, OR=2.6, 95% CI (2.1,3.3) or Cshock (28.6% vs 8.7%, OR=4.2, 95% CI 3.3, 5.3) Rates of PCI statewide and by region are reported in the table and demonstrate significant variation by region.

Conclusion:
We identified relatively low rates of PCI for post arrest patients, which was performed primarily for patients with final diagnosis AMI. Patients with initial VF, or cardiogenic shock were more likely to receive PCI. While geographic factors impact post cardiac arrest care, we observe that a minority of post arrest patients in Michigan receive aggressive reperfusion care.
Abstract 14658: Accuracy of 3D Printed Models of the Aortic Valve Complex for Transcatheter Aortic Valve Replacement (TAVR) Planning: Comparison to Computed Tomographic Angiography (CTA)
Authors: Cai Tianrun , Cheezum Michael K , Giannopoulos Andreas A , Blankstein Ron , Rybicki Frank J , Steigner Michael L , Mitsouras DImitrios
Published: April 2024

Background:
TAVR is a safe alternative to surgical valve replacement. 3D printing is an emerging technology transforming 2D medical images to tangible anatomically accurate models.

Hypothesis:
To determine the accuracy of 3D printed models of the aortic valve (AV) complex for TAVR planning compared to CTA.

Methods:
10 pts with pre TAVR contrast enhanced CTA were randomly selected. The blood pool of the AV complex from proximal ascending aorta above the coronary arteries to the AV annulus was automatically segmented. A 3D printable STL model was exported to Computer Aided Design software and further processed. Models were printed with a material extrusion 3D printer. One reader blinded to CTA measured the max and min diameter of the AV annulus and coronary ostia takeoff height of the printed model with a caliper. Two independent CV imagers performed these measurements in double-oblique CTA reformats. Model measurements were compared to CTA findings by Pearson’s correlation and via the mean and 95% confidence interval (CI) of the absolute difference to CTA compared to CTA interobserver differences.

Results:
3D printed model measurements had excellent correlation to CTA (r=.86-.97). Mean absolute difference in max diameter between 3D-printed model and CTA was 0.85 mm (CI: [.43, 1.28]), compared to 1.17mm (CI: [.59, 1.75]) between CTA readers; for min diameter it was 0.49mm (CI: [.2, .78]) compared to 0.45mm (CI: [.17, .73]) between CTA readers. Mean absolute difference of height to left main ostium was 1.62mm (CI: [.93, 2.3]) compared to 1.47 mm (CI: [.78, 2.16]) for CTA readers, and to right coronary ostium it was 1.0 mm (CI: [0.53-1.46]) compared to 1.98 mm (CI: [1.38, 2.58]) for CTA readers.

Conclusion:
CTA-derived 3D printed models of the AV complex provided excellent correlation to CTA measurements of the annulus and ostia height. 3D printing can assist towards planning of TAVR sizing and minimizing procedural complications such as paravalvular leak and coronary occlusion.
Abstract 14682: Impact of Life-Style Change on the Arrhythmia Status in Patients With Long-Standing Persistent Atrial Fibrillation
Authors: Mohanty Sanghamitra , Mohanty Prasant , Trivedi Chintan , Gianni Carola , Gunes Mahmut F , Gokoglan Yalcin , Al-Ahmad Amin , Burkhardt John David , Sanchez Javier , Horton Rodney , Hranitzky Patrick , Gallinghouse G. J , Hao Steven , Hongo Richard , Di Biase Luigi , Natale Andrea
Published: April 2024

Background:
Aggressive life-style changes by reversing obesity reportedly cause significant decrease in arrhythmia burden and symptom severity, thereby reducing or eliminating the need for arrhythmia medications in AF patients. However, these observations were documented in populations comprised primarily of paroxysmal and persistent AF patients. This study investigated the impact of lifestyle changes on AF status and quality of life (QoL) in long-standing persistent (LSPAF) patients.

Methods:
Fifty-two LSPAF patients [age 64±10 years, 71% male, weight 256 (IQR 216 -342) lb.] were included in this prospective analysis. Subjects that volunteered to try weight-loss interventions undertook aggressive diet and exercise measures for 1 year while remaining on anti-arrhythmic drugs. They received Individualized diet menus prepared by experienced nutritionists to achieve targeted weight loss and were prescribed moderate-intensity exercise; 150 minutes/week of brisk walking (15 minutes a mile) or bicycling slower than 10 miles per hour. At the beginning and end of the intervention period, body weight was measured; arrhythmia status was evaluated by ECG, Holter and Atrial Fibrillation Symptom Severity (AFSS) survey and QoL was assessed by SF-36 survey. A scoring algorithm with two summary measures, PCS and MCS was prepared for QoL analysis.

Results:
After 1-year of intervention, significant reduction in body weight (median -54 (IQR -42 to -120) lb., p<0.001) was observed. Also, the PCS and MCS scores demonstrated substantial improvement with a change from baseline of 8.4±3 (p=0.013) and 12.8±8.2 (p <0.02) respectively. However, no such impact was observed on the AF symptoms. Two (3.8%) and 3(5.8%) patients were asymptomatic, 18(34.6%) and 15(28.8%) had mild, 28(53.8%) and 31(56.9%) had moderate, and 4(7.7%) and 3(5.8%) patients experienced severe symptoms, pre- and post-intervention respectively (p=0.85). Similarly, very little change in AF burden was observed at the end of the intervention. All patients underwent catheter ablation for AF, eventually.

Conclusions:
In LSPAF patients, aggressive life-style changes lead to considerable weight-loss and improvement in quality of life. However, substantial weight loss does not alter the AF status.
Abstract 14687: Mortality Among Patients Hospitalized With Congestive Heart Failure and Diabetes Mellitus: Results From the National Inpatient Sample, 2000 - 2010
Authors: Win Theingi T , Davis Herbert T , Laskey Warren K
Published: April 2024

Background:
Case-fatality and hospitalization rates for heart failure (HF) patients have been steadily decreasing. However, the prevalence of diabetes mellitus (DM), a risk factor and frequent co-existing condition of HF, continues to increase in the general population. Our aims were to assess the prevalence and impact of DM among adult patients hospitalized with HF with particular emphasis on age-, sex- and race/ethnicity-specific in-hospital mortality rate.

Methods:
We used the National Inpatient Sample to estimate trends in DM prevalence and in-hospital mortality among hospital discharge records with HF as the primary discharge diagnosis from 2000-2010 using survey data-analysis methods. Multivariable logistic regression was used to assess the impact of the above demographic characteristics on in-hospital mortality while adjusting for time (year).

Results:
Overall mortality among 749,910 patients with HF declined from 4.0% in 2000 to 2.3% in 2010 (p<0.0001). Over this interval the prevalence of DM in HF patients increased from 35.9% to 37.5% (p < 0.0001). Age standardized mortality in this group (n=261,620) deceased from 3.2% in 2000 to 1.6% in 2010 (Figure). However, not all demographic sub-groups shared equally in this decrease. Males remained at increased risk compared to females (OR=1.069, 95% CI=0.96, 1.20), non-white minority patients remained at decreased risk compared to non-Hispanic whites (OR=0.612, 95% CI=0.54, 0.69) and older patients (≥ 60 years) remained at increased risk compared to their younger counterparts (< 60years) (OR=3.30, 95% CI=2.78, 3.92).

Conclusions:
In-hospital mortality among patients with HF and DM has significantly decreased over the past decade although important differences among demographic sub-groups remain and represent potential opportunities for further reduction in in-hospital mortality.
Abstract 14699: Patterns of Postoperative Transprosthesis Aortic Valve Gradients Predict Bioprosthetic Structural Valve Deterioration
Authors: Attia Tamer , Soltesz Edward , Rajeswaran Jeevanantham , Roselli Eric , Smedira Nicholas G , Sabik III Joseph F , Svensson Lars , Blackstone Eugene H , Johnston Douglas R
Published: April 2024

Objectives:
To identify 1) patient, procedure, and postoperative variables associated with the development of structural valve deterioration (SVD) in bioprosthetic aortic valves (AV), and 2) the relation between the initial and increasing postoperative gradients requiring explant for SVD

Methods:
From 1982 to 2011, 5,006 patients underwent aortic valve replacement (AVR) with a pericardial PERIMOUNT bioprosthesis and had at least 2 postoperative echocardiograms available for analysis. Mean size of the implanted prosthesis was 23±2.3 mm. Joint modeling of longitudinal AV mean gradient and time to explant for SVD was performed to assess the effect of pattern parameters on risk of explant for SVD.

Results:
Mean initial AV gradient was 14±3.0 mmHg. Mean increase in gradient was 0.51±0.74 mmHg/year. One hundred eighteen patients underwent prosthesis explant for SVD. The majority of patients had no to minimal gradient increase over 15 years. A small percentage had progressive gradient increase. Rate of mean gradient increase correlated with risk of explant (P<.0001; Figure). This effect was evident at a rate of increase above 1.5 mmHg/year. A sharper increase was associated with younger age, isolated AV replacement, smaller prosthesis size, and lower creatinine.

Conclusion:
After AVR with PERIMOUNT bioprosthesis, most patients have very stable gradients out to 15 years. A rate of AV gradient increase of ≥1.5 mmHg/year is predictive of SVD and need for early future reintervention. In contrast to current guidelines, early frequent echocardiographic surveillance is warranted.

Figure legend:
Effect of rate of change of aortic valve (AV) mean gradient (MnGrad) for different starting gradients on the risk of explant for structural valve deterioration (SVD).
Abstract 14706: Cardiac Phenotype in Children Undergoing Screening for Familial Hypertrophic Cardiomyopathy: Is it Time to Change Screening Guidelines?
Authors: Zahavich Laura , Mathew Jacob , Wilson Judith , George Kristen , Bowdin Sarah , Benson Leland N , Mital Seema
Published: April 2024

Introduction:
Current hypertrophic cardiomyopathy (HCM) screening guidelines recommend that clinical and/or genetic screening of children with family history of HCM be initiated from age 10 years (European Society of Cardiology 2014) or 12 years (American Heart Association 2011) onward and earlier only in the presence of malignant family history, presence of symptoms and/or participation in competitive sports. We assessed the proportion of asymptomatic children undergoing HCM screening that developed HCM phenotype or major adverse cardiac events (MACE) prior to age 12 years.

Methods:
This was a single centre retrospective study of HCM kindreds referred for screening to our cardiomyopathy clinic. Index cases with HCM, and cases with secondary cardiomyopathy (metabolic, neuromuscular, syndromic) were excluded. Genotype and phenotype status at initial screening and last follow-up were analyzed. MACE was defined as occurrence of death, transplant, resuscitated cardiac arrest, implantation of ICD or myectomy.

Results:
From 2005-2014, 427 children were referred for cardiac screening secondary to a family history of HCM. Of these, 379 (88.8%) had first-degree relatives with HCM and 146 (34.1%) had a family history of sudden cardiac death. The median age at first screening was 7.4 years (range 1 day-17 years), and median follow-up duration was 3 years. 45% (13/29 tested) phenotype-positive children, and 53% (32/60 tested) phenotype-negative children has positive genetic testing. 27/427 (6.3%) were phenotype-positive (maximal LV wall thickness Z-score >2.0) at initial screening and an additional 13 (3%) became phenotype-positive during follow-up. The median age at positive phenotypic diagnosis of HCM was 8 years (range 5 days-17 years) with 24 children being <12 years old (5.6%). 11/427 (2.6%) suffered a MACE during follow-up. Median age at MACE occurrence was 10.9 years (range 6-15 years) with 6 children being <12 years old at occurrence of MACE (1.4%).

Conclusion:
Overall, more than 5% children being screened for HCM were phenotype-positive and 1.4% suffered a MACE before 12 years of age. These data suggest the importance of revising existing guidelines to recommend clinical and/or genetic screening of HCM of all family members independent of age.
Abstract 14809: Murc/cavin-4 Regulates Cardiac Function via β-adrenergic Receptor Signaling
Authors: Hamaoka Tetsuro , Ogata Takehiro , Naito Daisuke , Nakanishi Naohiko , Miyagawa Kotaro , Maruyama Naoki , Kasahara Takeru , Nishi Masahiro , Shirayama Takeshi , Ueyama Tomomi
Published: April 2024

Background:
Muscle-restricted coiled-coil protein (MURC), also referred to as Cavin-4, is a member of the cavin family, which regulates caveolae function together with caveolins. In cardiomyocytes, caveolin-3, a critical and muscle-specific component of caveolae, regulates caveolar structure and function and forms a complex with MURC/Cavin-4. Caveolin-3 overexpression induces cardiac protection, and caveolin-3 deficiency causes progressive cardiomyopathy. The caveolin-3 scaffolding domain peptide inhibits type 5 adenylyl cyclase (AC5), which is an enzyme to synthesize cAMP and an effector of β-adrenergic receptor (AR) signaling. Mutations in MURC/Cavin-4 have been identified in patients with dilated cardiomyopathy. However, molecular mechanisms of MURC as a caveolar component in cardiac function remain unknown.

Methods and results:
To assess the role of MURC/Cavin-4 in cardiac function, wild-type (WT) and MURC/Cavin-4-knockout (MURC-KO) mice were subjected to a model of pressure overload induced by transverse aortic constriction (TAC). After TAC, WT mice showed cardiac hypertrophy and heart failure, whereas MURC-KO mice were resistant to pressure overload-induced cardiac hypertrophy and heart failure accompanied by fibrosis. We then focused on β-AR signaling, because β1-AR signaling is one of the essential parts in heart failure. MURC/Cavin-4 was co-localized with β1-AR in cardiomyocytes. Isoproterenol (ISO) treatment induced cardiac hypertrophy with fibrosis in WT mice, while ISO-induced cardiac hypertrophy and fibrosis was markedly attenuated in MURC-KO mice. In cardiomyocytes, MURC/Cavin-4 knockdown suppressed ISO-induced cAMP production, while MURC/Cavin-4 overexpression and caveolin-3 knockdown stimulated cAMP production, indicating that caveolin-3 and MURC/Cavin-4 have opposite effects on cAMP production. MURC/Cavin-4 bound to caveolin-3 and interferes with the association between caveolin-3 and AC5. Moreover, MURC-knockdown suppressed ISO-induced PKA activity and phospholamban phosphorylation.

Conclusion:
Our findings suggest that MURC/Cavin-4 regulates cardiac function via β-AR signaling.
Abstract 14810: Relationship of Baseline Right Ventricular Function With Response to Cardiac Resynchronization Therapy
Authors: Sharma Abhishek , Vallakati Ajay , Goel Sunny , Lavie Carl , Kassotis John , Warrier Nikhil , Mukherjee Debabrata , Lazar Jason , Einstein Andrew J
Published: April 2024

Background:
Right ventricular (RV) dysfunction has been associated with adverse clinical outcomes in patients with heart failure (HF). Cardiac resynchronization therapy (CRT) improves left ventricular (LV) size and function in patients with markedly abnormal ECG QRS duration. However, relationship of baseline RV function with response to CRT has not been well described.

Objective:
To investigate the relationship of baseline RV function with response to CRT as assessed by change in LV ejection fraction (LVEF).

Methods:
A systematic search of studies published between 1966 to February 2015 was conducted using Pub Med, CINAHL, Cochrane CENTRAL and the Web of Science databases. Studies were included if they have reported a) parameters of baseline RV function [tricuspid annular plane systolic excursion (TAPSE) or RV ejection fraction (RVEF) or RV basal strain or RV fractional area change (FAC)] and b) LVEF before and after CRT. Random-effects meta-regression was used to evaluate the effect of baseline RV function parameters and change in LVEF.

Results:
Sixteen studies (N=1764) were selected for final analysis. Random-effects meta-regression analysis showed no significant association between the magnitude of the difference in EF pre and post CRT with baseline TAPSE (beta 0.005, p 0.989); baseline RVEF (beta 0.270, p 0.493); baseline RVFAC (beta - 0.367, p 0.06); baseline basal strain (beta -0.342, p= 0.462) after a mean follow up period of 10.5 months

Conclusion:
Baseline RV function as assessed by TAPSE, FAC, basal strain or RVEF, does not determine response to CRT as assessed by change in LVEF. Future studies should assess the relationship of baseline RV function with response to CRT in terms of improvement in symptoms, quality of life and major HF morbidity and mortality.
Abstract 14838: Regional Contributions to Impaired Myocardial Mechanical Function in Heart Failure With Preserved Ejection Fraction
Authors: Biering-Sørensen Tor , Cikes Maja , Kraigher-Krainer Elisabeth , Shah Amil M , Solomon Scott D , Cheng Susan
Published: April 2024

Background:
The pathophysiology underlying the transition from hypertensive heart disease (HHD) to heart failure with preserved ejection fraction (HFpEF) remains unclear. Regional differences in impaired myocardial function may contribute to the more pronounced overall mechanical dysfunction seen in HFpEF compared to HHD.

Methods:
We assessed regional myocardial deformation in 129 HFpEF patients, 158 hypertensive patients with HHD and no heart failure, and 40 healthy controls. Peak systolic strain was assessed in the apical 4 and 2 chamber views and the average was calculated for the 4 apical (ALS), 4 mid ventricular (MLS) and 4 basal (BLS) regions.

Results:
All 3 groups had preserved left ventricular ejection fraction (LVEF ≥50%). Whereas BLS and MLS were more impaired in HHD than in controls, ALS was significantly more impaired in HFPEF than HHD (Figure). In area under the receiver operating curve (AUC) analyses, ALS was the best diagnostic marker for differentiating HFpEF from HHD (AUC: ALS=0.67; MLS=0.59; BLS=0.60). After adjusting for the main characteristics that differed between HFpEF and HHD (age, e’, systolic blood pressure, NT-pro BNP, LV end-diastolic volume, and LVEF), ALS remained independently associated with HFpEF vs. HHD status (OR 1.18 [1.02-1.37], P=0.030 per 1% decrease). By contrast, global longitudinal strain was not significantly associated with HFpEF vs. HHD status in multivariable analyses (P=0.09).

Conclusion:
We observed that whereas basal and mid-level longitudinal strain is more impaired in HHD than in controls, apical longitudinal strain is substantially more impaired in HFPEF than HHD. These findings suggest that preservation of apical mechanical function may play an important role in the transition from HHD to HFPEF.
Abstract 14916: Adverse Event Reporting in >48,000 Participants in Four Acute Coronary Syndrome Trials
Authors: Zimerman André , Stebbins Amanda L , Lopes Renato D , Guimarães Patrícia O , James Stefan K , Alexander John H , Tricoci Pierluigi , Roe Matthew T , Ohman E. Magnus , Mahaffey Kenneth W , Held Claes , Tinga Brian , Pieper Karen S , Alexander Karen P
Published: April 2024

Background:
Adverse event (AE) collection in randomized clinical trials establishes the safety of investigational products. Although costly and regulated, it is rarely a topic of study.

Methods and Results:
Post-discharge AEs were collected per protocol and classified as serious or non-serious in 48,118 participants from 40 countries enrolled in 4 clinical trials of antithrombotic therapy in acute coronary syndromes (APPRAISE-2, PLATO, TRACER, TRILOGY ACS). Pooled data was used to compare patterns and determinants of AE reporting; study endpoints were excluded. Overall, 46.1% of participants had no AEs, 16.3% had at least 1 serious AE (SAE), and another 37.7% had only non-serious AEs (nsAE). A total of 12,266 SAEs and 72,635 nSAEs were reported. AEs were generally well distributed in most system organ classes, including general disorders (11%), infection (10%), gastrointestinal (10%), respiratory (9%), and other (35%), whereas cardiac events were more common among SAEs (14.0% of SAEs, 8.4% of nSAEs). AE rates, particularly non-serious, were highest after hospital discharge, and decreased rapidly during the following 3 months (Figure 1). Using a Cox proportional hazards model, the independent predictors of having an SAE included older age (HR 1.07, 95% CI 1.05-1.09 for every 5-year increase), female sex (HR 1.11, 95% CI 1.03-1.18), and common comorbidities (HF, COPD, Afib, CKD, DM), while enrollment in Asia (HR 0.84, 95% CI 0.75-0.94) or Eastern Europe (HR 0.63, 95% CI 0.58-0.69) predicted fewer SAEs.

Conclusions:
Most reported AEs are non-serious, non-cardiac, and reported early in follow-up. The high volume of AEs and the significant variation in SAE reporting across patient characteristics and region of enrollment make efforts to focus the approach to AE collection in large trials warranted.
Abstract 14992: Outcomes of Off-Label Use of Transcatheter Aortic Valve Replacement (TAVR) in the U.S.: Insights From the STS/ACC TVT Registry
Authors: Hira Ravi S , Virani Salim S , Vemulapalli Sreekanth , Li Zhuokai , Alam Mahboob , Jneid Hani , McCabe James , Reisman Mark , Kleiman Neal S
Published: April 2024

Background:
TAVR was approved by the US FDA for treatment of severe aortic stenosis (AS) in symptomatic inoperable and high-risk patients. Off-label use of TAVR in the US has not been previously studied.

Methods:
Patients receiving commercially funded TAVR in the US are included in the Transcatheter Valve Therapy (TVT) Registry. Within this registry, we assessed 23,841 patients from 328 sites receiving TAVR between 11/201-9/2014. We evaluated the frequency and outcomes of off-label TAVR use, defined as TAVR in patients with known bicuspid or unicuspid valve, failing bioprosthetic aortic valve, moderate AS, severe mitral or aortic regurgitation or subaortic stenosis. Data were linked with CMS for 15,394 patients to evaluate 30-day and 1-year outcomes.

Results:
Off-label TAVR was used in 2682/23841 patients (11.2%); indications noted in the Table 1. Compared to on-label use, off-label use patients were more likely to be younger, male, receive care in urban, teaching hospitals with higher TAVR volume, have higher STS score (median 7.2 vs 6.8, p <0.0001) and less likely to have elective procedures. In CMS-linked data, patients undergoing off-label TAVR had higher 30-day mortality but similar 1 -year mortality compared to on-label TAVR (Table 2).

Conclusion:
About 1 in 10 patients in the US have received TAVR for an off-label indication. One-year outcomes were similar to on-label indication patients. These results reinforce the urgent need for additional research on the efficacy of TAVR in specific patient cohorts for whom TAVR is being considered in clinical practice.
Abstract 15066: Low Physical Activity and Short Sleep predict Cardiovascular Mortality in Former Male Athletes and Their Controls
Authors: Wennman Heini , Kronholm Erkki , Partonen Timo , Heinonen Olli , Backmand Heli , Kaprio Jaakko , Sarna Seppo , Kujala Urho , Borodulin Katja
Published: April 2024

Background:
Both short and long sleep associate with mortality, and physical activity potentially influences these associations. Former athletes are often physically more active and have a healthier lifestyle also later in life than non-athletic peers. Our aim was to study the interrelationship between sleep, physical activity and mortality in a cohort of former athletes and their healthy controls.

Methods:
The prospective cohort consists of male athletes who competed at national team-level between 1920-1965 and their healthy controls. A baseline health questionnaire was sent to all subjects alive in 1985. The cohort was followed for mortality from national registers until December 31, 2011. Hazard ratios (HR) and 95 % confidence intervals (CI) for all-cause and cardiovascular mortality were estimated by Cox proportional hazards models with age as the time variable and age at baseline in 1985 as the entry. Sleep duration, sleep quality and physical activity level in 1985 were the main predictive variables.

Results:
At baseline, 2141 cohort members answered to the questionnaire, and 1388 (871 former athletes, 517 controls) provided adequate information for the analyses. Former athletes and controls differed in baseline sleep duration, sleep quality and physical activity level. However, these behaviors did not predict mortality neither in athletes or controls after adjustment for baseline socioeconomic status, BMI, smoking, alcohol use, chronotype and history of disease. A significant interaction between sleep duration and physical activity predicting all-cause and cardiovascular mortality was detected. After full adjustments, those sleeping less than 6 hours and having less than 450 MET-hours per week of physical activity had a higher risk for cardiovascular mortality (HR 1.78, 95% CI 1.06-3.00) than those sleeping 6.5 to 8.5 hours and having at least 450 MET-hours physical activity.

Conclusions:
We found a combination of short sleep and low physical activity to be predictive of cardiovascular mortality irrespective of a previous sports career. Neither sleep duration nor sleep quality alone predicted mortality in former athletes or controls, suggesting important clustering of health behaviors.
Abstract 15099: Suppression of Autophagic Flux by Sequestration of p62 Promotes RIP1-mediated Necroptosis in Cardiomyocytes
Authors: Ogasawara Makoto , Yano Toshiyuki , Miki Takayuki , Tanno Masaya , Kuno Atsushi , Kouzu Hidemichi , Tobisawa Toshiyuki , Muratsubaki Shingo , Ohno Kohei , Nishizawa Keitaro , Ishikawa Satoko , Miura Tetsuji
Published: April 2024

Purpose:
Necroptosis, a programmed form of necrosis, has been implicated in various pathological conditions including heart failure. Here we examined whether and how receptor-interacting protein kinase (RIP) 1-dependent necroptosis is functionally linked with autophagy in cardiomyocytes.

Methods and results:
In H9c2 cells, the necroptotic pathway was activated by TNF-α (TNF, 50 ng/ml) alone or by co-incubation of TNF with 20 mM z-VAD-fmk (zVAD), a pan-caspase inhibitor. TNF increased LDH activity in the culture medium from 26.6±4.3% of total LDH activity in the vehicle-treated control to 39.1±4.8%, suggesting induction of necrosis. Addition of zVAD to TNF (TNF/zVAD) further increased the LDH activity to 70.6±2.7%. The augmented cell death by TNF/zVAD was completely reversed by necrostatin-1 (39.4±4.0%), a RIP1 inhibitor, and was attenuated by rapamycin (10 nM), a promoter of autophagy (49.4±2.0%). Immunoblot analyses showed that TNF/zVAD significantly increased the level of LC3-II. The accumulation of LC3-II protein was not further increased by bafilomycin A1 (100 nM), an inhibitor of lysosomal degradation, indicating that accumulation of LC3-II by TNF/zVAD reflected suppression of autophagic flux. Immunoprecipitation experiments revealed that TNF/zVAD reduced interaction between LC3-II and p62, an autophagy adaptor protein, and conversely increased interaction between RIP1 and p62. The changes in p62 interactosomes by TNF/zVAD were reversed by pretreatment with rapamycin. On the other hand, TNF/zVAD-induced cell death when p62 was knocked down was still sensitive to necrostatin-1, indicating that a p62-independent pathway is also involved in RIP1-mediated necroptosis.

Conclusions:
Suppression of autophagic flux by p62 sequesteration from p62-LC3-II complexes and its recruitment to RIP1 promotes RIP1-dependent necroptosis by TNF/zVAD.
Abstract 15310: Intracoronary Doppler Flow Velocity and Pressure Derived Hyperemic Microvascular Resistance is Independent of Epicardial Obstruction in Stable Coronary Artery Disease
Authors: de Waard Guus A , Marques Koen M , Nijjer Sukhjinder S , Teunissen Paul F , van de Ven Peter M , Davies Justin E , Knaapen Paul , van Royen Niels
Published: April 2024

Introduction:
Coronary microvascular function can be assessed invasively by combining measurements of coronary pressure and flow. The index of microcirculator resistance (IMR), obtained using thermodilution derived mean transit time, has conflicting data whether it is influenced by epicardial stenosis severity. For Doppler flow velocity derived hyperemic microvascular resistance (HMR) this has not been investigated. We aimed to explore whether HMR is a microcirculatory specific value.

Methods:
Simultaneous measurements of intracoronary distal Doppler flow velocity and pressure under hyperemic conditions, were obtained in an obstructed and non-obstructed coronary artery in 45 patients. 68 pairs containing one of the 57 obstructed vessels and one of the 55 non-obstructed vessels were formed. HMR was compared between obstructed and non-obstructed vessels using paired samples T-test and the correlation between HMR in the pairs was tested using the Pearson’s test. These analyses were repeated after excluding 3 patients and 7 pairs in which the obstructed vessel had an FFR < 0.60 - which may suggest collateral flow from different territories was present

Results:
In the entire cohort, HMR was 2.51±0.88 in obstructed versus 2.40±0.88 mmHg/cm per second in non-obstructed values, was not significantly different (P=0.331). HMR values in the obstructed and non-obstructed vessels were significantly correlated: R=0.491, P<0.001. After exclusion of obstructed vessels with an FFR < 0.60, HMR approached equipoise in obstructed and non-obstructed vessels: 2.41±0.84 vs. 2.40±0.90 mmHg/cm per respectively (P=0.922). The correlation coefficient improved to: R=0.540; P<0.001 after exclusion of vessels with FFR < 0.60.

Conclusions:
HMR is a microcirculatory specific value that is independent of the presence of a stenosis, especially in vessels not receiving collateral supply. These results indicate that HMR can indeed be used clinically to assess microcirculatory function regardless of the presence of an epicardial coronary stenosis.
Abstract 15395: Estimating Coronary Heart Disease Morbidity and Mortality From Heterozygous Familial Hypercholesterolemia in the United States
Authors: Mendelson Michael M , Sheldrick Radley C , Rodday Angie , Leslie Laurel , Cohen Joshua , Wong John B , de Ferranti Sarah D
Published: April 2024

Introduction:
With an estimated prevalence of 1 in 299 in the United States based on clinical criteria in NHANES (Circulation.2014;130:A19656), heterozygous Familial Hypercholesterolemia (FH) is widely suspected to be underdiagnosed and undertreated in the U.S. despite increased risk for premature coronary heart disease (CHD). The population burden of FH if undiagnosed and untreated in the US population is unknown.

Methods:
Using an FH prevalence of 1 in 250 (0.4%) to account for genotypic FH (in addition to our prior 1 in 299 estimate) and U.S. population census data and assuming 90% undetected and untreated, we developed, calibrated and validated a Markov model of the natural history of FH in the U.S. population, including fatal and nonfatal CHD. A sensitivity analysis considers alternative prevalence and detection rates.

Results:
For the base case 0.4% FH prevalence with 90% of individuals undiagnosed, the model projected that undetected FH led to over 44,000 CHD deaths and over 132,000 years of lost life for a ten-year period. The model also predicted that 37% (range 23-62%) would develop premature (age < 60 years) CHD and 59% (range 43-77%) would develop fatal or nonfatal CHD. Missed FH diagnosis account for 2.4% of premature CHD deaths and 0.6% of all CHD deaths in the U.S. The figure provides estimates of the proportion of premature CHD mortality attributable to undetected FH for varying estimates of prevalence and detection prior to CHD event.

Conclusions:
Undetected FH, a disease that can be safely and effectively treated, significantly contributes to overall CHD mortality in the U.S., particularly premature CHD. Strategies to attain AHA 2020 prevention goals would be enhanced by incorporating efforts to determine and implement optimal national population strategies to detect and treat FH.
Abstract 15470: Long Term Durability and Haemodynamic Performance of Freedom Solo Stentless Valve for Aortic Valve Replacement: A European, Multicenter Experience
Authors: Repossini Alberto , Passaretti Bruno , Di Bacco Lorenzo , Muneretto Claudio , Nicoli Flavia , Bisleri Gianluigi , Arena Vincenzo , Schäfer Christina , Claus Benjamin , Grubitzsch Herko
Published: April 2024

Introduction:
Stentless aortic valves have been developed to overcome the obstructive limitations associated with stented bioprostheses. The Freedom Solo (FS) bovine pericardial valve is a third generation stentless bioprosthesis introduced in 2004 and FDA approved in 2014.

Hypothesis:
The aim of the current study is to report the multi-institutional experience by the three European centers that started implanting FS extensively as first from its introduction, providing the largest series with long-term follow-up.

Methods:
From 2004 to 2009, 478 patients (mean age 73±8.6 years, 199 [41.6%] females) underwent isolated (n=321) or combined (n=157) aortic valve replacement (AVR) with the FS. Follow-up, including clinical and strict echocardiographic evaluation, was 97.4% complete with an average follow-up time of 6.5±3.2 years (maximum 11.4 years) and cumulative follow up was 2612 patient/years. Primary end-point was freedom from structural valve deterioration (SVD) while secondary end-points were freedom from reoperation and overall survival.

Results:
Overall operative mortality was 2.9% (1.5% for isolated and 5.7% for combined AVR) and none was valve-related. Preoperative peak(mean) gradients were 76.1±30.6 mmHg (47.1±18.7 mmHg) decreased to 17.7±9.1 mmHg (9.9±5.4 mmHg), stable over the follow-up. Post-operative effective orifice area was 1.8±0.6 cm2, 1.98±0.5 cm2, 2.13±0.43 cm2 and 2.21±0.56 cm2 for valve size 21, 23, 25, and 27 respectively. There was no severe prostheses-patient mismatch (PPM) and moderate PPM occurred only in 1 patient(0.2%). Twenty-four patients (5.7%) underwent reoperation (16 surgical replacement, 8 TAVR) due to endocarditis(9), blunt trauma(1), and SVD(14). SVD was reported in 5 other patients alive at time of censor. Freedom from SVD and reoperation were 90.6% [88.2-93%] and 88.3% [85.8-90.8%] respectively at 10 years follow-up, while overall actuarial survival was 55.8% [52.5-59.1%].

Conclusions:
The FS valve demonstrated excellent hemodynamic performance and long-term durability in this large, multi-institutional European experience. In particular, the FS proved to be a reliable bioprosthesis in aortic position given the low rate of structural valve deterioration along with a simple implantability.
Abstract 15513: Tolvaptan Alone Significantly Worsend Left Ventricular Remodeling and Survival Rate via Increase of the Aquaporin 1 in Kidney in Murine Heart Failure After Myocardial Infarction
Authors: Eguchi Akiyo , Hirotani Shinichi , Iwasaku Toshihiro , Okuhara Yoshitaka , Morisawa Daisuke , Sawada Hisashi , Oboshi Makiko , Naito Yoshiro , Mano Toshihiro , Masuyama Tohru
Published: April 2024

Background:
Little is known about the chronic effects of Tolvaptan, V2 receptor antagonist. Therefore, we examined the chronic effects of administration of tolvaptan and/or furosemide on survival, cardiac and renal histology in murine heart failure after myocardial infarction.

Methods:
Fourteen days after ligating the left anterior descending coronary artery (MI), mice were randomly assigned to either placebo (P), Tolvaptan (T), or furosemide and T (FT) treatment. Survival rate was examined in each group. After four weeks after diuretic treatments, mice were sacrificed and cardiac histological analyses and cardiac and renal mRNA expression were examined.

Results:
First, we compared survival rates of P- or T-treated mice. Surprisingly, the survival rate of P group was significantly higher than that of T group (73.7% vs. 58.3%, p<0.05). Four weeks after diuretic treatments, heart weight (HW)/body weight (BW) and lung W (LW)/BW were significantly higher in T group than in P group (HW/BW; 5.9 ± 0.2 vs. 6.8 ± 0.2 p <0.05, LW/BW 5.3 ± 0.2 vs. 7.8 ± 0.8 p <0.05). Next, to reduce congestion in T group, we fed the MI mice with FT containing chow. FT treatment improved survival rate compared with T treatment (61.5% vs. 71.4%, p<0.05). After four weeks of the treatment, HW/BW and LW/BW decreased in FT group compared with in T (HW/BW; 6.7 ± 0.2 vs. 5.5 ± 0.1 p <0.05, LW/BW; 7.0 ± 0.6 vs. 5.6 ± 0.2 p <0.05). FT treatment significantly suppressed myocardial fibrosis in remote myocardium compared with T treatment. Furthermore mRNA levels of ANP, BNP, and collagen I in the remote myocardium in FT group were lower compared with T group (ANP: 1 ± 0.1 vs. 0.5 ± 0.1 p <0.05, BNP; 1 ± 0.03 vs. 0.6 ± 0.04 p < 0.05, Collagen I; 1 ± 0.08 vs. 0.6 ± 0.1 p < 0.05). Interestingly, mRNA level of Aquaporin 1 (AQP1), which is a key transporter of free water absorption in proximal tubule, increased in T group compared with P group, and it reduced in FT group compared with T group (AQP1; 3.3 ± 0.4 vs. 4.2 ± 0.1 p < 0.05, 4.1 ± 0.05 vs. 2.0 ± 0.2 p < 0.05).

Conclusion:
T treatment increased congestion and worsenend survival in murine heart failure. FT treatment successfully improved congestion and survival compared with T treatment. The mechanism by which T treatment failed to reduce congestion and mortality may be due to upregulation of AQP1.