bluuebunny/crossref_metadata_2025 huggingface dataset:
P1027The risk of dementia and catheter ablation for atrial fibrillation: a nationwide cohort study
Authors: Yang P S , Sung J H , Jang E , Yu H T , Kim T H , Uhm J S , Kim J Y , Pak H N , Lee M H , Joung B
Published: October 2019

Background

Atrial fibrillation (AF) is associated with all forms of dementia, including Alzheimer's disease. Catheter ablation of AF reduces the number of AF episodes, prolongs the time in sinus rhythm, and improves quality of life. However, it is still unclear if catheter ablation for AF improve cognitive function and prevent dementia. Our objective was to compare long-term outcome regarding dementia and type of dementia in AF patients with and without ablation, and about long-term exposure to anticoagulants.

Methods

We identified all 801,701 patients with a diagnosis of AF from 2006 to 2015 in the Korean national health insurance service database. During ten years, 10,979 AF ablations were performed among 9,768 individuals. Propensity scores for the likelihood of AF ablation were obtained by logistic regression. Propensity score (PS) matching was used to construct two cohorts of equal size (n=9,768) with similar characteristics in 16 dimensions.

Results

Patients who had undergone catheter ablation were younger (57.2 vs. 65.6 years, P<0.001) and healthier (mean CHA2DS2-VASc scores 2.5±1.7 vs. 3.6±2.1, p<0.001) than other patients with AF. Mean follow-up was 5.5±3.1 years. After propensity score matching, in the ablated group, 184 patients suffered dementia compared with 650 in the matched non-ablated (annual rates 0.42 vs. 1.08%, P<0.001). While a total of 134 ablated and 379 non-ablated patients had Alzheimer disease (annual rates 0.31 vs. 0.62%, p<0.001), 40 ablated and 191 non-ablated patients had vascular disease (annual rates 0.09 vs. 0.31%, p<0.001). After multivariable adjustments, catheter ablation was associated with lower risk of dementia (hazard ratio [HR] 0.46, 95% confidence interval [CI] 0.37–0.58), lower risk of Alzheimer disease (HR 0.61, 95% CI 0.46–0.79) and lower risk of vascular dementia (HR 0.27, 95% CI 0.19–0.38). Although the reduction of dementia and Alzheimer disease was observed after AF ablation regardless of thromboembolic risk, vascular dementia was reduced only among patients with CHA2DS2-VASc score ≥2 (HR 0.29, 95% CI 0.20–0.42).

The risk of dementia, RFCA vs. no-RFCA Type Propensity score matched ablation group vs. no ablation group adjusted HR (95% CI) P-value Overall dementia 0.46 (0.37–0.58) <0.001 Alzheimer dementia 0.61 (0.46–0.79) <0.001 Vascular dementia 0.27 (0.19–0.38) <0.001

Conclusion

Ablation may be associated with a lower incidence of dementia and both type of dementia in patients with AF. This finding appears more pronounced in patients with high thromboembolic risk factors.
P1031The impact of the duration of atrial fibrillation persistence for arrhythmia free survival in patients undergoing catheter ablation
Authors: Furukawa Y , Yamada T , Morita T , Tamaki S , Kawasaki M , Kikuchi A , Kawai T , Seo M , Abe M , Nakamura J , Kayama K , Kawahira M , Tanabe K , Fukunami M
Published: October 2019

Background

Catheter ablation (CA) for atrial fibrillation (AF) is a curable treatment option. However, AF recurrence after CA remains an important problem. Although the success rate has been improved after catheter ablation (CA) in patients with paroxysmal AF (PAF), outcome data after CA for persistent AF (PeAF) are highly variable. Previous studies showed the PeAF is one of independent predictors for AF recurrence in comparison to PAF. However, there are little information available on the prognostic significance of AF duration after CA for AF. The aim of this study is to evaluate the impact of AF duration on long-term outcomes of AF ablation in patients with PeAF compared with PAF.

Methods

We enrolled 778 consecutive patients, who were referred our institution between August 2015 and December 2017 for undergoing the first time CA for AF. We divided 5 groups (Group 1; PAF (n=442), Group 2; PeAF duration ≤6 months (n=198), Group 3; PeAF duration of 6 months to 2 years (n=87), Group 4; PeAF duration of 2–5 years (n=30) and Group 5; PeAF duration ≥5 years (n=21)). All patients followed up for at least 1 year. Outcome data on recurrence of AF after ablation were collected.

Results

There were no significant differences in baseline clinical characteristics before CA among 5 groups, except for the prevalence of congestive heart failure, left atrial diameter and left ventricular ejection fraction. During a mean follow-up period of 511±298 days, 217 patients had AF recurrence. Kaplan-Meier analysis revealed that AF recurrence was significantly higher in group 2 compared to group 1 (31% vs 20%, p=0.002) and in group 4 compared to group 3 (83% vs 30%, p<0.0001). However, AF recurrence was no significantly differences between groups 2 and 3 (31% vs 30%, p=0.76) and between groups 4 and 5 (83% vs 81%, p=0.45). Of 217 patients with AF recurrence, 154 patients had undergone multiple procedures. After last procedures, during a mean follow-up period of 546±279 days, 61 patients had AF recurrence. Kaplan-Meier analysis revealed that AF recurrence was significantly higher in group 2 compared to group 1 (10% vs 3%, P=0.0005) and in group 4 compared with group 3 (35% vs 10%, p=0.0001). However, AF recurrence was no significantly difference between groups 2 and 3 (10% vs 10%, p=0.91) and between groups 4 and 5 (47% vs 35%, p=0.47).

AF Free Survival Curve

Conclusion

Although patients with PeAF within 2 years had significantly higher AF recurrence compared to PAF, AF ablation might still be a good contributor as the first line approach to improve outcomes in patient with PeAF within 2 years.
P1037Relationship between left atrium low voltage areas and atrial fibrillation radiofrequency ablation success-rate: preliminary results of the SMOP study
Authors: Rordorf R , Cornara S , Frigerio L , Sanzo A , Chieffo E , La Greca C , Sirico G , Scopinaro A , Solimene F , Fedele L , Augello G , Marrazzo N , Turreni F , Tritto M
Published: October 2019

Background

radio frequency catheter ablation (CA) is an effective therapy for atrial fibrillation (AF). Some authors have described a potential relationship between the presence of areas of fibrosis in the left atrium (LA) and the success of CA, nevertheless there is a lack of multicenter studies in this field.

Objective

the aim of our study was to assess the relationship between the of presence of low voltage areas of the LA detected during subtrate mapping at the time of the procedure and recurrences of AF after CA.

Methods

we analyzed 214 patients of the SMOP-AF (Substrate Mapping as Outcome Predictor in Atrial Fibrillation Ablation), a prospective multi-centric study enrolling patients with both paroxysmal and persistent AF undergoing a first radio-frequency CA procedure. High-density mapping was performed in sinus rhythm using the CARTO system before performing pulmonary vein isolation. Areas with less than 0,5 mV on mapping were defined as low voltage zone (LVZ), while between 0,5 mV and 1,5 mV intermediate voltage zone (IVZ). IVZ and LVZ were expressed as a percentage of the LA surface. Comparisons were made by Pearson correlation, cross-tables and Chi-square test or Student T test.

Results

the mean age of the enrolled population was 59±9 years, left ventricular ejection fraction was 59±9%, 86.4% of the pts had tested at least one anti-arrhythmic drug. Persistent atrial fibrillation was present in 10.3% of patients. The rate of documented AF recurrence at 3 months was 15,3% (n=29). There was a statistical significant correlation between the presence of IVZ and the rate of recurrences at 3 months (r=0.16, p value 0.03). Patients with IVZ greater than 4% of the left atrium surface showed a higher risk of recurrences (19.5% vs. 8,7%, p value 0.04). No statistical difference was observed in other procedural variables (number of lesions, contact force, force-time integral) among patients with or without recurrences.

Conclusion

Our study showed a relationship between CA short-term success rate and the presence of areas of intermediate voltage zone detected with high-density substrate mapping at the time of the procedure. The presence of areas of intermediate voltage zone greater than 4% of the LA determines a 2.5 folds increased risk of short-term recurrence. Our data needs to be confirmed in a longer follow-up.
1135Angiotensin receptor-neprilysin inhibition in patients with de novo acute decompensated heart failure: a prespecified subgroup analysis of the PIONEER-HF trial
Authors: Ambrosy A , Braunwald E , Morrow D , Devore A , McCague K , Duffy C , Rocha R , Velazquez E
Published: October 2019

Background

The efficacy, safety, and tolerability of an angiotensin receptor-neprilysin inhibitor (ARNi) in patients presenting with de novo heart failure (HF) has not been previously well-defined.

Methods

The PIONEER-HF trial was a prospective, multicenter, double-blind, active-controlled, randomized clinical trial which enrolled 887 patients (pts) at 129 sites in the United States. Pts with or without a history of prior HF and an ejection fraction (EF) <40% and a NT-proBNP >1600 pg/mL or BNP >400 pg/mL were eligible for participation no earlier than 24 hours while still hospitalized for acute decompensated HF (ADHF). Pts were randomly assigned 1:1 to in-hospital initiation of sacubitril/valsartan (S/V) titrated to 97/103 mg vs. enalapril titrated to 10 mg both by mouth twice daily for 8 weeks. We performed a pre-specified analysis in pts with de novo HF (i.e., defined as pts without a history of HF prior to the qualifying ADHF event).

Results

At the time of enrollment, 34% (N=303) had de novo HF. These pts experienced a similar improvement in NT-proBNP with S/V vs. enalapril (Ratio of geometric means 0.65, 95% Confidence Interval [CI] 0.53–0.81; p-value = 0.0002) compared to pts with worsening chronic HF (ratio 0.72 (0.63–0.83, p-value <0.0001) (Figure). In addition, the incidence of worsening renal function, hyperkalemia, and hypotension was comparable with S/V vs. enalapril regardless of whether they were hospitalized for de novo or worsening chronic HF. Finally, there was no interaction (p-value = 0.350) between previous HF status and the effect of S/V on the composite of cardiovascular death or rehospitalization for HF (de novo HF: Hazard Ratio [HR] 0.34, 95% CI 0.11–1.05 vs. worsening chronic HF: HR 0.60, 95% CI 0.39–0.93).

Conclusion

Among patients admitted for ADHF, irrespective of prior HF history, in-hospital initiation of an ARNi led to a greater reduction in natriuretic peptide levels, a comparable safety profile, and a significant improvement in clinical outcomes.

Acknowledgement/Funding

Novartis
1169Interim analysis of data from a long-term, extension trial of tafamidis meglumine in patients with transthyretin amyloid cardiomyopathy
Authors: Elliott P , Drachman B M , Gottlieb S S , Hoffman J E , Hummel S L , Lenihan D J , Ebede B , Gundapaneni B , Schwartz J H , Sultan M B , Shah S J
Published: October 2019

Background

Transthyretin amyloid cardiomyopathy (ATTR-CM), is an underdiagnosed, fatal disease caused by the deposition of transthyretin amyloid fibrils in the heart leading to heart failure. The Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT), an international, multi-center, double-blind, placebo-controlled, randomized study, demonstrated the efficacy and safety of tafamidis treatment for patients with ATTR-CM due to variant (ATTRm) or wild-type (ATTRwt) TTR.

Purpose

This is a pooled analysis of data from ATTR-ACT and interim data from the ongoing, long-term, extension study to evaluate longer term data on the efficacy of tafamidis in patients with ATTR-CM.

Methods

Patients who completed ATTR-ACT (which had a duration of 30 months) were eligible to be enrolled in a long-term, extension study in which patients either continued to receive tafamidis meglumine at the same dose (the tafamidis/tafamidis [T/T] group) or, for patients previously treated with placebo, were randomised (in a 1:2 ratio) to tafamidis meglumine 20 mg or 80 mg (the placebo/tafamidis [P/T] group) for up to 60 months. The primary efficacy outcome was all-cause mortality. This analysis combined data from the completed ATTR-ACT with interim data from the extension study (cut-off date: 15 Feb, 2018), and included patients treated with tafamidis meglumine across the two studies with a median follow up of 36 months.

Results

All-cause mortality was significantly lower in the T/T group (n=264; 88 events, 33.3%) compared with the P/T group (n=177; 88 events, 50.3%); hazard ratio (95% CI), 0.64 (0.47, 0.85); P=0.001. In the subgroup of ATTRwt patients, all-cause mortality was significantly reduced in the T/T group (55/201; 27.4%) compared with the P/T group (60/134; 44.8%); 0.64 (0.44, 0.92); P=0.002. In the 106 (24.0%) ATTRm patients, there was a trend towards a reduction in all-cause mortality in the T/T group (33/63; 52.4%) compared with the P/T group (29/43; 67.4%); 0.66 (0.39, 1.09); P=0.17. In patients who were NYHA Class I or II at baseline, all-cause mortality was significantly reduced in the T/T group (38/186; 20.4%) compared with the P/T group (45/114; 39.5%); 0.49 (0.32, 0.75); P=0.001. In those patients with more severe symptoms at baseline (NYHA Class III), there were fewer deaths in the T/T group (50/78; 64.1%) compared with the P/T group (44/63; 69.8%); 0.80 (0.53, 1.21), but this difference was not statistically significant (P=0.50).

Conclusions

In ATTR-ACT, tafamidis was shown to significantly improve survival, functional capacity, and quality of life in patients with ATTR-CM. This pooled analysis with data from the ongoing extension study further supports the efficacy of tafamidis in patients over a longer period of time and the importance of early diagnosis and treatment.

Acknowledgement/Funding

This study was sponsored by Pfizer.
1176Hepatocyte growth factor has prognostic utility in light chain and transthyretin cardiac amyloidosis
Authors: Zhang K W , Kraja A , Miao J , Tomasek K , Su Y R , Lenihan D J
Published: October 2019

Background

With the advent of multiple novel therapeutics for light chain (AL) and transthyretin (ATTR) amyloidosis, there is a critical need for validated prognostic markers in cardiac amyloidosis. A discriminatory serum biomarker may improve prognostic and staging systems in AL and ATTR cardiac amyloidosis.

Purpose

Our objective was to test the hypothesis that hepatocyte growth factor (HGF) is associated with clinical outcomes in patients with AL and ATTR cardiac amyloidosis.

Methods

102 patients with AL or ATTR and suspected cardiac involvement were prospectively enrolled. HGF, NT-proBNP, troponin-T, and eGFR were measured upon study enrollment. Cardiac involvement was established by 1) endomyocardial biopsy, or 2) non-cardiac biopsy with concentric hypertrophy on echocardiography, low voltage or pseudo-infarction on ECG, elevated NT-proBNP or troponin-T, or characteristic delayed myocardial enhancement on cardiac MRI. Patients were followed for the occurrence of all-cause mortality, cardiac transplantation, and left-ventricular assist device implantation.

Results

Of the total amyloidosis cohort, 72 had cardiac involvement while 30 had non-cardiac disease. HGF, NT-proBNP, and troponin-T levels were significantly higher in patients with cardiac involvement than in patients with non-cardiac disease (p<0.05 for all comparisons). Over a median follow-up period of 1.9 years there were 20 deaths, 1 cardiac transplant, and 1 left-ventricular assist device implant, all in patients with cardiac involvement. Patient stratification by cut-off levels of NT-proBNP (332 pg/mL), troponin-T (35 ng/L), and eGFR (45 mL/min/1.73m2) used in published staging models for AL and ATTR cardiac amyloidosis showed no association between abnormal biomarker level and adverse clinical outcome (p>0.05). In contrast, stratification by HGF level of 310 pg/mL (identified by the Youden Index for cardiac involvement by AL and ATTR in our cohort) showed that elevated HGF was associated with worse clinical outcomes (p=0.0211). Furthermore, event-free survival was worse in patients with elevated HGF, with survival curves diverging soon after enrollment (p=0.0730).

HGF is Prognostic in Cardiac Amyloidosis

Conclusions

Elevated HGF is associated with worse clinical outcomes in patients with AL and ATTR cardiac amyloidosis and has potential for clinical utility.
1182The novel mitophagic receptor protein bcl2-like protein 13: new insights for the molecular mechanisms of the pathogenesis of heart disease
Authors: Murakawa T , Otsu K
Published: October 2019

Cardiac function highly depends on energy generated by mitochondria, which are injured by various stresses such as pressure overload or aging. Damaged mitochondria in failing hearts are removed by a mitochondria-specific autophagy, called mitophagy. Dysregulation of mitophagy is implicated in the pathogenesis of heart disease such as heart failure. Mitochondrial morphologies change continuously through actions of mitochondrial dynamics (fission and fusion) and mitophagy is closely associated with mitochondrial fission to make mitochondria engulfable size by autophagosomes.

Atg32 is an essential protein for mitophagy in yeast. Some molecules have been reported to be involved in mitophagy, such as Parkin, FUNDC1 and Bnip3l. However, no Atg32 homologue has been identified in mammalian cells. We hypothesized that an unknown mammalian mitophagy receptor will share the molecular features with Atg32. By screening a public protein database for Atg32 homologues, we identified Bcl-2-like protein 13 (Bcl2-L-13).

Initially, we examined the function of Bcl2-L-13 in cardiomyocytes from 1-day-old Wistar rats. Forty-eight hours after infection of cardiomyocytes with an adenoviral vector expressing Bcl2-L-13, mitochondrial fragmentation was induced. In contrast, knockdown of Bcl2-L-13 induced mitochondrial elongation.

We carried out further investigation into functions of Bcl2-L-13 using cell lines. Bcl2-L-13 is localized at the mitochondrial outer membrane and bound to LC3 through the WXXI motif and induced mitochondrial fragmentation and mitophagy. In Bcl2-L-13, the BH domains are important for mitochondrial fragmentation, while the WXXI motif facilitates mitophagy. Bcl2-L-13 induces mitochondrial fragmentation in the absence of Drp1 which is the master regulator of mitochondrial fission, while it induces mitophagy in Parkin-deficient cells.

Next, we investigated physiological function of Bcl2-L-13. Knockdown of Bcl2-L-13 attenuated CCCP (carbonyl cyanide m-chlorophenyl hydrazone)-induced fragmentation and mitophagy. CCCP upregulated the phosphorylation level of Bcl2-L-13 Ser272 and Ser272Ala mutant showed less ability for inducing mitophagy. Considering of these, phosphorylation of this protein may regulate its activity. Furthermore, Bcl2-L-13 completely restored mitophagy in atg32-deficient yeast, suggesting that Bcl2-L-13 is a mammalian functional homologue of Atg32.

Our findings thus offer novel insights into molecular mechanisms of the pathogenesis of heart disease.

Acknowledgement/Funding

British Heart Foundation
1205Zero-fluoroscopy catheter ablation of right- and left-sided supraventricular tachycardias
Authors: Prolic Kalinsek T , Zizek D , Kuhelj D , Antolic B , Stublar J , Jan M
Published: October 2019

Background

Catheter ablation (CA) of supraventricular tachycardias (SVTs) is traditionally performed with the aid of fluoroscopy. However, ionizing radiation is associated with potentially harmful deterministic and stochastic effects to the patient and operator. Many methods have been suggested to reduce the radiation exposure, one of the methods, which completely eliminates ionizing radiation exposure, is zero-fluoroscopy catheter ablation.

Purpose

Our aim was to assess feasibility, success rate and safety of zero-fluoroscopy CA for treatment of various right and left-sided SVTs with the use of three-dimensional (3D) electroanatomical mapping system (EAM) and intracardiac echocardiography (ICE).

Methods

Consecutive 274 patients (140 male, mean age 33.5±21.8 years) with documented SVTs underwent CA in our center from April 2014 to May 2018. All procedures were performed with the 3D EAM without any use of fluoroscopic guidance. ICE was used as primary visual modality when left-sided approach was required. The procedural endpoint for atrioventricular nodal reentrant tachycardia (AVNRT) was nodal rhythm during radiofrequency (RF) energy delivery and non-inducibility. The procedural endpoint for focal atrial tachycardia (AT) was termination and non-inducibility. The procedural endpoint for accessory pathway (AP) mediated tachycardia was absence of bidirectional conduction over the AP. The procedural endpoint for typical atrial flutter (AFL) was bidirectional block over the cavo-tricuspid isthmus.

Results

One hundred thirty two patients had AVNRT, 79 had AP mediated tachycardia (47 left-sided, 25 septal and 7 right-sided), 31 patients had AT (8 left-sided), 32 patients had AFL. Cryo-ablation was used in 14 (14/132, 10.6%) patients with AVNRT and 5 patients with septal AP (5/25, 20%), RF was used in the rest. The procedural endpoint was achieved in all procedures (100%). During the mean follow-up of 343±253 days the recurrence rate for AVNRT, AP mediated tachycardia, focal AT, AFL was 7.5%, 16.4%, 32.3% and 9.4%, respectively. No procedural complications were observed.

Conclusions

Zero-fluoroscopy CA of right and left-sided SVTs with the use of the 3DEAM and ICE is feasible, safe and results in promising long-term success rates after single CA procedure.

Acknowledgement/Funding

None
1207Pulsed Field Ablation: Acute and Chronic Safety and Lesion Efficacy
Authors: Verma A , Haines D , Kirchhof N , Onal B , Martien M , Grassl E , Barka N , Howard B , Stewart M
Published: October 2019

Introduction

Thermal ablation methods are the cornerstone of treatment for atrial fibrillation. However, they pose a risk to extra-cardiac structures and may result in inadequate efficacy. Nonthermal, pulsed-field ablation (PFA) delivery to cardiac tissues may create durable, efficacious lesions while avoiding collateral damage.

Purpose

The purpose of this preclinical GLP study was to assess acute and chronic electrical isolation combined with a pathology assessment of chronic lesion extent in response to PFA delivery to cardiac tissue, and to document any collateral damage.

Methods

Six pigs were treated with biphasic, bipolar PFA doses through a circular multi-electrode catheter. PFA was delivered at four locations at specified voltages: superior vena cava (SVC at 700V), right atrial appendage (RAA at 1500V), left atrial appendage (LAA at 1200V), and right pulmonary vein (RPV at 1500V). Phrenic nerve pacing thresholds and electrical block at SVC, RPV, and RAA sites were investigated acutely, and electrical block at the SVC sites chronically. Pigs were survived for 4 weeks. After euthanasia, necropsies and histopathological assessments documented the findings at the lesion sites and collateral tissues.

Results

Post PFA, entrance block was achieved in all SVC, RPV, and RAA sites. Histopathology showed characteristic replacement fibrosis of the myocardium at all ablation sites. The PFA lesions in the SVC and RPV were all continuously circumferential and histopathology did not detect any remaining myofiber conduits across the post-ablation fibrosis (consistent with the electrical assessments). PFA of the appendages caused wide-ranging fibrosis in the RAA, and limited fibrosis in the LAA. Histologically, the atrial fibrosis was almost exclusively transmural in both, with the RAA lesions overall diagnosed as circumferentially complete in all but one case. The right phrenic nerve (RPN) pacing thresholds were unchanged from baseline to the end of the procedure and were all <1.0V. The examined juxtaposed RPN segments exposed to PFA at the SVC and RPV sites were normal. None of the ablated targets was associated with stenosis, aneurysms, luminal thrombus or collateral damage on the abluminal side.

Continuous lesion sites

Conclusions

This limited preclinical study evaluated the acute and chronic safety and efficacy of PFA in multiple cardiac and vascular treatment sites. In this porcine model, PFA results in acute and chronic electrical isolation, confirmed by pathology data, for all of the RPV and SVC targets. Pathology findings of the RAA revealed the ability to achieve chronic transmural lesions in highly trabeculated cardiac tissue. No collateral damage was seen to the adjacent RPN.

Acknowledgement/Funding

Medtronic
1349Effect of bariatric surgery on long-term cardiovascular outcomes in patients with obesity: a nation-wide nested cohort study
Authors: Ardissino M , Moussa O M , Tang A R , Heaton T , Ziprin P , Khan O , Darzi A , Purkayastha S , Collins P
Published: October 2019

Background

Obesity is a cardinal risk factor for the development of atherosclerotic cardiovascular disease. Bariatric surgery is an effective method of achieving weight reduction and improving control of cardiovascular risk factors in patients with obesity. However, the effect of bariatric surgery on long-term cardiovascular outcomes has yet to be defined.

Purpose

The aim of this study is to evaluate the effect of bariatric surgery on long-term risk of major adverse cardiovascular events in a large population of patients with obesity.

Methods

A nested cohort study was carried out; including the 3,701 patients of the Clinical Practice Research Datalink database who had undergone bariatric surgery, and 3,701 age, gender and BMI matched controls. The primary endpoint was the composite of fatal or non-fatal myocardial infarction; and fatal or non-fatal acute ischaemic stroke. Secondary endpoints included all-cause mortality, new diagnosis of heart failure, fatal or non-fatal myocardial infarction, and fatal or non-fatal acute ischaemic stroke. Data was analysed using a Cox proportional hazards model to account for multiple covariates.

Results

Patients were followed up for a median of 11.2 years; 20.3% of the population were female, the median age was 36 years and median BMI was 40.4 kg/m2. Patients who had undergone bariatric surgery had a significantly lower occurrence of the primary composite outcome (HR 0.450; 95% CI 0.312–0.671, p<0.001, NNT=62); this was driven by a reduction in myocardial infarction (HR 0.444; 95% CI 0.302–0.654, p<0.001, NNT=64) and not in acute ischaemic stroke (HR 0.528; 95% CI 0.159–1.751, p=0.296). A significant reduction was observed in rates all-cause mortality (HR 0.254; 95% CI 0.183–0.353; p<0.001, NNT=27) and of new diagnosis of heart failure (HR 0.519; 95% CI 0.311–0.864, p=0.012, NNT=153).

Table 1. Primary and secondary endpoints during follow-up Events No Bariatric Surgery Bariatric Surgery HR 95% CI p (n=3,701) (n=3,701) Primary endpoint 93 37 0.458 0.312–0.671 <0.001 Secondary endpoints   All-cause mortality 182 45 0.254 0.183–0.353 <0.001   Heart failure 46 22 0.519 0.311–0.864 0.012   Fatal or non-fatal myocardial infarction 93 36 0.444 0.302–0.654 <0.001   Fatal or non-fatal ischaemic stroke 9 4 0.528 0.159–1.751 0.296

Adjusted primary endpoint rates

Conclusion

The results of this large, nation-wide nested cohort study support the role of bariatric surgery in reducing the risk of major cardiovascular events, all-cause mortality and new onset of heart failure in patients with obesity.
1350Outcome after diagnosis with hypertrophic cardiomyopathy: a nationwide study
Authors: Jacobsen M , Modin D , Koeber L , Fosboel E L , Axelsson A
Published: October 2019

Background

Patients with hypertrophic cardiomyopathy (HCM) are generally considered to have an increased morbidity and mortality due to symptomatic heart failure, atrial fibrillation, stroke and sudden cardiac death. Data reporting the mortality compared with background populations are however conflicting and primarily based on small cohorts from tertiary centers.

Purpose

We aimed to investigate whether a nationwide cohort of patients with HCM had an increased risk of death compared with a matched cohort derived from the general Danish population.

Methods

Using nationwide registries, we identified all patients with a first-time HCM diagnosis in Denmark between 2007 and 2016. Patients were matched 1:5 on age, sex and HCM diagnosis date to controls using risk set sampling. The study population was followed until death, emigration, or end of study period Jan. 1, 2017–whichever came first. Mortality was compared using Kaplan Meier plots and multivariable adjusted Cox proportional hazard analysis.

Results

We identified 3010 patients diagnosed with HCM (53.8% male) per registry codes. Men were on average 8.5 years younger at diagnosis than women (62.6 years [p25-p75: 49.8–73.9] vs. 71.1 years [p25-p75: 59.7–80.6]). Patients with HCM had more comorbidities than matched controls. The median time of follow-up was 4.4 years (p25-p75: 2.3, 6.7). For HCM patients and matched controls, 1-year, 5-year and 10-year probabilities of death were 10% (95% CI 9–12%), 28% (95% CI 26–30%) and 47% (95% CI 42–51%) and 2% (95% CI 1–3%), 13% (95% CI 12–14%) and 24% (95% CI 23–25%) respectively (Figure 1). After adjusting for comorbidities and medications a diagnosis of HCM was associated to a 107% increased risk of death (hazard ratio 2.07 [95% confidence interval 1.60, 2.68], p<0.0001).

Figure 1

Conclusion

In a Danish nationwide cohort, HCM was associated with a significantly higher risk of death compared with the background population. This study emphasizes the importance of continued, life-long follow-up of patients with HCM with the aim to anticipate and treat preventable adverse events. Furthermore, the findings stress the need to develop effective disease-modifying treatment strategies.
1386Reduction of mitral regurgitation in patients with heart failure and secondary mitral regurgitation: relationship between changes in brain natriuretic peptide and outcomes from the COAPT trial
Authors: Abraham W , Lindenfeld J , Mack M , Ellis J , Morishetti D , Weissman N , Stone G
Published: October 2019

Background

Brain natriuretic peptide (BNP) is a well-established predictor of hospitalization and death in patients with heart failure (HF). In the COAPT trial, treatment of patients with HF and secondary mitral regurgitation (SMR) with transcatheter mitral valve repair (TMVr) reduced the 2-year rates of all-cause mortality and HF hospitalization compared with maximally-tolerated guideline-directed medical therapy (GDMT) alone. Whether these improvements in outcomes were reflected in serial changes in BNP levels has not been reported.

Purpose

Herein, we report the first results of serial changes in BNP levels by treatment group in patients from the COAPT trial.

Methods

614 patients with HF and 3+ or 4+ SMR were randomized 1:1 to TMVr + GDMT or GDMT alone. Key inclusion criteria included NYHA functional class II-IVa (ambulatory), ischemic or non-ischemic cardiomyopathy with LVEF 20%-50% and LVESD ≤70 mm. Baseline BNP or NT-proBNP levels were drawn at baseline and at 6 and 12 months. For the present analysis NT-proBNP (pg/ml) values were converted to BNP values (pg/ml) using a ratio of 7 to 1.

Results

At baseline, mean values of BNP were not significantly different between treatment groups (945 pg/ml vs. 964 pg/ml in the TMVr + GDMT and GDMT groups respectively, p=0.84). At 6 months, mean values of BNP in the TMVr + GDMT group were significantly lower than in the GDMT alone group (690 pg/ml vs 893 pg/ml, p=0.02) but not at 12 months (584 pg/ml vs. 728 pg/ml, p=0.22). By analysis of covariance, BNP decreased to a greater degree after TMVr + GDMT compared with GDMT only at both 6 and 12 months (least squares mean differences of −121 pg/ml and −166 pg/ml respectively, both p<0.05) (Figure).

Change in BNP level from baseline

Conclusions

In patients with HF and 3+ or 4+ SMR enrolled in the COAPT trial, reduction of SMR with TMVr reduced BNP compared with maximally-tolerated GDMT only, a change which paralleled the reductions noted in all-cause mortality and HF hospitalizations with TMVr.

Acknowledgement/Funding

Abbott
1416Combined therapy of empagliflozin and linagliptin is superior to metformin and insulin glargine in improving blood pressure and vascular function in type 2 diabetes
Authors: Jung S , Bosch A , Kannenkeril D , Karg M , Striepe K , Bramlage P , Ott C , Schmieder R E
Published: October 2019

Background and purpose

The optimal choice of antidiabetic medication in patients that need combined therapy is under debate. The aim of this study was to analyze whether beyond glucose control the combination of empagliflozin (E) and linagliptin (L) improves blood pressure (BP) and vascular function in patients with type 2 diabetes (T2DM) as opposed to the combination of metformin (M) and insulin glargine (I).

Methods

This was a prospective, randomized, controlled, single center study including 101 patients with T2DM, who were randomized 1:1 to E 10–25mg combined with L 5mg once daily or M 850 or 1000mg twice daily combined with I once daily. All patients underwent BP measurement and vascular function analysis by validated systems at baseline and after 12 weeks of treatment.

Results

In comparison to baseline, office, 24-hour ambulatory BP as well as central blood and pulse pressure (PP) values decreased significantly after 12 weeks of treatment with E+L, whereas there was no change in the M+I group (see table). Twenty-four-hour peripheral systolic (mean difference: −5.2±1.5mmHg, p=0.004) and diastolic BP (−1.9±1.0mmHg, p=0.036), central clinical systolic BP (−5.56±1.9mmHg, p=0.009), forward pressure pulse height (−2.0±0.9mmHg, p=0.028), 24-h central systolic BP (−3.6±1.4mmHg, p=0.045) and 24-h pulse wave velocity (−0.14±0.05m/s, p=0.043) were reduced to a greater extent in the E+L than in the M+I group.

Empagliflozin+Linagliptin Metformin+Insulin Baseline 12 weeks p value Baseline 12 weeks p value Peripheral ambulatory BP values   24-h SBP [mmHg] 131.0±10.9 127.0±8.8 <0.001 131.0±9.7 131.0±8.6 0.438   24-h DBP [mmHg] 81.5±7.1 79.7±7.0 0.013 81.0±7.1 81.0±7.5 0.976 Clinical (laboratory) central vascular parameters   Central SBP [mmHg] 123.0±9.6 117.0±10.4 <0.001 121.0±9.9 121.0±8.3 0.944   Central PP [mmHg] 44.4±8.0 41.4±6.6 0.004 43.5±8.6 42.8±7.5 0.471   Forward pressure pulse height [mmHg] 33.0±5.7 30.2±4.6 <0.001 32.5±5.6 31.8±4.5 0.216   Central office PWV [m/s] 8.2±1.6 8.0±1.5 0.039 8.4±1.3 8.3±1.2 0.400 24-h ambulatory central vascular parameters   Central 24-h SBP [mmHg] 120.5±9.3 117.3±7.9 0.007 121.0±9.1 121.0±8.0 0.608   Central 24-h DBP [mmHg] 83.2±7.3 81.1±6.9 0.016 82.4±7.1 82.4±7.7 0.928   Central 24-h PWV [m/s] 8.9±1.3 8.8±1.3 0.010 9.0±1.4 9.0±1.3 0.349 SBP, systolic blood pressure; DBP, diastolic blood pressure; PP, pulse pressure; PWV, pulse wave velocity.

Conclusion

The combination of E+L significantly improves BP and vascular function in contrast to the combination of M+I.

Acknowledgement/Funding

This IIS was supported by a research grant from Boehringer Ingelheim International GmBH
1417Effect of sodium glucose cotransporter 2 inhibitor on sympathetic nerve activity in type 2 diabetes mellitus patients
Authors: Hamaoka T , Murai H , Sugimoto H , Mukai Y , Okabe Y , Tokuhisa H , Inoue O , Takashima S , Kato T , Usui S , Furusho H , Takamura M
Published: October 2019

Background

Diabetes mellitus (DM) is a well-known risk factor for cardiovascular diseases. Augmented sympathetic nerve activity plays an important role in the progressive worsening disease severity. Most of anti-diabetic drugs were demonstrated to not only decrease blood glucose, but also increase sympathetic nerve activity. Recently, it has been reported that sodium glucose cotransporter 2 (SGLT2) inhibitor has beneficial effects on cardiovascular events in spite of the decrease in blood glucose in type 2 DM patients. The underlying mechanisms remain speculative; however, it is assumed that SGLT2 inhibitor would improve sympathetic nerve activity in type 2 DM patients.

Purpose

The purpose of this study was to evaluate the effect of SGLT2 inhibitor on sympathetic nerve activity in type 2 DM patients.

Methods

This study was designed as the prospective single-arm study. Type2 DM patients whose HbA1c >7.0% with at least one atherosclerotic risk factors (Hypertension, obesity, smoking history, aging ...) were included. Patients who had renal failure (eGFR<45ml/min/1.73m2) or high age patients (>80 years old) were excluded. We measured blood glucose, HbA1c and blood insulin concentration at baseline and 12 weeks after treatment of dapagliflozin (5mg/day). Muscle sympathetic nerve activity (MSNA) was applied to scrutinize accurate sympathetic nerve activity in type 2 DM patients. Also, baroreflex sensitivity was calculated by examining the relationship between MSNA and beat to beat diastolic blood pressure.

Results

Eleven type2 DM patients were included in this study. Body mass index, blood pressure, HbA1c and blood insulin concentration tended to decrease at 12weeks after dapagliflozin (body mass index: 27.2±6.3 vs. 24.9±3.2 kg/m2. systolic blood pressure: 121±12.3 vs. 118±13.6 mmHg. diastolic blood pressure: 74.3±6.3 vs. 72.5±7.6 mmHg. HbA1c: 7.6±0.3 vs. 7.2±0.7%. insulin: 9.7±7.2 vs. 8.8±5.1 μU/ml). Dapagliflozin significantly decrease MSNA and heart rate compared to baseline (46.7±7.5 vs. 38.6±6.9 bursts/minute, P<0.05. Heart rate: 80.6±8.5 vs. 72.8±7.4 beats per minute, P<0.05). However, there is no interaction between the reduction in MSNA and baroreflex sensitivity or insulin resistance.

12 weeks administration decreased MSNA

Conclusion

Our data demonstrated that dapagliflozin significantly decreased MSNA and HR beyond the lowering effect of blood glucose in type2 DM patients. These results indicate the favorable effect of SGLT2 inhibitor might be, in part, attributed to the improvement in sympathetic nerve activity.
1421Dyskalemias in hypertensive patients treated with combination of antihypertensive drugs: a nested case-control study using Danish national registries
Authors: Krogager M L , Mortensen R N , Lund P E , Boeggild H , Hansen S M , Kragholm K , Aasbjerg K , Soegaard P , Torp-Pedersen C
Published: October 2019

Aims

Little is known about the occurrence of potassium disturbances in relation to combination therapy in hypertension. Using data from Danish electronic registries, we investigated the association between different combinations of antihypertensive therapy and potassium imbalances, in 22,060 individuals, between 1995–2012.

Methods

Using incidence density matching, two comparison patients without hypokalemia were matched to each corresponding patient with hypokalemia on age, gender, renal function, time from HTN date to date of potassium measurement. The same approach was applied to identify matches for patients with hyperkalemia. The ten most common antihypertensive drug combinations in our population were: (1) Beta-blockers + Angiotensin converting enzyme inhibitors, (2) Angiotensin converting enzyme inhibitors + Thiazides, (3) Angiotensin converting enzyme inhibitors + Thiazides + Potassium supplement, (4) Angiotensin receptor blockers + Other diuretics, (5) Beta-blockers + Angiotensin converting enzyme inhibitors + Potassium supplement (ATC: A12B), (6) Beta-blockers + Calcium channel blockers, (7) Beta-blockers + Thiazides + Potassium supplement, (8) Calcium channel blockers + Angiotensin converting enzyme inhibitors, (9) Calcium channel blockers + Thiazides + Potassium supplement, (10) Other antihypertensive drug combinations. We used conditional logistic regression analysis to examine the risk of developing hypo- and hyperkalemia in relation to different combinations of antihypertensive drugs within one year. The multivariable model was adjusted for serum sodium, malignancy, inflammatory bowel disease, diabetes, alcoholism and beta2-agonists.

Results

The multivariable analysis showed 10.5 times increased odds for developing hypokalemia if administered Calcium channel blockers + Thiazides + Potassium supplement (95% CI 4.97–22.06) compared to Angiotensin converting enzyme inhibitors + Beta blockers. Other drug combinations significantly associated with increased hypokalemia risk were: Angiotensin converting enzyme inhibitors + Thiazides (OR 5.01, 95% CI 2.32–10.79), Angiotensin converting enzyme inhibitors + Loop + Potassium supplement (A12B) (OR 4.03, 95% CI 1.69–9.62), Angiotensin converting enzyme inhibitors + Thiazides + Potassium supplement (OR 4.16, 95% CI 2.01–8.64) and Calcium channel blockers + Angiotensin converting enzyme inhibitors (OR 4.04, 95% CI 1.72–9.50). None of the ten groups were associated with increased odds for developing hyperkalemia in the multivariable analysis.

Cumulative incidence curves for hypokale

Conclusion

Thiazide diuretics in combination with angiotensin converting enzyme inhibitors or calcium channel blockers were strongly associated with hypokalemia risk within one year from treatment initiation.

Acknowledgement/Funding

None
1424The diagnosis of non-adherence in hypertension using a urine biochemical screen is unaffected by drug pharmacokinetics
Authors: Lane D , Alghamdi R , Muscat M , Kaur M S , Davis T , Cole R , Patel P , Tomaszewski M , Gupta P
Published: October 2019

Introduction

Suboptimal drug adherence in hypertension is pandemic and traditional diagnostic tools to detect non-adherence have lacked accuracy and robustness. The inability to identify non-adherence has therefore driven the development of biochemical drug screening by liquid chromatography tandem mass spectrometry (LC- MS/MS) in urine and blood, which are the most accurate metrics presently available. Urinary antihypertensive testing is evidenced to improve non-adherence rates, significantly decrease blood pressure after physician intervention, and be cost effective. The European Society of Cardiology (ESC) and European Society of Hypertension (ESH) 2018 guidelines have recommended the use of biochemical testing for non-adherence diagnosis. However, it has been argued that the variable pharmacokinetic parameters of the medication (such as their half-lives and clearance rates) may affect the detection of medications in urine and hence the determination of adherence. We hypothesized that pharmacokinetic parameters do not affect the detection of antihypertensive medications in urine.

Aim

This study compared the pharmacokinetic parameters of the most commonly prescribed antihypertensive medications against their detection in urine by LC-MS/MS.

Methods

Results of urinary drug screens from 463 hypertensive patients (total prescribed medications N=1709) were collated. An adherence score termed as the C score (number of detected vs. prescribed medication) was generated for each of the 27 common antihypertensive medications. Pharmacokinetic parameters such as bioavailability, plasma concentration, volume of distribution, half-life, plasma clearance and urinary excretion values for each drug were obtained from published literature. Partial linear correlation was conducted between the C score of all the medications and each pharmacokinetic parameter studied.

Results

40% of patients were non-adherent. The average number of prescribed medications was high (N=3.7, SD: 1.5), and the average number of drugs detected was lower (N=2.5, SD: 1.6). Amlodipine was the most prescribed (N=224), and clonidine was the least (N=10). The half-lives ranged from 0.87 to 39 hours for bumetanide and amlodipine respectively. The urinary excretion percentage varied from <1% for nifedipine, and 94% for benfroflumethiazide. No significant correlation was found between any drug C score and their respective pharmacokinetic variables such as the medication half-lives (figure1).

Half-life versus adherence score

Conclusion

This study reports no significant correlation between drug pharmacokinetics and adherence. To the best of our knowledge this is the first study of its kind. Urinary biochemical testing by LC-MS/MS for non-adherence remains a valid tool for diagnosis although further detailed pharmacokinetic studies are needed to confirm this finding.

Acknowledgement/Funding

None
1441LRP5 and PCSK9 in inflammatory cells immunomodulation
Authors: Borrell M , Crespo J , Badimon L
Published: October 2019

Background

Atherosclerosis, the leading cause of cardiovascular diseases, is driven by high blood cholesterol levels and chronic inflammation. The disruption of the hepatic interaction between Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) and Low-Density Lipoprotein Receptor (LDLR) downregulates blood cholesterol levels and reduces cardiovascular events. Recent data suggest that other members of the LDLR superfamily may be targets of PCSK9.

Purpose

The aim of this work is to determine if LDLR-related protein 5 (LRP5) is a PCSK9 target, and to study the role of PCSK9 and LRP5 in foam cell formation and hence, in the mechanism of lipid accumulation and atherosclerotic plaque formation.

Methods

Intracellular protein and lipid localization, cholesteryl esters (CE) accumulation; quantification of structural and inflammatory proteins expression and immunoprecipitation analyses were performed in primary cultures of human inflammatory cells (monocytes and macrophages) silenced for LRP5 or PCSK9 and challenged with modified LDLs.

Results

We first show that LRP5 is needed for macrophage lipid uptake since LRP5-silenced macrophages have less intracellular CE accumulation. In LDL treated macrophages internalization of LRP5-bound LDL starts after 30 minutes of incubation and lasts up to 24hours. The SREBP-2 promoter is not involved in LRP5 regulation but it does regulate macrophage PCSK9 expression. Immunoprecipitation experiments show that LRP5 forms a complex with PCSK9 in lipid-loaded macrophages. Finally we studied the role of PCSK9 and LRP5 in the inflammatory response by TLR4/NFkB signaling pathway. We show decreased TLR4 protein expression levels and decreased nuclear translocation of NFκB in PCSK9 silenced-inflammatory cells after lipid loading indicating a downregulation of the proinflammatory pathway TLR4/NFκB. Increased gene expression is observed in TNF-α and IL1β after lipid-loading that is abolished in PCSK9-silenced macrophages. Furthermore release of the proinflammatory cytokines TNF-α and IL1β is decreased in PCSK9-silenced macrophages. LRP5 protein expression is increased in lipid-loaded macrophages independent of the presence or absence of PCSK9.

Conclusions

These results demonstrate that, in human macrophages, LRP5 is internalized with lipids. Furthermore, PCSK9 and LRP5 can form a complex in the cytoplasm of lipid-loaded macrophages opening the possibility that PCSK9 induces lysosomal LRP5 degradation in a similar manner than it does with LDLR. Finally we also show that PCSK9 gene interference decreases inflammation and supports a role for PCSK9 as an inflammatory mediator in atherosclerosis.

Acknowledgement/Funding

CN16/11/00411-LB; TERCEL RD16/0011/018-LB; FIS2016-02014 -MBP; SEC2015 to MBP