bluuebunny/crossref_metadata_2025 huggingface dataset:
4965Non-transcriptional disruption of Ca2+i homeostasis and Cx43 function in the right ventricle precedes overt arrhythmogenic cardiomyopathy in PKP2-deficient mice
Authors: Kim J C , Perez-Hernandez M , Alvarado F J , Maurya S R , Montnach J , Yin Y , Zhang M , Lin X , Heguy A , Rothenberg E , Lundby A , Valdivia H H , Cerrone M , Delmar M
Published: October 2019

Background

Plakophilin-2 (PKP2) is classically defined as a protein of the desmosome, an intercellular adhesion structure that also acts as a signaling hub to maintain structural and electrical homeostasis. Mutations in PKP2 associate with most cases of gene-positive arrhythmogenic right ventricular cardiomyopathy (ARVC). A better understanding of PKP2 cardiac biology can help elucidate the mechanisms underlying arrhythmic and cardiomyopathic events that occur consequent to its mutation. Here we sought to captureearly molecular/cellular events that can act as nascent substrates for subsequent arrhythmic/cardiomyopathic phenotypes.

Methods

We used multiple quantitative imaging modalities, as well as biochemical and high-resolution mass spectrometry methods to study the functional/structural properties of cells/tissues derived from cardiomyocyte-specific, tamoxifen-activated, PKP2 knockout mice (“PKP2cKO”). Studies were carried out 14 days post-tamoxifen injection, a time point preceding an overt electrical or structural phenotype.Myocytes from right or left ventricular free wall were studied separately, to detect functional/structural asymmetries.

Results

Most properties of PKP2cKO left ventricular (LV) myocytes were not different from control; in contrast, PKP2cKO right ventricular (RV) myocytes showed increased amplitude and duration of Ca2+transients, increased frequency of spontaneous Ca2+release events, increased [Ca2+] in the cytoplasm and sarcoplasmic reticulum compartments, and dynamic Ca2+accumulation in mitochondria. In addition, RyR2 in RV presented enhanced sensitivity to Ca2+and preferential phosphorylation in a domain known to modulate Ca2+gating. RNAseq at 14 days post-TAM showed no relevant difference in transcript abundance between RV and LV, neither in control nor in PKP2cKO cells, suggesting that in the earliest stage, [Ca2+]i dysfunction is not transcriptional. Rather, we found an RV-predominant increase in membrane permeability that can permit Ca2+entry into the cell. Cx43 ablation mitigated the increase in membrane permeability, the accumulation of cytoplasmic Ca2+and the early stages of RV dysfunction.

Conclusions

Loss of PKP2 creates an RV-predominant arrhythmogenic substrate (Ca2+ dysregulation) that precedes the cardiomyopathy and that is, at least in part, mediated by a Cx43-dependent membrane conduit. Given that asymmetric Ca2+ dysregulation precedes the cardiomyopathic stage, we speculate that abnormal Ca2+ handling in RV myocytes can be a trigger for gross structural changes observed at a later stage.
4968Increased Gao expression underlies cardiac dysfunction and lethal arrhythmias accompanied with abnormal Ca2+ handling
Authors: Inazumi H , Kuwahara K , Kuwabara Y , Nakagawa Y , Kinoshita H , Moriuchi K , Yanagisawa H , Nishikimi T , Oya M , Yamada M , Kashihara T , Kurebayashi N , Sugihara M , Nakao K , Kimura T
Published: October 2019

Background

We previously demonstrated that a transcriptional repressor, neuron restrictive silencer factor (NRSF), maintains normal cardiac function and electrical stability. Transgenic mice expressing a dominant-negative mutant of NRSF in their hearts (dnNRSF-Tg) exhibit systolic dysfunction with cardiac dilation and premature death due to lethal arrhythmias like human dilated cardiomyopathy (DCM). Underlining mechanisms remain to be elucidated, however.

Purpose

We studied underling mechanisms by which NRSF maintains normal cardiac function to identify novel therapeutic targets for heart failure.

Methods and results

We generated cardiac-specific NRSF knockout mice (NRSFcKO) and confirmed that cardiac phenotypes of NRSFcKO are similar to those of dnNRSF-Tg.

cDNA microarray analysis revealed that cardiac gene expression of GNAO1 that encodes Gαo, a member of inhibitory G protein Gαi family, is increased in both dnNRSF-Tg and NRSFcKO ventricles.

We confirmed that GNAO1 is a direct target of NRSF through ChIP-seq analysis, reporter assay and electrophoretic mobility shift assay.

In dnNRSF-Tg, pharmacological inhibition of Gαo with pertussis toxin improved systolic dysfunction and knockdown of Gαo by crossing with GNAO1 knockout mice improved not only systolic function but also frequency of ventricular arrhythmias and survival rates.

Electrophysiological and biochemical analysis in ventricular myocytes obtained from dnNRSF-Tg demonstrated that genetic reduction of Gαo ameliorated abnormalities in Ca2+ handling, which include increased current density in surface sarcolemmal L-type Ca2+ channel, reduced content of sarcoplasmic reticulum Ca2+ and lowered peak of Ca2+ transient. Furthermore, genetic reduction of Gαo attenuated increased phosphorylation levels of CAMKII in dnNRSF-Tg ventricles, which presumably underlies the improvement in Ca2+ handling. In addition, we identified increased Gαo expression in ventricles of heart failure model mice induced by transverse aortic constriction and cardiac troponin T mutant DCM model mice, in both of which, genetic reduction of Gαo ameliorated cardiac dysfunction.

Figure 1

Conclusions

We found that increased expression of Gαo, induced by attenuation of NRSF-mediated repression, plays a crucial role in the progression of cardiac dysfunction and lethal arrhythmias by evoking Ca2+ handling abnormality. These data demonstrate that Gαo is a potential therapeutic target for heart failure.
5162Novel insights into desminopathy in the era of next generation sequencing
Authors: Kubanek M , Schimerova T , Piherova L , Krebsova A , Hansikova H , Zeman J , Palecek T , Houstek J , Zamecnik J , Macek Jr M , Ridzon P , Stranecky V , Kmoch S , Melenovsky V , Kautzner J
Published: October 2019

Aims

The pleomorphic clinical presentation makes the diagnosis of desminopathy difficult. This disease of intermediate filaments causes not only a contractile dysfunction in cardiomyopathy and skeletal myopathy, but also a secondary mitochondrial dysfunction. We aimed to describe prevalence, phenotypic expression and mitochondrial function in desmin mutation carriers identified in a large cohort of patients with unexplained cardiomyopathy.

Methods and results

A representative cohort of 327 Czech patients with unexplained cardiomyopathy underwent whole exome sequencing. The cohort consisted of cases with familial and sporadic dilated cardiomyopathy (81%), left ventricular noncompaction cardiomyopathy (LVNC) (13%), and less frequently of restrictive (3%) or arrhythmogenic cardiomyopathy (3%). Clinical and laboratory data of desmin mutation carriers were collected. Morphology, desmin expression and mitochondrial function were studied in available myocardial and skeletal muscle specimens.

Rare, conserved and possibly pathogenic desmin variants were identified in 6 (1.8%) probands. Two desmin mutations previously classified as variants of uncertain significance (p.K43E, p.S57L), one novel desmin variant (p.A210D) and two known pathogenic desmin mutations (p.R406W, p.R454W) were in affected individuals associated with characteristic pathological desmin aggregates in myocardial and/or skeletal biopsy samples. The individual with the novel desmin variant p.Q364H had decreased myocardial expression of desmin with absent desmin aggregates in myocardial/skeletal biopsy and presented with familial left ventricular non-compaction cardiomyopathy, a novel phenotype of desminopathy. Assessment of mitochondrial function in four carriers of desmin mutations with fresh-frozen skeletal and/or myocardial muscle specimens confirmed decreased metabolic capacity of mitochondrial respiratory chain complexes, which was in case of myocardial succinate respiration more profound than in end-stage heart failure of other etiologies. Genetic testing corrected an inappropriate clinical diagnosis in two probands previously diagnosed with mitochondrial disease and inflammatory cardiomyopathy. During a median follow-up of 56 months, 5 (83%) probands developed end-stage heart failure.

Conclusions

Desminopathy is a rare cause of cardiomyopathy and/or skeletal muscle myopathy with a pleomorphic clinical presentation and poor prognosis. The presence of desminopathy should be considered also in individuals with left ventricular non-compaction cardiomyopathy, and in the differential diagnosis of mitochondrial diseases and inflammatory cardiomyopathy.

Acknowledgement/Funding

Research grant of the Ministry of Health, Czech Republic [MZ 15-27682A], No. 00023001 (IKEM, Prague, CZ), the Czech Science Foundation [14-36804G].
5197Correlates and prognostic significance of nuisance bleeding after acute myocardial infarction. The FAST-MI programme
Authors: Danchin N , Puymirat E , Isaaz K , Druelles P , Dibon O , Lefevre T , Bernasconi F , Drouet E , Ferrieres J , Schiele F , Simon T
Published: October 2019

Background

Following acute myocardial infarction (AMI), most patients receive potent antithrombotic medications, which may promote nuisance bleedings (ecchymoses, minor nose or dental bleeds etc.). Little information is available on the factors related to nuisance bleedings, nor on their prognostic significance in post-AMI patients.

Aims and methods

A health status questionnaire was sent to all patients participating in the nationwide French FAST-MI cohorts (2010 and 2015) one year after the acute episode, with a specific question on the presence of nuisance bleedings. Overall, 3968 patients answered the question on the presence nuisance bleedings. In the 2010 cohorts, we also analysed whether the presence of nuisance bleedings at one year was an independent correlate of 5-year mortality.

Results

54% of the patients reported the presence of nuisance bleedings (59% in 2010 and 51% in 2015). In univariate analyses, nuisance bleedings were more frequently found in younger patients, women, patients with STEMI, current smokers, patients treated with PCI, those receiving newer P2Y12 inhibitors or ACE-inhibitors but less frequent in patients with diabetes, hypertension, or those receiving ARBs or direct oral anticoagulants. Using logistic regression analysis, however, the only independent correlates of nuisance bleedings were: female gender (OR 1.45, 1.25–1.68), age ≤60 years (OR 1.22, 1.06–1.41), VKAs (OR 1.72, 1.28–2.31), clopidogrel (OR 1.62, 1.29–2.03), prasugrel (OR 3.16, 2.43–4.09), ticagrelor (OR 2.61, 2.04–3.35) at discharge, diabetes (OR 0.74, 0.63–0.88) and year 2015 vs 2010 (OR 0.62, 0.53–0.73).

In the 2010 cohort, the presence of nuisance bleeding at one year was not a predictor of mortality at 5 years (90% survival in both patients with or without nuisance bleedings; adjusted HR 0.96, 95% CI 0.69–1.33) (Figure).

Figure 1. 5-yr survival by nuisance bleed

Conclusion

Nuisance bleedings one year after AMI are extremely frequent. They are more common in women, younger patients, in patients receiving P2Y12 inhibitors, especially newer P2Y12-i, and in those receiving VKAs; in contrast, diabetic patients report less nuisance bleedings. The presence of nuisance bleeding at one year does not appear to impact 5-year mortality.

Acknowledgement/Funding

Amgen, AstraZeneca, Bayer, Daiichi-Sankyo, Eli-Lilly, GSK, MSD, Novartis, Pfizer, Sanofi, Servier
5208Use of renal denervation in the electrical storm management
Authors: Gorev M , Nardaya S H , Petelko S , Rzaev F , Vasilieva E , Shpektor A
Published: October 2019

Background/Introduction

Electrical storm (ES) is a potentially lethal state developing in 4–28% of ICD patients. Neuroaxial modulation (beta-blockers, deep sedation, epidural anesthesia, stellate ganglion blockade etc) is used to decrease arrhythmogenic predisposition of ventricular myocardium to trigger and maintain ventricular arrhythmias. Catheter renal arterial denervation (RDN) is recently described to prevent atrial fibrillation recurrence after pulmonary vein isolation. We used this procedure in addition to standard care to improve the results of ES treatment.

Purpose

This retrospective single-center case-series is aimed to analyze ES patient population and to describe the effect of RDN on the in-hospital number of ventricular tachycardia (VT) episodes and ICD shocks and on the mid-term survival.

Methods

Pts admitted to the CCU for more than 3 sustained VT episodes or more than 3 appropriate ICD shocks during the 24h period in 2017–18 were enrolled into study. Demographic, echocardiographic, ICD check up, renal arteries anatomy and mid-term mortality/transplant data were retrospectively analysed.

Results

Eleven pts (all male, age 69±9 years) were included. Seven pts (73%) had CAD, 3 pts (27%) – DCM. Echocardiography revealed LVEF 28±8%, and LV EDV - 226±91 ml. Time from ICD implantation to ES onset was from 4 mos to 13 yrs. In 5 pts RDN was performed without VT ablation, in 3 pts – prior to VT ablation, in 2 – after VT ablation and in 1 pt – both RDN and VT ablation were performed during the same procedure. Mean number of renal arteries was 2,5 per pt. Mean number of ablations was 4,8 per artery. The power was 2 to 11 Wt and lesion duration was 90 sec. Dramatic decrease in the number of VT episodes (49±52 vs. 6±2) was found in 6/11 pts directly after RDN procedure. In-hospital rhythm control was accessed in 10/11 pts, 1 pt with DCM was transferred for heart transplant due to recurrence of VT after VT ablation and RAD (excluded from survival analysis). There were no RDN procedure related complications in this group of pts. In mean 6 mos of follow-up 9/10 pts are free from ES recurrence, 1/10 was lost for the follow up.

Conclusion(s)

Catheter renal artery denervation is effective and safe additional procedure to treat ES patients. It allows to decrease the number of ICD shocks and stabilize arrhythmogenicity of ventricular myocardium. Larger multi-center randomized trials are warranted.
5949Interleukin-6 and growth differentiation factor-15 in hypertensive heart failure
Authors: Fernandez C , Rysa J , Nilsson J , Engstrom G , Orho-Melander M , Ruskoaho H , Melander O
Published: October 2019

Background

Hypertension is the leading cause for the development of heart failure (HF). Increased hemodynamic load, including mechanical stretch and neurohumoral factors, is able to trigger hypertrophic growth of cardiac myocytes. Although hypertensive HF is prevalent, there is no useful biomarker to identify HF due to chronic hypertension.

Aims

To identify plasma markers associated with incidence of hypertensive HF.

Methods

Circulating levels of 149 proteins were measured by proximity extension assay at baseline examination in 4469 individuals from the Malmö Diet and Cancer study. Protein levels were compared to stretch-activated gene expression changes in cultured neonatal rat ventricular myocytes (NRVM) in response to 1, 4, 12, 24 or 48 hours of cyclic mechanical stretch. Association between plasma proteins level and HF incidence and hypertension was studied using respectively Cox proportional hazards model and binary logistic regressions.

Results

After Bonferroni correction, 44 circulating proteins were significantly differentially expressed in individuals who developed HF during follow-up versus controls (P<3.4E-4). Out of these, 5 proteins (Interleukin-6 (IL-6), Growth Differentiation Factor-15 (GDF15), Interleukin-1 Receptor-Like-1 (ST2), Plasminogen Activator Urokinase Receptor (U-PAR), Transforming Growth Factor-α (TGF-α)), corresponding mRNA levels were upregulated by mechanical stretch in NRVM at all time points (P<0.05). Similar upregulation for the 5 proteins was shown in hypertensive versus normotensive individuals (P≤8.05E-4). In a model with all 5 proteins entered simultaneously, GDF15 and IL-6 were predictive of incident HF after adjustment for age, sex and NT-BNP levels (205 events; hazard ratio [HR] per SD increment of protein: HR=1.29, CI=1.05–1.58, P=0.013 and HR=1.16, CI=1.02–1.33, P=0.028). Using the same model, IL-6 but not GDF15 associated with hypertension (Odds ratio [OR] per SD increment of IL-6: OR=1.18, CI=1.09–1.27, P=3.3E-5). In hypertensive individuals GDF15 and IL-6 were individually predictive of future HF after adjustment for age, sex, NT-BNP levels, smoking, BMI and diabetes (183 events; HR=1.36, CI=1.16–1.60, P=1.64E-4 and HR=1.21, CI=1.05–1.40, P=0.008). Furthermore, in these hypertensive individuals, GDF15 and IL-6 were predictive of HF in a model with IL-6, GDF15, ST2 and TGF-α entered simultaneously after adjustment for age, sex and NT-BNP levels (176 events; HR=1.36, CI=1.13–1.64, P=0.001 and HR=1.16, CI=1.01–1.34, P=0.041).

Conclusions

Circulating levels of IL-6 and GDF15 might be used as NT-BNP independent biomarkers for HF development in hypertensive patients.

Acknowledgement/Funding

Påhlsson, Crafoord, Lundström, Åke Wiberg, Royal Physiographic Society and the Swedish Foundation for Strategic Research for IRC15-0067
5952The involvement and interplay of HMGB1 with soluble MD-2 in dilated cardiomyopathy and its impact in immune cell recruitment
Authors: Kuemmel A , Feldtmann R , Stohbach A , Riad A , Chamling B , Felix S B
Published: October 2019

Objective

Dilated cardiomyopathy (DCM) is characterized by systolic dysfunction and simultaneous dilatation of the left or both ventricles. Besides other causes, the innate immune system plays a major role in the development and progression of the disease. To uncover links between molecular mechanisms and disease progression our group has focused on the toll like receptor 4 / myeloid differentiation factor-2 (MD-2) system.

Purpose

We already reported that soluble MD-2 (sMD-2) is a risk factor for survival in patients with DCM. High mobility group box protein 1 (HMGB1) is a potent intrinsic interaction partner of MD-2. In the current study, we quantified HMGB-1 in plasma from patients with DCM at baseline, upon first hospital admission. Furthermore, we studied the impact of different HMGB-1 isoforms on monocyte adhesion in vitro.

Methods

We included 77 DCM patients divided by median time point of death after first hospital admission into “early death”, “late death” and “alive” group. MD-2 was quantified by means of ELISA. MD-2 and HMGB1 was quantified by means of ELISA. Statistical analysis was performed using a linear regression model.

Human umbilical vein endothelial cells (HUVEC; n=6) were treated for 48h with two isoforms of HMGB1 (disulfide (ds) and fully reduced (fr)) alone and in combination with MD-2. Subsequently, those activated HUVEC were incubated with fresh isolated peripheral blood mononuclear cells (PBMCs) for 20 min. Finally, monocyte adhesion was quantified using multicolour FACS.

Results

At baseline, we found significantly increased sMD-2 level in the “early death” group (591.3±75.5 ng/ml) compared to the “later death” group (369.2±46.5 ng/ml; p=0.015) and the “alive” group (303.2±18.1 ng/ml; p<0.001). Likewise, we could demonstrate significantly increased levels of HMGB1 in the “early death” group (0.93±0.14 ng/ml) compared to the “later death” (0.57±0.17 ng/ml; p=0.04) and the “alive” group (0.49±0.06 ng/ml; p<0.001). In all patients who died during the observation period, sMD-2 and HMGB1 plasma levels showed a positive correlation.

In vitro, we could demonstrate a significantly increased monocyte adhesion on HUVECs in the dsHMGB1 and the frHMGB1 group compared to controls (p=0.001; p=0.004). In contrast, the dsHMGB1 MD-2 group showed a significantly decreased monocyte adhesion on HUVECs compared to dsHMGB1 treatment alone (p=0.049). In the frHMGB1 MD-2 group, however, the reduction of the monocyte adhesion was less pronounced and did not reach significance (Fig. 1).

Conclusion

Our findings give a first hint that the interplay between HMGB1 and MD-2 is particularly involved in the development and progression of DCM. Furthermore, the data suggest that soluble MD-2 is capable of reducing the pro-inflammatory effects of dsHMGB1 but not of frHMGB1
5962Incremental prognostic value of hybrid PET-CT assessed myocardial blood flow, coronary stenosis severity and adverse plaque characteristics
Authors: Bom M J , Driessen R S , Van Diemen P A , Everaars H , Schumacher S P , Van Rossum A C , Raijmakers P G , Lammertsma A A , Knuuti J , Ahmadi A , Min J K , Leipsic J A , Narula J , Danad I , Knaapen P
Published: October 2019

Background

Management of patients with suspected coronary artery disease (CAD) can be optimized with prognostic information derived from non-invasive imaging such as positron emission tomography (PET) perfusion imaging and coronary computed tomography angiography (CCTA). The aim of the present study was to determine the incremental prognostic value of combined functional testing using PET perfusion imaging and anatomical testing using CCTA-derived stenosis severity and morphological assessment of CCTA-derived plaque morphology.

Methods

In this retrospective study, 539 patients referred for hybrid [15O]H2O PET – CCTA imaging because of suspected CAD were investigated. PET perfusion imaging was used to determine hyperemic myocardial blood flow (MBF), whereas CCTA images were evaluated for obstructive stenosis and high-risk plaque morphology. Major adverse coronary events (MACE) included all-cause death, non-fatal myocardial infarction (MI), urgent revascularization and late non-urgent revascularization (i.e. not guided by initial diagnostic work-up with non-invasive imaging). Kaplan Meier analysis and Cox proportional hazard regression were used to evaluate the independent prognostic value of PET-derived MBF, CCTA-derived stenosis and CCTA-derived high-risk plaque.

Results

During a mean follow-up of 6.8 [4.8–7.9] years, 79 (14.7%) patients experienced MACE, including 23 (4.3%) deaths, 19 (3.5%) MIs, 8 (1.5%) urgent revascularizations and 29 (5.4%) late non-urgent revascularizations. Annualized event rates for normal vs. abnormal results of PET perfusion imaging, CCTA-derived stenosis and high-risk plaque morphology were 1.2% vs 4.1%, 0.6% vs 4.4%, and 1.7% vs 5.6%, respectively (p<0.001 for all). The combined use of these three imaging parameters resulted in excellent long-term risk prediction, with a MACE-free survival of 97% in patients with no positive imaging findings. In contrast, MACE-free survival was only 69% in patients in whom all imaging findings were positive (figure 1). Multivariate Cox proportional hazard regression demonstrated incremental prognostic value of PET perfusion imaging, CCTA-derived stenosis and CCTA-derived high-risk plaques for the occurrence of MACE (p<0.05 for all)

MACE-free survival stratified by PET-CT

Conclusion

PET-derived myocardial blood flow and CCTA-derived stenosis severity and high-risk plaque morphology are independent long-term predictors of adverse cardiac events and provide incremental prognostic value. Combined functional, anatomical and morphological assessment may allow for improved risk stratification in patients with suspected CAD.
5967A randomized trial of yoga therapy for reflex syncope
Authors: Sinam S I , Gangwar R S , Banavalikar B , Padmanabhan D , Gangwar V , Valappil S P , Ghadei M K , Ali M , Shenthar J
Published: October 2019

Background

Reflex syncope (RS), the most common cause of syncope is usually recurrent, associated with decreased quality of life, and frustrates both the clinicians and the patients with a paucity of effective treatment options.

Purpose

To assess the effectiveness of yoga therapy on the recurrence of reflex syncope.

Methods

Subjects with recurrent RS (>3 episodes) and positive head-up tilt test were enrolled prospectively, and randomized to conventional therapy with physical maneuvres (Group 1) and yoga therapy (Group 2). Group 1 patients were taught physical counter-pressure maneuvers as per guidelines. Group 2 patients were taught yoga for 7 sessions by a certified Yoga instructor/therapist, and then advised to perform yoga for 60 minutes at least five days/week for six months. The Yoga module consisted of Pranayama (breathing techniques), Asanas (Postures) and Dhyana (Meditation) for 60 minutes/session. Both groups were followed up monthly for 6 months in the syncope clinic noting down the recurrences and the quality of life using the syncope functional status questionnaire score.

Result

The study group consisted of 97 patients (group 1: 46 patients and group 2: 51 patients) enrolled prospectively between June 2015 to February 2017. The mean age was 33.1±16.6 years, with male: female ratio 1.1:1, and a mean of 6.4±6.06 syncope episodes (group 1: 6.8±8.0 vs. group 2: 6.0±4.0; p=0.551). The mean duration of symptoms was 17.1±20.71 months (group 1: 16.1±22.8 months vs. group 2: 17.8±19.1 months; p=0.694). There was a significant decrease in the recurrences of syncope in the yoga group compared to the conventional group at three months (group 1: 1.8±1.4 vs group 2: 0.8±0.9, P<0.001) as well as six months follow-up (group 1: 3.38±3.0 vs group 2: 0.98±1.23, P<0.001). The quality of life score at 6 months improved in 20 patients in group 1 and in 45 patients in group 2 (<0.001).

Conclusion

Guided yoga therapy is superior to conventional measures in reducing the number of syncopal episodes and improves the quality of life in patients with reflex syncope. Yoga therapy should be considered as treatment strategy for patients with reflex syncope.
6108Efficacy of the PCSK9 inhibitor for lipid-rich coronary plaque reduction: a near-infrared spectroscopy analysis
Authors: Ota H , Omori H , Tanigaki T , Okamoto S , Hirata T , Kikuchi J , Sobue Y , Miyake T , Kawamura I , Kawase Y , Okubo M , Kamiya H , Tsuchiya K , Matsuo H
Published: October 2019

Background

Recently, some studies have highlighted proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors produce incremental low-density lipoprotein cholesterol (LDL-C) lowering effect. However, it is unknown whether the lipid composition of plaque changes is associated with serum LDL-C reduction due to PCSK9 inhibitors administration.

Purpose

The purpose of this study was to determine the effects of PCSK9 inhibitor (PCSK9i) on coronary plaque component in patients with a history of coronary artery disease (CAD) assessed by near-infrared spectroscopy intravascular ultrasound (NIRS-IVUS).

Methods

A total of 67 non-culprit coronary segments were identified in 34 patients. These lesions were analyzed utilizing NIRS-IVUS at baseline and follow-up coronary angiography (CAG). The subjects were divided into two groups according to lipid-lowering treatment; administration of PCSK9i group (PCSK9i: 19 segments, 9 patients) and traditional statin treatment group (Control: 48 segments, 25 patients). The change of lipid-rich plaque distribution between baseline and follow-up NIRS-IVUS was defined as the change of maximal lipid core burden index (LCBI) score for each of the 4-mm longitudinal segments (maxLCBI4mm).

Results

Mean duration from baseline to follow-up CAG was 239.4±52.4 days in the PCSK9i group and 341.0±84.1 days in the Control group (p<0.001). Despite the higher total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) in the PCSK9i group at baseline (206.6±40.9 mg/dl vs. 168.5±37.1 mg/dl, 131.5±35.4 mg/dl vs. 100.0±29.5 mg/dl; respectively, p<0.001 for both), the PCSK9i group was significantly lower TC and LDL-C at the follow-up (111.5±23.5 mg/dl vs. 157.4±27.8 mg/dl, 40.8±15.7 mg/dl vs. 86.2±19.6 mg/dl; respectively, p<0.001 for both). Furthermore, the PCSK9i group induced greater regression of maxLCBI4mm than that of Control group (99.6±156.6 vs. 27.9±118.0, p=0.046) (Figure).

Figure 1

Conclusion

Compared with traditional statin therapy, PCSK9i treatment resulted in a greater decrease in lipid component in non-culprit coronary plaques. Therefore, PCSK9i may be useful option in preventing from adverse coronary events for the patients with CAD.
6121Phrenic nerve injury during pulmonary vein isolation using the second-generation cryoballoon: characteristics and follow-up - The YETI registry
Authors: Heeger C H , Pott A , Sohns C , Rillig A , Kuniss M , Cay S , Miyazaki S , Aryana A , Jedrzejczyk-Patej E , Aytemir K , Inaba O , Chun J K R , Sommer P , Dahme T , Tilz R R
Published: October 2019

Background

Second-generation cryoballoon (CB2) based pulmonary vein isolation (PVI) has emerged as a safe and effective treatment option for symptomatic atrial fibrillation (AF). Although published complication rates of CB2 based-PVI are relatively low and several safety algorithms have been implemented in the protocols the most frequent complication is right-sided phrenic nerve injury (PNI). The reported incidence of PNI varies from 2–5% of patients. However data on PNI characteristics as well as follow-up is sparse.

Purpose

We aimed to evaluate the incidence, characteristics and outcome of PNI during after CB2 based-PVI in a large patients population.

Methods and results

From July 2012 to November 2018 a total of 13693 patients received CB2 or CB3 (third-generation) based-PVI in 23 EP centers (Germany: 12, China: 1, Turkey: 3, Japan: 3, USA: 1, Austria: 1, Poland: 1, Swizerland: 1). A total of 596 (4.4%) of patients experienced PNI during treatment of the right superior (84%) right inferior (15%) right middle (0.3%) (and left superior (0.3%) pulmonary veins. The mean time to PNI was 127±51 seconds and the mean temperature at the time of PNI was −49±7 °C. The target PV was isolated at time of PNI in 84% of cases. The applications were interrupted using double-stop technique in (71%). In 212/306 (52%) a CMAP was utilized.

At the end of the procedure PNI persistent in 45% of patients. Fluoroscopic or sonographic evaluation of PNI was performed 1–3 days after the procedure and revealed persistent PNI in 35% of patients. Dyspnea before discharge was reported in 18% of patients with persistent PNI. Patients follow up at 1–3, and 6–12 months included fluoroscopy and a visit in an outpatient clinic. After 1–3 months 18% of patients showed persistent PNI including 13% of patients complaining of dyspnea. After 6–12 months of follow-up including fluoroscopic evaluation PNI was persistent in 1.8% of patients while dyspnea was reported by 1.7% patients. Only 0.08% of the overall population of 13693 patients showed permanent and symptomatic PNI.

Conclusion

The incidence of PNI during CB2-based PVI is low. About 55% of PNI recovered until the end of the procedure. Most of PNI recovered within 12 months. Symptomatic permanent PNI is very rare in patients after CB2/CB3-based PVI.
P4981The reduction of coronary flow velocity reserve in heart failure with reduced, mid-range or preserved ejection fraction
Authors: Daros C , Cortigiani L , Ciampi Q , Gaibazzi N , Zagatina A , Wierzbowska-Drabik K , Pretto J L C S , Torres M A R , Djordjevic-Dikic A , D'Andrea A , Simova I , Amor M , Merlo P M , Lowenstein J , Picano E
Published: October 2019

Background

Coronary microvascular disease has been described in heart failure (HF) in presence of angiographically normal epicardial coronary arteries. The prevalence of a reduction of coronary flow velocity reserve (CFVR) in different types of HF and its link with left ventricular contractile reserve (LVCR) is unclear.

Aim

To assess CFVR and LVCR in HF.

Methods

In a prospective, observational, multicenter study, we recruited 380 patients (234 male, 61%, age 66±11 years): 143 (38%) with HF and reduced (<40%) ejection fraction (HFrEF); 98 (26%) with HF and mid-range (40–50%) ejection fraction (HFmrEF); 139 (36%) patients with HF and preserved (>50%) ejection fraction (HFpEF). A control group of 52 asymptomatic patients (23 male, 44%, age 61±14 years) referred to testing for screening was also selected (Controls). All patients underwent dipyridamole (0.84 mg/kg) stress echocardiography in 12 accredited laboratories of 3 countries (Argentina, Brazil and Italy). CFVR was calculated as the stress/rest ratio of diastolic peak flow velocity pulsed-Doppler assessment of left anterior descending (LAD) artery flow. We assessed left ventricular contractile reserve (LVCR) based on global LV Force (systolic blood pressure/end-systolic volume).

Results

Reduced (≤2.0) CFVR was observed in 0/52 controls (0%); 25/139 HFpEF (18%); 28/98 HFmrEF (29%); 78/143 HFrEF (54%, p<0.001 vs all other groups). CFVR was highest in controls (2.80±0.57), lower in HFpEF (2.51±0.57) and HFmrEF (2.26±0.44), lowest in HFrEF (2.04±0.48, p<0.001 vs all other groups). The correlation with LVCR was absent in controls (r=0.098, p=0.491) and HFmrEF (r=0.032, p=0.756), present in HFrEF (r=0.375, p<0.001) and HFpEF (r=0.314, p<0.001).

LVCR vs CFVR

Conclusions

CFVR is frequently abnormal in all types of HF, although more frequently and more profoundly in HFrEF. CFVR mirrors contractile reserve in HFrEF and - less tightly - in HFpEF.
P5014The NPAC score for predicting survival after incident acute myocardial infarction
Authors: Li K H , Ho J , Xu Z , Lakhani I , Bazoukis G , Liu T , Wong W T , Cheng S H , Chan M T V , Gin T , Wong M C S , Wong I , Wu W K K , Zhang Q , Tse G
Published: October 2019

Background

Risk stratification in acute myocardial infarction (AMI) is important for guiding clinical management. Current risk scores are mostly derived from clinical trials with stringent patient selection. We aimed to establish and evaluate a composite scoring system to predict short-term mortality after index episodes of AMI, independent of electrocardiography (ECG) pattern, in a large real-world cohort.

Methods

Using electronic health records, patients admitted to our regional teaching hospital (derivation cohort, n=2127) and an independent tertiary care center (validation cohort, n=1276) with index acute myocardial infarction between January 2013 and December 2017 as confirmed by principal diagnosis and laboratory findings, were identified retrospectively.

Results

Univariate logistic regression was used as the primary model to identify potential contributors to mortality. Stepwise forward likelihood ratio logistic regression revealed that neutrophil-to-lymphocyte ratio, peripheral vascular disease, age, and serum creatinine (NPAC) were significant predictors for 90-day mortality (Hosmer-Lemeshow test, P=0.21). Each component of the NPAC score was weighted by beta-coefficients in multivariate analysis. The C-statistic of the NPAC score was 0.75, which was higher than the conventional Charlson's score (C-statistic=0.63). Application of a deep learning model to our dataset improved the accuracy of classification with a C-statistic of 0.81.

Multivariate binary logistic regression Variable β Adjusted Odds ratio (95% CI) P-value Points Age ≥65 years 1.304 3.68 (2.63–5.17) <0.001 2 Peripheral vascular disease 1.109 3.03 (1.52–6.04) 0.002 2 NLRt ≥9.51 1.100 2.73 (2.12–3.51) <0.001 1 Creatinine≥109 μmol/L 1.003 3.00 (2.35–3.85) <0.001 2

NPAC deep learning model

Conclusions

The NPAC score comprised of four items from routine laboratory parameters and basic clinical information and can facilitate early identification of cases at risk of short-term mortality following index myocardial infarction. Deep learning model can serve as a gate-keeper to provide more accurate prediction to facilitate clinical decision making.
P5026Diagnostic yield in victims of sudden cardiac death and their relatives
Authors: Hansen B L , Jacobsen E M , Kjerrumgaard A , Winkel B G , Christensen A C , Bundgaard H
Published: October 2019

Background

International guidelines recommend screening of relatives in families with sudden cardiac death (SCD) if the cause of death is suspected to be an inheritable cardiac disease. The inheritable cardiac diagnosis may either have been known before the death, established at the autopsy or identified through screening of relatives.

Purpose

To provide an estimate of the diagnostic yield of inherited cardiac disease in SCD victims.

Methods

In an observational study, we included all families consecutively referred to our tertiary unit for inheritable cardiac diseases in the period from 2005 to 2018 due to SCD. Families with SCD victims under 1 year of age were excluded. In total, 697 relatives from 305 families were included and all relatives underwent a standard screening protocol, which included clinical and genetic work-up. Premortem medical records and postmortem findings on the SCD victim were ascertained whenever possible.

Results

A definite inheritable cardiac disease was identified in 113 out of 305 SCD families prior to family screening. The diagnosis was established through autopsy findings (n=89), genetic analysis (n=3) or was established prior to death (n=21). In the remaining 192 families with no or a borderline diagnosis only, screening of the relatives yielded a diagnosis in additional 28 families (15%). On a family-basis, a total of 141 out of 305 families (46%) were diagnosed. Seventy-seven (11%) out of the 697 screened relatives received either a phenotype-positive and/or genotype-positive inheritable diagnosis and 70 (10%) relatives received a borderline diagnosis. The most common diagnoses in the relatives were ARVC (n=17) followed by DCM (n=10) (see figure).

Conclusion

Almost half of SCD families were diagnosed with an inheritable cardiac disease of which one fifth of the families were diagnosed as a result of family screening. In 11% of the screened relatives a probable inheritable diagnosis was identified.
P5238Rate, cause and costs of Heart Failure hospitalizations following ICD/CRT-D replacement: preliminary data from an Italian multicenter registry
Authors: Zaca' V , Narducci M L , Parisi Q , Quartieri F , Zanon F , Zoni Berisso M , Saporito D , Notarstefano P , Miracapillo G , Ferretti C , Calo' L , Del Rosso A , Carinci V , Malacrida M , Biffi M
Published: October 2019

Background

Heart failure hospitalizations (HFHs) likely represent the main health care expenditure also in implantable cardiac defibrillators (ICDs) and cardiac resynchronization therapy defibrillators (CRT-D) recipients yet the event rate of HFH and the associated costs after device replacement or upgrade are unknown.

Purpose

To report HFH rates and associated costs within 12 months following ICD/CRT-D device replacement or upgrade procedure from ICD to CRT-D.

Methods

The DEtect long-term COmplications after icD rEplacement (DECODE) was a prospective, single-arm, multicenter cohort study exploring complications in ICD/CRT-D recipients undergoing device replacement or upgrade from ICD to CRT-D. All clinical and survival data of these patients at 12-month follow-up were prospectively analyzed. For each adjudicated HFH, the admission and discharge date were recorded, and ICD-9-CM diagnoses and procedure codes were obtained. The estimated reimbursement for each hospitalization was calculated according to the 2012 Italian national reimbursement rates.

Results

Between 2013 and 2015, 983 patients (mean age = 71 years, mean LVEF = 35%, NYHA class I/II = 75.6%) were enrolled: 900 (91.6%) patients underwent device replacement (446 ICD/454 CRT-D) and 83 (8.4%) upgrade from ICD to CRT-D. After 12 months, 66 (6.7%) patients died, 40 (60.6%) for cardiovascular reasons. Fifty-five (5.6%) patients experienced at least 1 HFH. Overall, 91 HFH (9.6% event rate 95% CI, 7.7–11.7) occurred. Among the variables tested at univariate analysis, only LVEF ≤35%, AF history and renal disease were confirmed as HFH predictors at multivariate analysis. HFH rate was significantly higher following upgrade procedures and occurrence of HFH was associated with an eleven-fold increased mortality risk (95% CI: 5.9 to 20.5; p<0.0001). The cumulative cost associated with HFHs incurred over the 12 months follow-up was 515305 €. The mean cost per HFH was 5662±9497 € [ranging from 3144 € to 64479 €] while the mean cost per patient with events was 9369±12687 €.

Conclusion

Underlying cardiac disease and renal failure are the main drivers of HFH and mortality, and of higher healthcare expenditures in ICD/CRT-D recipients following device replacement or upgrade. Accurate clinical assessment is needed to support the decision-maker at the time of ICD replacement to take an appropriate clinical and economic sustainable decision.

Acknowledgement/Funding

None
P5251Prognostic value of unrecognized myocardial infarction detected by cardiac magnetic resonance imaging in patients presenting with first acute myocardial infarction
Authors: Kanaji Y , Sugiyama T , Hoshino M , Hirano H , Yuki H , Horie T , Kanno Y , Ohya H , Sumino Y , Hada M , Yamaguchi M , Yonetsu T , Kakuta T
Published: October 2019

Background

Unrecognized myocardial infarction (UMI) has been reported to be strongly associated with worse outcome in patients with cardiovascular disease. Cardiac magnetic resonance (CMR) imaging is a useful instrument for the assessment of pathological and functional conditions.

Purpose

This study sought to evaluate the prognostic value of the presence of unrecognized non-infarct-related late gadolinium enhancement (non-IR LGE) evaluated by cardiac magnetic resonance imaging in patients presenting with a first acute myocardial infarction (AMI).

Methods

We studied 311 AMI patients including 213 STEMI and 98 NSTEMI patients without the history of prior MI who underwent uncomplicated primary or emergent PCI within 48 hours of symptom onset between October, 2012 and June, 2017. CMR images were acquired at 28 [21, 32] days after primary/emergent PCI. UMI was defined as having LGE separately in the different and remote area from the perfused territory by infarct-related artery. In case of multiple LGE areas of infarction, the coronary angiography findings were used to support identification of the area corresponding to the culprit artery of AMI. The association of CMR variables and other clinical characteristics with major adverse cardiac events (cardiac death, nonfatal myocardial infarction, nonfatal stroke) were investigated.

Results

Forty-six patients (14.8%) showed UMI defined by the presence of non-IR LGE (27 STEMI and 19 NSTEMI). During the follow up for 830 [385, 1309] days, cardiovascular death occurred in 7 patients (2.3%), and non-fatal MI and non-fatal stroke occurred in 10 and 1 patients, respectively (3.2%, 0.3%, respectively). There was no significant difference in the prevalence of UMI and incidence of MACE between the patients with STEMI and NSTEMI (p=0.13, p=0.11, respectively). Event-free survival was significantly worse in patients with UMI (log-rank χ2=16.3, P=0.001) in a total cohort. Cox proportional hazards analysis showed that UMI was independent predictors of adverse cardiac events during follow-up in patients with first MI (hazard ratio, 7.60, 95% confidence interval, 2.78–20.8, p=0.0001).

Conclusions

In first AMI patients, UMI defined by non-IR LGE obtained by noninvasive CMR provides significant prognostic information. Early detection of UMI by CMR may help risk stratification of patients with AMI and support adjunctive aggressive patient management such as strong statin therapy and life style intervention.
P5258Native T1 time of right ventricular insertion points by CMR: relation with invasive hemodynamics and outcome in HFPEF
Authors: Nitsche C , Kammerlander A , Binder C , Duca F , Aschauer S , Koschutnik M , Snidat A , Beitzke D , Loewe C , Hengstenberg C , Bonderman D , Mascherbauer J
Published: October 2019

Background

Increased afterload to the right ventricle (RV) has been shown to induce myocardial fibrosis at the RV insertion points (RVIPs). Such changes can be discrete but potentially detected by cardiac magnetic resonance (CMR) T1-mapping. Whether RVIP fibrosis is associated with prognosis in heart failure with preserved ejection fraction (HFpEF) is unknown.

Methods

We prospectively investigated 167 consecutive HFpEF patients, a population frequently suffering from postcapillary pulmonary hypertension (PH), who underwent CMR including T1-mapping. 92,8% also underwent right heart catheterization for hemodynamic assessment. Kaplan–Meier analysis, cox regression analysis and Spearman's rank order correlation were applied as statistical methods. The parameter with the strongest discriminative power of each group (clinical, hemodynamic and CMR) by receiver operating curve analysis was selected to the enter the multivariate cox model.

Results

Native T1 times were 995±73 ms at the anterior and 1040±90 ms at the inferior RVIP. By Spearman's rank order testing, RVIP T1 times were significantly correlated with pulmonary artery pressure (mean PAP, r=0.313 and 0.311 for anterior and inferior RVIP, respectively), pulmonary artery wedge pressure (r=0.301 and 0.251) and right atrial pressure (r=0.245 and 0.185; p for all<0.05). During a mean follow-up of 43.2±22.6 months, 30 (18.0%) subjects died. By multivariable Cox regression, NTproBNP (Hazard ratio [HR] 2.105, 95% confidence interval [CI] 1.332–3.328; p=0.001), systolic PAP (HR 1.618, 95% CI 1.175–2.230; p=0.003), and native T1 time of the anterior RVIP (HR 1.659, 95% CI 1.125–2.445; p=0.011) were significantly associated with outcome. Also, by Kaplan-Meier analysis, T1 time at the anterior RVIP had a significant effect on survival (log-rank, p=0.002).

Kaplan Meier Curve

Conclusions

Interstitial expansion of the anterior RVIP as detected by CMR T1-mapping reflects hemodynamic alterations, and is independently related with prognosis in HFpEF.
P5260Differences in myocardial mechanics between dilated cardiomyopathy and ischemic cardiomyopathy by CMR derived feature tracking strain - A propensity score-matched study
Authors: Vietheer J , Unbehaun C , Weferling M , Fischer-Rasokat U , Kriechbaum S , Zipse L , Keller T , Hamm C W , Rolf A
Published: October 2019

Background

Adult heart failure in industrialized nations is primarily due to dilated (DCM) and ischemic cardiomyopathy (ICM). Both diseases are characterized by different pathological pathways. While ICM is predominantly caused by local, subendocardial myocyte necrosis, DCM is characterized by a general myocyte apoptosis involving all myocardial layers. Using feature tracking, longitudinal, circumferential, and radial motion of the left ventricle (LV) can be measured, which allows the function of subendocardial, mostly longitudinal orientated, and subepicardial, mostly circumferential orientated fibers to be assessed independently.

Purpose

It was the aim of our study to detect differences of LV motion between DCM and ICM patients in a propensity score-matched cohort.

Methods

Between April 2017 and December 2018 we included 845 patients with a clinical indication for CMR in our tertiary care center registry. Out of this cohort we identified 273 patients with ICM and 126 with DCM. Propensity score matching was used to pair patients in each group based on their indexed enddiastolic volume (EDVi), ejection fraction (EF), septal T1. Feature tracking technique was used for strain analyses quantified on steady state free precession cine CMR images yielding six strain parameters.

Results

Propensity score matching yielded 59 patients in each group (ICM mean age 59.4±13.0 years, 11 females; DCM mean age 66.5±10.6 years, 15 females; LV-EF 32.6±11.4% vs. 33.0±14.2%, p=0.8178; EDVi 124.2±36 ml/m2 vs. 132.9±42 ml/m2, p=0.0909; native T1 values 1161±66 ms vs. 1164±59 ms, p=0.7049). There was no difference in global longitudinal strain between ICM and DCM patients (−10.9±4.4% vs. −10.6±5.8%, p=0.686), whereas global circumferential strain and radial strain were reduced in DCM patients (−12.0±4.3% vs. −10.31±4.8%, p=0.0190 and 21.1±8.9% vs. 18.0±15.5%, p=0.0386).

Conclusion

Our data confirm the inherently different mechanics of ICM and DCM patients. While myocardial fibres are globally affected in DCM, myocardial damage is predominantly confined to subendocardial layers in ICM despite equally reduced EF.