Real-World Patent Foramen Ovale (PFO) Closure in Japan　- 30-Day Clinical Outcomes From the AmplatzerTM PFO Occluder Japan Post-Marketing Surveillance Study.

BACKGROUND: The AmplatzerTM PFO Occluder was approved for marketing in Japan in May 2019, and the Amplatzer PFO Occluder Japan Post-marketing Surveillance (PFO Japan PMS) study was initiated in December 2019. This analysis presents 30-day clinical outcomes for PFO Japan PMS study patients.Methods and Results: PFO Japan PMS is a prospective single-arm non-randomized multicenter clinical study. Eligible patients were indicated for patent foramen ovale (PFO) closure and underwent an implant attempt with the AmplatzerTM PFO Occluder. Technical success was defined as successful delivery and release of the occluder; procedural success was defined as technical success with no serious adverse events (SAEs) within 1 day of the procedure. The primary safety endpoint includes predefined device- and/or procedure-related SAEs through 30 days after the procedure. From December 2019 to July 2021, 500 patients were enrolled across 53 Japanese sites. The mean (±SD) patient age was 52.7±15.4 years, and 29.8% of patients were aged >60 years. Technical and procedural success rates were both high (99.8% and 98.8%, respectively). Further, there was only one primary safety endpoint event (0.2%): an episode of asymptomatic paroxysmal atrial fibrillation that occurred 26 days after the procedure. CONCLUSIONS: In this real-world Japanese study with almost one-third of patients aged >60 years, PFO closure with the AmplatzerTM PFO Occluder was performed successfully and safely, with a low incidence of procedure-related atrial arrhythmias.

J wave dynamicity during coronary angiography and intracoronary acetylcholine administration.

BACKGROUND: J-waves may be observed during coronary angiography (CAG) or intracoronary acetylcholine (ACh) administration, but their significance is unknown. METHODS: Forty-nine patients, 59.1 ± 11.5 years old and 59% male, were studied on suspicion of vasospastic angina, and J wave dynamicity was compared between CAG and Ach administration. RESULTS: Diagnostic (≥0.1 mV) or nondiagnostic (<0.1 mV) J waves in 9 and 3 patients, respectively, were augmented, and J waves were newly observed in 2 patients during CAG and Ach administration. Similar changes in the J-wave amplitude were observed: from 0.10 ± 0.09 mV to 0.20 ± 0.15 mV (p < .002) and from 0.10 ± 0.10 mV to 0.20 ± 0.16 mV (p < .001) during CAG and Ach administration, respectively. J waves were located in the inferior leads and changed only during the right coronary interventions. In the remaining 35 patients, J waves were absent before and during the coronary interventions. Augmentation of J waves was found when the RR interval was shortened in some patients. Injection of anoxic media into the coronary artery might induce a conduction delay from myocardial ischemia that manifests as augmentation or new occurrence of J waves. CONCLUSIONS: Both CAG and intracoronary Ach administration affected J waves similarly in the same individuals. A myocardial ischemia-induced conduction delay may be responsible for the changes in J waves, but further studies are needed.

Prospective screening for myocarditis in cancer patients treated with immune checkpoint inhibitors.

BACKGROUND: Immune checkpoint inhibitors (ICIs) improve clinical outcomes in various cancers, but sometimes induce autoimmune adverse effects, including myocarditis, which is the most serious complication. There are many reports on ICI-induced myocarditis; however, only a few prospective surveillance reports exist. Therefore, we developed a prospective screening protocol and performed monitoring clinically suspected myocarditis in every patient treated with ICIs. METHODS: We prospectively enrolled 126 consecutive patients treated with ICIs in this cohort. Outcomes of patients were determined and analyzed between April 2017 and May 2020. We evaluated vital signs, biomarkers, electrocardiograms, chest radiographs, and echocardiographs before and at 7 ±â€¯3, 14 ±â€¯3, 21 ±â€¯3, and 60 ±â€¯7 days after ICI initiation. RESULTS: Eighteen (14.3 %) presented troponin I elevation and 13 of them presented signs of clinically suspected myocarditis (10.3 %). Among the 13 patients, ICI was discontinued in four cases (3.2 %) without fatal events. Myocarditis appeared at an early stage of ICI treatment, regardless of severity (median, 44 days). CONCLUSIONS: We observed the frequency of patients with myocarditis or myocardial damage through a prospective screening program in the real world. Although the frequency was higher than expected, most cases were mild and ICI treatment could be continued under careful observation.

Usefulness of Global Longitudinal Strain-Guided Management in Preventing Human Epidermal Growth Factor Receptor 2 (HER2) Inhibitor-Induced Myocardial Damage.

Background: Trastuzumab, an anti-human epidermal growth factor receptor 2 (HER2) monoclonal antibody, is a specific first-line treatment for patients with HER2-positive cancers. Cardiac dysfunction is among the most problematic adverse events associated with trastuzumab. Although regular echocardiographic screening is recommended for early detection of cardiac damage, few reports have investigated the validity of echocardiographic screening in chemotherapy. Therefore, the aim of this study was to determine whether a GLS-guided management approach could reduce cardiotoxicity and discontinuation of trastuzumab chemotherapy. Methods and Results: To evaluate the usefulness of global longitudinal strain (GLS)-guided cardioprotective interventions, we retrospectively analyzed 67 patients treated with trastuzumab who underwent structured echocardiographic assessments before and after 1, 3, and 6 courses of trastuzumab administration. If a >15% relative decrease in GLS was identified, cardioprotective agents were administered. Thirty (44.8%) patients had breast cancer; the remaining patients had salivary gland cancer. The median observation period for the intervention group was 304 days from the initial evaluation. Nineteen (28.4%) patients exhibited a >15% relative decrease in GLS, and consequently received cardioprotective agents. The incidence of trastuzumab discontinuation for cardiogenic reasons was significantly lower among patients receiving GLS-guided interventions than among those not receiving the intervention (2.4% vs. 24.0%; P=0.009). The incidence of a subsequent decline in left ventricular ejection fraction was lower among patients receiving the intervention than among those not receiving the intervention (4.8% vs. 24.0%; P=0.04). Conclusions: GLS-guided cardioprotective intervention significantly decreased the incidence of trastuzumab discontinuation.

Routine assessment of cardiotoxicity in patients undergoing long-term immune checkpoint inhibitor therapy.

The indications for immune checkpoint inhibitors (ICIs) are expanding in cancer drug therapy, and while cardiac events associated with ICIs are often fatal, there are few reports regarding cardiac complications associated with long-term ICI therapy. We aimed to study cardiac complications in patients undergoing long-term ICI therapy. From the database of our local cardio-oncology unit, we enrolled patients with cancer undergoing ICI therapy for more than 6 months and for whom cardiologists continuously performed routine follow-ups. We defined the primary endpoint as discontinuation of ICI due to cardiac events. We also analyzed changes in cardiac biomarkers and echocardiographic parameters. We retrospectively analyzed 55 consecutive patients (43 males, mean age: 65 ± 11 years) treated with ICI therapy in our hospital between January 2017 and June 2021. None of the patients discontinued ICI therapy due to cardiac events more than 6 months after treatment was initiated. Among the participants, we observed four patients with elevated serum troponin I levels, seven patients with decreased global longitudinal strain values, and two patients with elevated plasma brain natriuretic peptide levels. No patient required drug intervention for these cardiac events; furthermore, there were no cases of clinically diagnosed myocarditis. In the present study, there were no cardiac events causing ICI discontinuation in patients undergo ICI therapy for more than 6 months.

Long-term safety of a structured transition protocol from parenteral prostanoids to selexipag in pulmonary arterial hypertension.

There was no structured method for safely transition from parenteral prostanoids to oral medication. We enrolled 37 idiopathic/hereditary pulmonary arterial hypertension patients receiving triple combination therapy including parenteral prostanoids into structured transition program to oral selexipag. Four (10.8%) patients successfully transitioned under the protocol, and all of them presented long-term safety.

Comparison of left ventricular pacing performance among pre-shaped guidewires designed for transfemoral-approach transcatheter aortic valve implantation.

TAVI is an established therapy for patients with severe aortic stenosis. Rapid or control pacing is necessary for TAVI, and most centers are familiar with right ventricular (RV) pacing. Although there are several reports on the efficacy and safety of LV pacing, they are still few. In addition, LV pacing has not been studied for different LV guidewires. Our aim is to study the effectiveness of left ventricular (LV) pacing and the thresholds of LV guidewires in patients who underwent transcatheter aortic valve implantation (TAVI). We retrospectively analyzed 252 consecutive patients who underwent trans-femoral TAVI (TF-TAVI) with LV pacing in our institute between December 2017 and November 2020. We excluded 48 patients from the total cohort due to TAVI with RV pacing, and the remaining 204 patients were analyzed (52 males, mean age 85 ± 5 years). Among them, 202 patients (99.0%) had successful LV pacing. In the two patients with failed LV pacing, SAFARI2™ Small was used. The CONFIDA™ group (n = 34) showed a significantly lower threshold than the SAFARI2™ group (n = 163) (median 3.0 vs. 5.0 V; P = 1.1 × 10-7). LV pacing with Lunderquist® was successful in all patients (n = 7). LV pacing in TAVI was an effective and safe strategy. CONFIDA™ wire may be particularly well suited for LV pacing in TAVI.

Liver fibrosis index as a novel prognostic factor in patients with pulmonary arterial hypertension.

Liver dysfunction is an important determinant of the prognosis of left heart failure patients. However, few studies have reported on cardiohepatic interactions in right heart failure patients, a condition that is an important prognostic factor in pulmonary arterial hypertension (PAH). This study aimed to evaluate the existence and extent of hepatic fibrosis and its contribution as a prognostic factor in PAH. This prospective study enrolled 60 consecutive patients with PAH in the International University of Health and Welfare Mita Hospital from June 2016 to December 2017. After the application of the exclusion criteria, 35 patients were assessed for hepatic fibrosis, using real-time tissue elastography, and for clinical deterioration. Sixteen healthy controls were also assessed for comparison. The liver fibrosis index (LFI) was significantly higher in PAH patients than in healthy controls (1.214 ± 0.047 vs. 0.911 ± 0.059, P < 0.001), suggesting that PAH patients exhibited mild liver fibrosis. However, patients with deterioration (vs. no deterioration) had significantly higher LFI values (1.507 ± 0.078 vs. 1.080 ± 0.034, P < 0.001), independent from other established liver function parameters. A receiver operating characteristic curve analysis identified that an LFI ≥ 1.275 indicated a significant probability of clinical deterioration (hazard ratio: 8.4 (95% CI 1.5-45.4, P = 0.012), independent from other known PAH prognostic factors. PAH patients may exhibit subclinical liver fibrosis associated with chronic right heart failure. The LFI can serve as both a non-invasive evaluation of liver fibrosis and a predictive marker for the deterioration of PAH patients.

Longitudinal Strain and Troponin I Elevation in Patients Undergoing Immune Checkpoint Inhibitor Therapy.

Background: Immune checkpoint inhibitors (ICIs) are a central part of cancer therapy; however, cardiac complications, such as myocarditis, have the potential for significant morbidity and mortality. Within this population, the clinical significance of longitudinal strain (LS) remains unknown. Objectives: This study sought to define the changes in LS in ICI-treated patients, and their associations with high-sensitivity troponin I (hsTnI) and myocarditis. Methods: We conducted a retrospective cohort study of patients who received ICIs at our hospital from April 2017 to September 2021. All patients underwent echocardiography and blood sampling at standardized time intervals. We measured the changes in global and regional LS before and after ICI administration. Age- and sex-adjusted Cox regression analysis was used to evaluate the association between LS and elevations in hsTnI and myocarditis. Results: In a cohort of 129 patients with a median follow-up period of 170 (IQR: 62-365) days; 6 and 18 patients had myocarditis and hsTnI elevation, respectively. In an age- and sex-adjusted Cox proportional hazards model, an early relative worsening of ≥10% in the basal and mid LS and ≥15% in global LS was associated with hsTnI elevation. Relative reductions in LS were not significantly associated with myocarditis; however, 4 of the 6 patients with myocarditis had relative reduction of ≥10% in the basal LS. Conclusions: An early worsening in the global and regional LS was associated with increased hsTnI in patients receiving ICIs. Assessment of LS early after ICI administration should be further studied as a strategy for risk stratification of ICI-treated patients.

Predictors of hypoxemia in type-B acute aortic syndrome: a retrospective study.

Acute aortic syndrome (AAS) can be life-threatening owing to a variety of complications, and it is managed in the intensive care unit (ICU). Although Stanford type-B AAS may involve hypoxemia, its predictors are not yet clearly understood. We studied clinical factors and imaging parameters for predicting hypoxemia after the onset of type-B AAS. We retrospectively analyzed patients diagnosed with type-B AAS in our hospital between January 2012 and April 2020. We defined hypoxemia as PaO2/FiO2 ≤ 200 within 7 days after AAS onset and used logistic regression analysis to evaluate prognostic factors for hypoxemia. We analyzed 224 consecutive patients (140 males, mean age 70 ± 14 years) from a total cohort of 267 patients. Among these, 53 (23.7%) had hypoxemia. The hypoxemia group had longer ICU and hospital stays compared with the non-hypoxemia group (median 20 vs. 16 days, respectively; p = 0.039 and median 7 vs. 5 days, respectively; p < 0.001). Male sex (odds ratio [OR] 2.87; 95% confidence interval [CI] 1.24-6.63; p = 0.014), obesity (OR 2.36; 95% CI 1.13-4.97; p = 0.023), patent false lumen (OR 2.33; 95% CI 1.09-4.99; p = 0.029), and high D-dimer level (OR 1.01; 95% CI 1.00-1.02; p = 0.047) were independently associated with hypoxemia by multivariate logistic analysis. This study showed a significant difference in duration of ICU and hospital stays between patients with and without hypoxemia. Furthermore, male sex, obesity, patent false lumen, and high D-dimer level may be significantly associated with hypoxemia in patients with type-B AAS.

Thyroid Hormone Plays an Important Role in Cardiac Function: From Bench to Bedside.

Thyroid hormones (THs) are synthesized in the thyroid gland, and they circulate in the blood to regulate cells, tissues, and organs in the body. In particular, they exert several effects on the cardiovascular system. It is well known that THs raise the heart rate and cardiac contractility, improve the systolic and diastolic function of the heart, and decrease systemic vascular resistance. In the past 30 years, some researchers have studied the molecular pathways that mediate the role of TH in the cardiovascular system, to better understand its mechanisms of action. Two types of mechanisms, which are genomic and non-genomic pathways, underlie the effects of THs on cardiomyocytes. In this review, we summarize the current knowledge of the action of THs in the cardiac function, the clinical manifestation and parameters of their hemodynamics, and treatment principles for patients with hyperthyroid- or hypothyroid-associated heart disease. We also describe the cardiovascular drugs that induce thyroid dysfunction and explain the mechanism underlying the thyroid toxicity of amiodarone, which is considered the most effective antiarrhythmic agent. Finally, we discuss the recent reports on the involvement of thyroid hormones in the regulation of myocardial regeneration and metabolism in the adult heart.

Successful Leadless Pacemaker Implantation in an Elderly Patient With Dextrocardia and Situs Inversus.

Leadless pacemaker is indicated in patients with symptomatic bradycardia as an alternative therapy when transvenous pacemaker implantation is considered difficult or at high risk. The experience of implanting leadless pacemaker in patients with dextrocardia and situs inversus is limited. A 94-year-old male was transferred to our hospital due to advanced atrio-ventricular block with episode of syncope. Chest radiograph and computed tomography revealed dextrocardia with situs inversus. Emergency cardiac catheterization was performed and a temporary pacemaker was inserted, but the patient removed it due to delirium. So, a leadless pacemaker was implanted to him. Shorter time of bed-rest after the implantation and shorter hospital stay would be beneficial of implanting a leadless pacemaker. Precise anatomical evaluation would be important to perform implantation efficiently and safely.

Case Report: BMPR2-Targeted MinION Sequencing as a Tool for Genetic Analysis in Patients With Pulmonary Arterial Hypertension.

Background: Mutations in the bone morphogenetic protein receptor type 2 gene (BMPR2) represent a major genetic cause of pulmonary arterial hypertension (PAH). Identification of BMPR2 mutations is crucial for the genetic diagnosis of PAH. MinION nanopore sequencer is a portable third-generation technology that enables long-read sequencing at a low-cost. This nanopore technology-based device has not been used previously for PAH diagnosis. This study aimed to determine the feasibility of using MinION nanopore sequencing for the genetic analysis of PAH patients, focused on BMPR2. Methods: We developed a protocol for the custom bioinformatics pipeline analysis of long reads generated by long-PCR. To evaluate the potential of using MinION sequencing in PAH, we analyzed five samples, including those of two idiopathic PAH patients and a family of three members with one affected patient. Sanger sequencing analysis was performed to validate the variants. Results: The median read length was around 3.4 kb and a good mean quality score of approximately 19 was obtained. The total number of reads generated was uniform among the cases and ranged from 2,268,263 to 3,126,719. The coverage was consistent across flow cells in which the average number of reads per base ranged from 80,375 to 135,603. We identified two polymorphic variants and three mutations in four out of five patients. Certain indel variant calling-related errors were observed, mostly outside coding sequences. Conclusion: We have shown the ability of this portable nanopore sequencer to detect BMPR2 mutations in patients with PAH. The MinION nanopore sequencer is a promising tool for screening BMPR2 mutations, especially in small laboratories and research groups.

Pulmonary hypertension associated with neurofibromatosis type 2.

Although precapillary pulmonary hypertension is a rare but severe complication of patients with neurofibromatosis type 1 (NF1), its association with NF2 remains unknown. Herein, we report a case of a 44-year-old woman who was initially diagnosed with idiopathic pulmonary arterial hypertension and treated with pulmonary arterial hypertension-specific combination therapy. However, a careful assessment for a relevant family history of the disease and genetic testing reveal that this patient had a mutation in the NF2 gene. Using immunofluorescence and Western blotting, we demonstrated a decrease in endothelial NF2 protein in lungs from idiopathic pulmonary arterial hypertension patients compared to control lungs, suggesting a potential role of NF2 in pulmonary arterial hypertension development. To our knowledge, this is the first time that precapillary pulmonary hypertension has been described in a patient with NF2. The altered endothelial NF2 expression pattern in pulmonary arterial hypertension lungs should stimulate work to better understand how NF2 is contributing to the pulmonary vascular remodelling associated to these severe life-threatening conditions.

Sudden cardiac death after acute decompensation in heart failure patients: implications of discharge haemoglobin levels.

AIMS: Heart failure (HF) patients have a high risk of mortality due to sudden cardiac death (SCD) and non-SCD, including pump failure death (PFD). Anaemia predicts more severe symptomatic burden and higher morbidity, as noted by markedly increased hospitalizations and readmission rates, and mortality, underscoring its importance in HF management. Herein, we aimed to determine whether haemoglobin (Hb) level at discharge affects the mode of death and influences SCD risk prediction. METHODS: We evaluated the data of 3020 consecutive acute HF patients from a Japanese prospective multicentre registry. Patients were divided into four groups based on discharge Hb levels. SCD was defined as an unexpected and otherwise unexplained death in a previously stable patient or death due to documented or presumed cardiac arrhythmia without a clear non-cardiovascular cause. The mode of death (SCD, PFD or other cause) was adjudicated by a central committee. Finally, we investigated whether adding Hb level to the Seattle Proportional Risk Model (SPRM; established risk score utilized to estimate 'proportion' of SCD among death events) would affect its performance. RESULTS: The mean age of studied patients was 74.3 ± 12.9 years, and 59.8% were male. The mean Hb level was 12.0 ± 2.1 g/dL (61.3% of patients had anaemia defined by World Health Organization criteria). During the 2-year follow-up, 474 deaths (15.7%) occurred, including 93 SCDs (3.1%), 171 PFDs (5.7%) and 210 other deaths (7.0%; predominantly non-cardiac death). Absolute risk of PFD (P < 0.001) or other death (P < 0.001) increased along with the severity of anaemia, whereas the incidence of SCD was low but remained consistent across all four groups (P = 0.440). As a proportion of total deaths in each Hb level group, the contributions from non-SCD increased and from SCD decreased along with anaemia severity (P = 0.007). Adding Hb level to the SPRM improved the overall discrimination (c-index: 0.62 [95% confidence interval (CI) 0.56-0.69] to 0.65 [95% CI 0.59-0.71]), regardless of the baseline ejection fraction (EF) (c-index: 0.64 [95% CI 0.55-0.73] to 0.67 [95% CI 0.58-0.75] for reduced EF and 0.55 [95% CI 0.45-0.66] to 0.61 [95% CI 0.52-0.70] for preserved EF). CONCLUSIONS: The discharge Hb level provides information about both absolute and proportional risks for each mode of death in acute HF patients, and the addition of Hb level improves the performance of SPRM by identifying more non-SCD cases. Future 'proportional' SCD risk models should incorporate Hb level as a covariate to meet this high performance.

Ambient Temperature and Cardiorenal Connection in Elderly Patients with Stable Heart Failure.

Heart failure increases among the elderly; however, the influence of ambient temperature on cardiorenal function has not been well investigated. Patients (n = 110, mean age 82.9 years, 43 males) with stable heart failure and creatinine < 3.0 mg/dl were studied. Medical records, such as ejection fraction, B-type natriuretic peptide (BNP), and estimated glomerular filtration rate (eGFR) at each visit every 1-3 months were collected by the end-point for death, additional prescription to treat heart failure, or heart failure hospitalization. The ambient temperatures at each visit were obtained from the Japan Meteorological Agency. During the follow-up period (median 399 days and 7 visits), follow-up BNP showed a trend toward a positive correlation with the diurnal temperature range. After dividing into two groups by median baseline eGFR, follow-up BNP was positively correlated with minimum temperature (p = 0.039) and the diurnal temperature range (p = 0.007) in the Low-eGFR group but not in the High-eGFR group. Follow-up eGFR was negatively correlated with the ambient day temperature in both groups (p ≤ 0.002). Follow-up BNP was positively correlated with follow-up eGFR (p < 0.0001) only in the Low-eGFR group and not in the High-eGFR group, suggesting that BNP and eGFR increase in winter and BNP and eGFR decrease in summer in the Low-eGFR group. In conclusions, heart failure may be worsened by larger diurnal temperature range or in winter in patients with renal impairment. This population should be carefully managed in the clinic according to the ambient temperature.

Explainable Artificial Intelligence Model for Diagnosis of Atrial Fibrillation Using Holter Electrocardiogram Waveforms.

Atrial fibrillation is a clinically important arrhythmia. There are some reports on machine learning models for AF diagnosis using electrocardiogram data. However, few reports have proposed an eXplainable Artificial Intelligence (XAI) model to enable physicians to easily understand the machine learning model's diagnosis results.We developed and validated an XAI-enabled atrial fibrillation diagnosis model based on a convolutional neural network (CNN) algorithm. We used Holter electrocardiogram monitoring data and the gradient-weighted class activation mapping (Grad-CAM) method.Electrocardiogram data recorded from patients between January 4, 2016, and October 31, 2019, totaling 57,273 electrocardiogram waveform slots of 30 seconds each with diagnostic information annotated by cardiologists, were used for training our proposed model. Performance metrics of our AI model for AF diagnosis are as follows: sensitivity, 97.1% (95% CI: 0.969-0.972); specificity, 94.5% (95% CI: 0.943-0.946); accuracy, 95.3% (95% CI: 0.952-0.955); positive predictive value, 89.3% (95% CI: 0.892-0.897); and F-value, 93.1% (95% CI: 0.929-0.933). The area under the receiver operating characteristic curve for AF detection using our model was 0.988 (95% CI: 0.987-0.988). Furthermore, using the XAI method, 94.5 ± 3.5% of the areas identified as regions of interest using our machine learning model were identified as characteristic sites for AF diagnosis by cardiologists.AF was accurately diagnosed and favorably explained with Holter ECG waveforms using our proposed CNN-based XAI model. Our study presents another step toward realizing a viable XAI-based detection model for AF diagnoses for use by physicians.