Heart rate modulation therapy using ivabradine improves mortality and morbidity in patients with systolic dysfunction. However, a target heart rate remains uncertain. Echocardiography-guided ivabradine therapy, in which we attempt to approach zero overlap between two diastolic filling inflow waves, has recently been proposed to maximize cardiac output, facilitate reverse remodeling, and reduce mortality and morbidity, instead of using an absolute value for the target heart rate. Prospective studies are needed to validate the clinical implication of these therapeutic strategies. Also, this concept should be expanded to other clinical scenarios.

The coronavirus disease 2019 (COVID-19) pandemic has changed the lives of healthcare professionals, especially vulnerable physicians such as young or female cardiologists. In Japan, they are facing the fear of not only infection but also weak and unstable employment, difficulties in medical practice and training anxiety, implications for research and studying abroad, as well as worsened mental health issues due to social isolation. Conversely, some positive aspects are seen through the holding of remote meetings and conferences. Here, we suggest a new working style for cardiologists, as well as offer solutions to the medical employment problems that have been taken place in Japan.

Dilated cardiomyopathy (DCM) is a common cause of heart failure. TTN, which encodes titin protein, is a representative causative gene of DCM, and is presented mainly as a truncation variant. However, TTN truncation variants are also found in healthy individuals, and it is therefore important to evaluate the pathogenicity of each variant. In this study, we analyzed 67 cardiomyopathy-associated genes in a male Japanese patient who was hospitalized for recurrent severe heart failure and identified a novel truncation variant, TTN Ser17456Arg fs*14. This TTN truncation variant was located in the A-band region. Moreover, the patient's mother with heart failure harbored the same variant, whereas the father and brother without heart failure did not harbor the variant. To examine the functional changes associated with the truncation variant, H9c2 cells were subjected to genome editing to generate cells with a homologous truncation variant. The cells were differentiated using all-trans-retinoic acid, and the mRNA expression of skeletal actin and cardiac actin were found to be increased and decreased, respectively, consistent with known changes in patients with DCM or heart failure. In contrast, another cell with the titin truncation variant used as a control showed no changes in heart failure-related genes. In summary, we found a novel TTN truncation variant in familial DCM patients and confirmed its functional changes using a relatively simple cell model. The novel truncation variant was identified as a pathogenic and disease-causing mutation.

Left bundle branch pacing (LBBP) has been adopted as a new pacing therapy whether in routine pacing or patients with heart failure, but the criteria for a completely captured LBBP are too complicated and have a low success rate in routine clinical practice.

Consecutive patients with pacing therapy indications were enrolled. Left bundle branch area pacing (LBBAP) was conducted, and the presence of LBB potential, paced QRS duration, stimulus to left ventricular activation time (Stim-LVAT), and LBB potential to left ventricular activation time (LBB po-LVAT) were determined and utilized to characterize LBBAP modalities. Pacing parameters and safety were assessed at 6-month follow-up. LBBAP succeeded in 95.6% of patients (103/106) who completed the 6-month follow-up. Complete LBBP was achieved in 21 (20%) patients, characterized with a short Stim-LVAT equal to LBB po-LVAT. Incomplete LBBP was achieved in 58 (56%) patients with a short Stim-LVAT equal to LBB po-LVAT at a high pacing output and a relatively longer Stim-LVAT at a low pacing output. Deep septal pacing (DSP) characterized with no LBB potential and a longer Stim-LVAT (83.3 ± 7.7 ms) than that in LBBP (71.37 ± 7.1 ms, P < 0.01 versus DSP) was observed in 24 (23%) patients. Complete LBBP had a longer total procedure time and longer fluoroscopic time than the other two groups.

This study describes the similarities and differences in electrophysiological characteristics and the possible mechanisms of the different types of LBBAP, classified into 3 modalities in routine clinical practice, each with narrow paced QRS duration and stable parameters, indicating LBBAP can be a near-physiological pacing modality.

Patients with impaired kidney function have a high frequency of intraplaque hemorrhage (IPH) in their coronary arteries. Levels of cyclophilin A (CyPA), an indirect matrix metalloproteinase inducer, are increased in deceased patients who had impaired kidney function. In this study, we have examined the relationship between IPH and CyPA.

We examined 47 samples of coronary plaque from 27 cadavers with coronary stenosis. These sections, all with > 50% coronary stenosis, were stained with an antibody against CyPA and the expression of CyPA was semi-quantified. Cadavers and plaques were classified into one of two groups depending on the presence or absence of IPH. IPH was defined as the presence of red blood cells stained with hematoxylin and eosin (HE) indicative of overt acute hemorrhage.

In an individual analysis, estimation of glomerular filtration rate (eGFR) in the IPH group was significantly lower than that in the non-IPH group (P = 0.002). In a histological analysis, the percentage of stained area of CyPA in the IPH group was significantly higher than that in the non-IPH group (P < 0.0001).

IPH was associated with a significantly higher expression of CyPA in this study. In addition, patients with IPH in their coronary arteries had significantly impaired kidney function.

An 84-year-old woman with hypertension, Alzheimer's disease, and chronic kidney disease presented with fever and was diagnosed with corona virus disease 2019 (COVID-19). During the hospitalization, she experienced unexpected sinus bradycardia with prolonged QTc, which was thought to be closely related to the short-term use of hydroxychloroquine (HCQ), an old drug used to treat malaria and autoimmune diseases, but now used against COVID-19. The cardiac side effects of HCQ were rare, seen with short-term and low-dose use. With the COVID-19 pandemic, this case alerts clinicians to be aware of the arrhythmogenic effects of HCQ when it is used as an antiviral drug, especially in patients with preexisting cardiovascular diseases.

We prospectively collected device and heart rate data through remote monitoring (RM) of patients with an implantable cardioverter defibrillator (ICD). The objective was to identify the predictors of lethal arrhythmic events (VT/VF).

Thirty-three patients (mean age: 50 years) with ICDs [with functionality of heart rate variability (HRV) analysis] were divided into two groups [VT/VF (+), VT/VF (−) ]. Clinical, device (ventricular lead impedance; amplitude of ventricular electrogram), and HRV data were compared between the two groups. The NN interval-index (SDNNi) was calculated for every 5 minutes, and the mean, maximum, minimum, and standard deviation of SDNNi during the 24-hour period were used.

During the observation period of 13 ± 10 months, 10 patients experienced VT/VF events. Total mean, max, and min SDNNi were higher in the VT/VF (+) than the VT/VF (−) group (132.9 ± 9.3 versus 93.5 ± 6.1, P = 0.0013; 214.6 ± 10.6 versus 167.0 ± 7.0, P = 0.0007; 71.2 ± 7.5 versus 43.9 ± 4.9, P = 0.0047). On logistic regression analysis, a total mean SDNNi of 100.1, max SDNNi of 185.0 and min SDNNi of 52.0 as cut-off values for prediction of a VT/VF event demonstrated significant receiver operating characteristic (ROC) curves (AUC = 0.86, P = 0.0007; AUC = 0.84, P = 0.0005; AUC = 0.78, P = 0.0030). The max ΔSDNNi, i.e., difference from baseline SDNNi, and min ΔSDNNi in 7 and 28 days preceding VT/VF events were significant predictors of VT/VF events.

Time-domain HRV analysis through a RM system may help identify patients at high risk of lethal arrhythmic events; in addition, it may help predict the occurrence of lethal arrhythmic events in specific cases.

The properties of glucose changes in patients with chronic heart failure remain elusive. In the present study, we investigated the sequential changes of interstitial glucose concentrations in patients with chronic heart failure and heart disease who were not undergoing antidiabetic therapy.

A glucose monitoring device (FreeStyle Libre Pro) was attached to the backside of an upper arm and the interstitial glucose concentration was monitored every 15 minutes for 1 week. Eleven patients with chronic heart failure (Heart failure (+) ) and 7 patients with chronic heart diseases but not with heart failure (Heart failure (−) ) were enrolled. The average level and peak value of interstitial glucose concentrations, and the duration of hyperglycemia (≥ 140 mg/dL) were not significantly different between Heart failure (+) and Heart failure (−). The duration of hypoglycemia (< 80 mg/dL) was significantly longer and the trough value was significantly lower in Heart failure (+) compared with Heart failure (−). Most of the patients in Heart failure (+) were exposed to a long duration of hypoglycemia from midnight to morning. Importantly, none of the patients who showed hypoglycemia complained of any subjective symptoms during hypoglycemia. Malabsorption may be one of the mechanisms of hypoglycemia.

In summary, patients with chronic heart failure are at risk of developing hypoglycemia even if they do not undergo any antidiabetic therapy.

There is increasing evidence linking plasma homocysteine levels and atrial fibrillation (AF). The association between an elevated level of plasma homocysteine and AF was examined by meta-analysis in this study.

The PubMed and ScienceDirect databases until August 2019 were utilized to collect previous literature on homocysteine and the potential relation to AF. The pooled effects were evaluated depending on standardized mean differences (SMDs) or odds ratios (ORs) with 95% confidence intervals (CIs), and the calculation was performed using Stata 12 software.

A total of 11 validated articles were included in the meta-analysis. For pooled effect, the results confirmed that AF patients had higher homocysteine levels than control subjects (SMD: 0.58, 95%CI: 0.09-1.06). Compared with control subjects, homocysteine levels were higher in paroxysmal AF (SMD: 0.45, 95%CI: 0.18-0.72) and persistent AF patients (SMD: 1.21, 95%CI: 0.50-1.92). The pooled analysis suggested that patients with elevated homocysteine levels had markedly higher risk of AF compared with lower homocysteine levels in the categorical variable (OR: 2.21, 95%CI: 1.16-4.21) and continuous variable analyses (OR: 1.13, 95%CI: 1.00-1.27), respectively. In addition, the pooled analysis indicated that recurrent AF patients had significantly higher homocysteine levels than those without recurrence (SMD: 0.65, 95%CI: 0.42-0.88). The pooled analysis of the categorical variables indicated that elevated homocysteine levels were associated with increased risk of AF recurrence (OR: 3.81, 95%CI: 3.11-4.68). However, the association was weak in the pooled analysis of continuous variables (OR: 1.88, 95%CI: 0.74-4.81).

Our meta-analysis identified that plasma homocysteine levels were significantly elevated in AF and recurrent AF patients. Elevated homocysteine is associated with increased risk of AF and AF recurrence.

Resistin is an adipocytokine that is abundantly secreted from lipid cells and is related to the inflammatory process and cardiometabolic diseases. This study aimed to examine the role of resistin on inflammation and its effect on the clinical outcome of patients with atrial fibrillation (AF) following catheter ablation.

A total of 108 patients (56.9 ± 12.0 years, 76.8% male) with symptomatic and drug-refractory AF undergoing catheter ablation were enrolled. Inflammatory biomarkers and epicardial fat volume by contrast computed tomography (CT) images were assessed in all patients before the procedure. Baseline resistin correlated with epicardial fat volume, tumor necrosis factor-α (TNF-α), and left atrial (LA) scar area. After the index procedure, the univariate analysis revealed that hypertension, persistent AF, LA diameter, and plasma resistin level were related to recurrent atrial arrhythmia. Multivariate regression analysis revealed that persistent AF, LA diameter, and plasma resistin level all independently predicted recurrent atrial arrhythmia after ablation. Plasma resistin with a level higher than 777 (pg/mL) could predict recurrence following catheter ablation of AF.

High plasma resistin level is associated with poor left atrial substrate, high epicardial fat volume, and elevated TNF-α level in patients with AF. Plasma resistin may predict the recurrence of atrial arrhythmia after ablation.

An 18-year-old male who had a past medical history of an intracardiac total cavopulmonary connection (TCPC) operation was referred to our hospital for radiofrequency catheter ablation (RFCA) of supraventricular tachycardia (SVT). Two types of SVTs were induced, and 3-dimensional (3D) maps were created using an ultra-high-density 3-dimensional mapping system (Rhythmia). The earliest atrial activation site (EAAS) of SVT1 was at the superior part of the conduit, and the EAAS of SVT2 was at the inferior part of the single atrium (SA). The SVTs were terminated by energy deliveries to the EAAS from the conduit in SVT1 and from inside the single atrium in SVT2. Detailed maps of the SVTs were important to understand the mechanisms of the SVTs. The Rhythmia system was useful for the detailed mapping of complex arrhythmias. The use of Rhythmia in patients after a TCPC is difficult, because puncturing the TCPC conduit and proceeding and manipulating the Orion catheter via a narrow puncture hole are difficult. We were the first to succeed in ablating two atrial tachycardias (ATs) originating from the inside and outside of the conduit after a TCPC operation by using an ultra-high-density 3-dimensional mapping system.

The effect of restoring sinus rhythm by pulmonary vein isolation (PVI) on the quality of life (QOL) of patients with persistent atrial fibrillation (PerAF) has not been adequately investigated. This study was performed to compare the changes in QOL after extended PVI between patients with PerAF and paroxysmal AF (PAF).

Patients with PAF (n = 38) and PerAF (n = 22) who underwent their first PVI and developed no AF recurrence 6 months after PVI were enrolled. QOL surveys were performed at baseline and 6 months post-ablation using Short Form-36 surveys.

The mental component summary score (MCS) (53.4 ± 10.2 to 56.5 ± 7.1, P = 0.019) and physical component summary score (PCS) (46.1 ± 10.6 to 48.5 ± 8.3, P = 0.015) improved after PVI in the PAF group. The PCS, but not the MCS, improved after PVI in the PerAF group (45.8 ± 7.9 to 51.5 ± 6.2, P < 0.001). Changes in the PCS were greater in the PerAF group than in the PAF group (8.6 ± 6.9 versus 2.8 ± 5.2, P = 0.009). Multivariate regression analysis demonstrated that a low baseline MCS and the type of AF (PAF) were independent predictors of an increased MCS and that a low baseline PCS and the type of AF (PerAF) were independent predictors of an increased PCS.

The changes in QOL differed between PAF and PerAF after PVI. Although most patients with PerAF were asymptomatic before PVI, their improvement in physical QOL was greater than that in patients with PAF. Such beneficial effects on physical QOL are likely expected in patients with PerAF with a low PCS before PVI.

Transcatheter aortic valve implantation (TAVI) has been recognized as a standard therapy for severe aortic valve stenosis. However, since some patients who receive TAVI have poor outcomes, the predictors of clinical outcomes after TAVI are important. The aim of this study was to investigate the association between appetite and long-term clinical outcomes.

We screened consecutive cases who received TAVI at our medical center between July 2014 and October 2018. A total of 139 patients who received transfemoral TAVI were included as the final study population. They were divided into a good appetite group (n = 105) and a less appetite group (n = 34) according to their dietary intake rate (> 90%: good appetite group, ≤ 90%: less appetite group). We defined the intake rate as the average for breakfast, lunch, and dinner on the day just before discharge. We defined two-year major adverse cardiovascular and cerebrovascular events (MACCE) as a composite of cardiovascular death, myocardial infarction, any coronary revascularization, history of hospitalization due to heart failure, and disabling acute cerebral infarction. Kaplan-Meier analyses and multivariate Cox regression analysis were performed.

The median duration of the follow-up period was 372 (189-720) days. Kaplan-Meier curves showed that the less appetite group got MACCE more frequently (event free rate of the less appetite group: 76.5% versus the good appetite group: 94.3%, Log Rank P = 0.01). In multivariate Cox regression analysis, having less appetite was a significant predictor of two-year MACCE (HR 5.26, 95%CI 1.66-16.71, P < 0.01).

In conclusion, among the patients who received transfemoral TAVI, appetite status just before discharge was significantly associated with long-term outcome.

Therapy-resistant ventricular arrhythmias can occur during accidental advanced hypothermic conditions. On the other hand, hypothermic therapy using mild cooling has been successfully accomplished with infrequent ventricular arrhythmia events.

To further clarify the therapeutic-resistant arrhythmogenic substrate which develops in hypothermic conditions, an experimental study was performed using a perfusion wedge preparation model of porcine ventricle, and electrophysiological characteristics, inducibility of ventricular arrhythmias, and effects of therapeutic interventions were assessed at 3 target temperatures (37, 32 and 28°C).

As the myocardial temperature decreased, myocardial contractions and the number of spontaneous beats deceased. Depolarization (QRS width, stimulus-QRS interval) and repolarization (QT interval, ERP) parameters progressively increased, and dispersion of the ventricular repolarization increased. At 28°C, VF tended to be inducible more frequently (1/11 at 37°C, 1/11 at 32°C, and 5/11 hearts at 28°C), and some VFs at 28°C required greater defibrillation energy to resume basic rhythm.

An advanced but not a mild hypothermic condition had an enhanced arrhythmogenic potential in our model. In the advanced hypothermic condition, VF with relatively prolonged F-F intervals and a greater defibrillation energy were occasionally inducible based on the arrhythmogenic substrate characterized as slowed conduction and prolonged repolarization of the ventricle.

Myocardial infarction (MI) occurs when the heart muscle is severely damaged due to a decrease in blood flow from the coronary arteries. During recovery from an MI, cardiac fibroblasts become activated and produce extracellular matrices, contributing to the wound healing process in the damaged heart. Inappropriate activation of the fibroblasts leads to excessive fibrosis in the heart. However, the molecular pathways by which cardiac fibroblasts are activated have not yet been fully elucidated.

Here we show that serum deprivation, which recapitulates the cellular microenvironment of the MI area, strikingly induces collagen production in C3H/10T1/2 cells. Based on transcriptomic and pharmacological studies, we found that cell cycle perturbation is directly linked to collagen production in fibroblasts. Importantly, collagen synthesis is increased independently of the transcriptional levels of type I collagen genes. These results reveal a novel mode of fibroblast activation in the ischemic area, which will allow us to gain insights into the molecular mechanisms underlying cardiac fibrosis and establish a basis for anti-fibrotic therapy.

Severe ventricular arrhythmias such as high-grade atrioventricular block and ventricular tachycardia may cause lethal conditions or sudden death in patients with cardiac sarcoidosis (CS). Physicians should examine patients carefully for these conditions and treat them appropriately. As arrhythmias are being better diagnosed and treated, physicians are increasingly aware of atrial arrhythmias, which have not been focused upon as CS-related conditions, in patients with CS. This article reports a case of atrial flutter in sarcoidosis, and discusses literature findings on atrial arrhythmias and atrial involvement of CS. It is highly likely that atrial arrhythmia and supraventricular conduction disorder associated with or caused by CS are more common than previously thought. Physicians should pay careful attention for these conditions in the diagnosis and treatment of CS.

The evaluation of baroreflex sensitivity (BRS), which maintains systemic circulatory homeostasis, is an established tool to assess cardiovascular autonomic neuropathy in type 2 diabetes mellitus (T2DM). As BRS plays an important function in blood pressure regulation, reduced BRS leads to an increase in blood pressure variability, which further leads to reduced BRS. This sequence of events becomes a vicious cycle. The major risk factors for reduced BRS are T2DM and essential hypertension, but many other risk factors have been reported to influence BRS. In recent years, reports have indicated that glycemic variability (GV), such as short- and long-term GV that are considered important risk factors for macrovascular and microvascular complications, is involved in reductions in BRS independently of blood glucose levels. In this review, we discuss reduced BRS in T2DM, its features, and the potential for its reversal.

A 70-year-old man with dyspnea was admitted to our department and received standard therapy for recurrent heart failure. He was diagnosed with polycystic kidney disease (PKD) in his thirties and received hemodialysis for 4 years before undergoing renal transplantation at age 45. Although his left ventricular ejection fraction (LVEF) was preserved in his 50s, LVEF decreased progressively from 61% to 24%, while left ventricular diastolic dimension (LVDd) increased from 54 mm to 65 mm between 63 and 69 years of age. Right ventricular endomyocardial biopsy demonstrated myocardial disarray and interstitial fibrosis. Genetic analysis identified a heterozygous frameshift mutation in PKD1, which encodes polycystin-1, a major causative gene of PKD. We detected PKD1 protein expression in myocardial tissue by immunostaining. Recent epidemiological studies and animal models have clarified the pathological correlation between ventricular contractile dysfunction and PKD1 function. Here, we present a case of old-age onset progressive cardiac contractile dysfunction with a PKD1 gene mutation.

The progression of renal dysfunction reduces serum albumin and deteriorates the binding capacity of protein-bound uremic toxins. We evaluated the prognostic implications of serum indoxyl sulfate (IS) and albumin levels in patients with cardiovascular disease.

We prospectively enrolled 351 consecutive patients undergoing percutaneous revascularization for coronary artery disease or peripheral artery disease. The primary endpoint was all-cause mortality. Patients were assigned to four groups according to the median levels of serum IS (0.1 mg/dL) and albumin (3.9 g/dL).

During the median follow-up time of 575 days, 16 patients died. The IS level was significantly higher in nonsurvivors (0.33 versus 0.85 mg/dL, P < 0.05). On the Kaplan-Meier curve, the high IS/low albumin group presented the highest mortality rate (log-rank test, P < 0.01). Cox proportional hazard analysis revealed that high IS/low albumin (hazard ratio (HR): 5.33; 95% confidence interval (CI): 1.71-16.5; P < 0.01), diastolic pressure (HR: 0.94; 95% CI: 0.91-0.98; P < 0.01), prior stroke (HR: 4.54; 95% CI: 1.33-15.4; P = 0.01), and left ventricular ejection fraction (LVEF) (HR: 0.92; 95% CI: 0.88-0.96; P < 0.001) were associated with increased mortality. Furthermore, the combination of IS and albumin levels significantly conferred an additive value to LVEF for predicting mortality (C-statistic: 0.69 versus 0.80; P < 0.001; net reclassification improvement: 0.83; P < 0.001; integrated discrimination improvement: 0.02; P = 0.02).

A lower albumin level adds potentiating effects on IS as a prognostic factor for cardiovascular disease.