Takayasu arteritis (TA or TAK) is a chronic large vessel vasculitis with predilection to affect the aorta and its branches. The new 2022 ACR/EULAR classification criteria for Takayasu arteritis incorporated imaging characteristics as an absolute requirement. ESR and CRP fails in accuracy as disease activity markers. Pentraxin 3 appears to be a relatively superior biomarker, which correlates with ITAS 2010 as per several studies. PET-CT is also increasingly being studied for assessing disease activity with variable results. The management of TAK involves use of steroids with upfront steroid sparing immunosuppressive agents. MMF is one such conventional DMARD/immunosuppressant with good efficacy and better safety profile, as reported in various cohort studies. Tocilizumab is proved to be a rapid remission inducing agent in refractory Takayasu arteritis in observational studies. TNF inhibitors in many uncontrolled studies showed good responses, and there is a need for good RCTs for confirmation. JAK inhibitors have also been used with success in a few reports.
Arrhythmia-induced cardiomyopathy (AIC) occurring in patients with atrial fibrillation (AF) is a reversible form of cardiomyopathy characterized by LV systolic dysfunction. However, it is difficult to predict the reversibility before rhythm control therapy. We performed this study to develop a parameter for the identification of AIC in routine transthoracic echocardiography (TTE) in patients with presumptive AIC due to AF.
We retrospectively studied 72 patients treated with catheter ablation therapy for persistent AF, and LV ejection fraction (LVEF) ≤ 45%. The patients were divided into 2 groups by follow-up TTE performed within 12 ± 6 months postoperatively. Patients with ≥ 15% improvement in LVEF or ≥ 10% improvement and ≥ 50% in LVEF were classified as the AIC group, and the others were classified as the non-AIC group.
A total of 57 (79%) patients were classified as the AIC group. In the stepwise multivariate logistic regression model, LV end-diastolic dimension (LVDd) and e' (septal) were independent predictors of AIC. The sensitivities of LVDd ≤ 53 mm and e' (septal) ≥ 6.3 cm/second were 60% and 75%, respectively. Their specificities were 80% and 67%, respectively. The presence of either LVDd ≤ 53 mm or e' (septal) ≥ 6.3 cm/second had a higher sensitivity (90%); their co-occurrence had a higher specificity (93%) in predicting AIC.
The functional recovery in patients with AIC can occur in LV systolic dysfunction without remodeling and impairment of relaxation. The combination of LVDd and e' (septal) is useful in predicting AIC due to AF with routine TTE.
In heart failure with preserved ejection fraction (HFpEF), left atrial enlargement is a surrogate marker reflecting chronic left ventricular diastolic dysfunction. As a result, the left atrial volume is often evaluated in daily clinical practice to determine the presence of left ventricular diastolic dysfunction. However, recent studies have shown that left atrial dysfunction is an important factor contributing to the pathogenesis of HFpEF, and it is expected to become one of the therapeutic targets of HFpEF, rather than just a surrogate marker. Echocardiography plays a central role in the identification of left atrial dysfunction and remodeling in HFpEF. In this review, we describe an approach to the evaluation of left atrial function in HFpEF using echocardiography.
Immunosuppressive therapy with prednisolone (PSL) is the first-line treatment for cardiac sarcoidosis (CS), and 18F-fluoro-2-deoxyglucose positron emission tomography (FDG-PET) is used to evaluate its efficacy to guide treatment. However, the appropriate timing of FDG-PET in CS remains unknown. This single-center, retrospective, observational study included 15 consecutive CS patients who underwent 3 serial FDG-PET scans (at baseline, in the early phase [1-2 months after PSL introduction], and in the late phase [≥ 5 months after PSL introduction with a maintenance dose of PSL]). We adhered to the PSL tapering protocol by the Japanese Circulation Society even when early FDG-PET showed positive results (SUVmax ≥ 4.0). No patient died during the 908 (644-1600) days of observation. Negative results in the late phase were observed in 3 of 6 early-positive patients, and 3 of 9 early-negative patients showed positive results in the late phase. Changes in echocardiographic parameters from baseline to the late phase were significantly better in late-negative patients than in late-positive patients (left ventricular end-diastolic diameter: -0.7 (-9.3-[-0.5]) mm versus +3.5 (0.8-7.5) mm, P = 0.039; left ventricular end-systolic diameter: -4.2 (-6.9-[-0.1]) mm versus +5.1 (0.5-7.0) mm, P = 0.015; left ventricular ejection fraction: +4.7% (-1.0-9.0%) versus -1.5% (-11.3-1.5%), P = 0.045) ), although early FDG-PET did not predict those consequent changes. An interval of ≥ 5 months after introducing the PSL with a maintenance dose of PSL is long enough for FDG-PET to reflect consequent left ventricular functions, while an interval of 1-2 months can be too short.
Sinus of Valsalva aneurysm (SVA) is a rare cardiovascular disease with male predominance. Recently, an association with aortic aneurysm and SVA has been revealed in periventricular nodular heterotopia patients with loss-of-function Filamin A (FLNA) mutations, which were located on chromosome X and almost exclusively affect females.
Among patients hospitalized for aortic surgery with aortic root diameter over 4.0 cm, next-generation sequencing was performed to investigate 30 candidate genes related to inherited aortic aneurysm syndromes and familial thoracic aortic aneurysm and dissection. The present report reviewed an electronic case database and identified two female cases of unruptured SVA with heterozygous FLNA truncating mutations.
Case 1 displaying a rare SVA phenotype involving left and noncoronary sinus harbored a nonsense variant p.Tyr1720Ter/c.5160C > G. Case 2 displayed right and noncoronary SVA with predominantly enlarged right coronary sinus, posterior mitral valve prolapse, and harbored a frameshift variant p.Val1724fs*68/c.5171_5172delTG. Both novel mutations resulted in the premature termination of filamin A with the loss of functional Rod 2 and dimerization region.
The present report raised the possibility of the presence of a cardiovascular onset form in the spectrum of FLNA hereditary diseases. The association between SVA and loss-of-function FLNA mutations indicates a unique etiology and pathogenesis among female patients, which requires further investigation to establish the linkage between FLNA variants and a wide spectrum of phenotypes.
Nonalcoholic fatty liver disease (NAFLD) is an emerging driver of cardiac arrhythmias. However, the relationship between NAFLD and malignant arrhythmia in non-ST-segment elevation myocardial infarction (NSTEMI) patients is still unclear.
In this study, 358 NSTEMI inpatients were enrolled. They all received 24-hour Holter monitoring after percutaneous coronary intervention. All inpatients were divided into two groups: the non-NAFLD group (236 cases, 65.9%) and the NAFLD group (122 cases, 34.1%). Compared with the non-NAFLD group, the NAFLD group had a significantly higher incidence of PVCs/hour > 5 (premature ventricular complexes, 32.0% versus 9.3%, P < 0.001), ventricular tachycardia (VT, 22.1% versus 5.9%, P < 0.001), and sinus arrest (SA, 7.4% versus 1.3%, P = 0.002). We found that NAFLD was closely associated with the occurrence of VT [unadjusted odds ratio (OR) 4.507, 95% confidence interval (CI) 2.263-8.974, P < 0.001] and SA (OR 6.186, 95%CI 1.643-23.291, P = 0.007). After adjusting for age, sex, body mass index, and other confounding factors, the above differences were still statistically significant (VT: OR 4.808, 95%CI 2.254-10.253, P < 0.001; SA: OR 9.589, 95%CI 2.027-45.367, P = 0.004).
NAFLD is associated with the occurrence of VT and SA in NSTEMI patients. It indicates that NAFLD might be a risk factor for malignant arrhythmias in post-NSTEMI patients.
There are several causes of heart failure during pregnancy and the peripartum period, which include peripartum cardiomyopathy, Takotsubo cardiomyopathy or stress cardiomyopathy, exacerbation of a preexisting cardiomyopathy, and acute myocarditis. It is important to determine the cause of the heart failure as the medical treatment may be different based on the diagnosis. However, it has been sometimes challenging to diagnose the cause because of the limited diagnostic tools, especially in pregnant women. Cardiac MRI can characterize myocardial injury and can be used to track the changes in myocardial tissue. We herein report a 35-year-old woman diagnosed with peripartum mid-ventricular-type Takotsubo cardiomyopathy, who was referred to our hospital due to worsening dyspnea the day after cesarean delivery. On admission, electrocardiography showed sinus tachycardia and poor progression of R waves in the precordial leads. Bedside echocardiography revealed severe hypokinesis in the mid- and apical left ventricle (LV) with a LV ejection fraction of 20%. Cardiac catheterization showed normal coronary arteries, and myocardial biopsy revealed contraction band necrosis. On acute phase (Day 4), cardiac MRI showed prolonged native T1 and T2, and severe hypokinesis and decreased regional longitudinal peak strain in the mid-anterior LV wall. During the 1st week, precordial ST fluctuation was observed, and LV wall motion had gradually recovered. Repeat cardiac MRI revealed normalized LV wall motion and shortened values for global native T1 and T2. Thus, she was diagnosed with peripartum Takotsubo cardiomyopathy. Serial cardiac MRI may be able to differentiate Takotsubo cardiomyopathy during pregnancy and the peripartum period from other preexisting cardiomyopathies.
This study aims to explore the associations between uric acid (UA) and long-term outcomes among patients with acute coronary syndrome (ACS). A total of 1068 consecutive patients with ACS who underwent percutaneous coronary intervention (PCI) were analyzed retrospectively. The patients were divided into 3 groups based on the levels of serum UA upon admission (bottom quintile, middle 3 quintiles, and top quintile). The primary endpoint was all-cause mortality. The patients in the higher UA groups were associated with younger age (71 ± 11 versus 68 ± 12 versus 67 ± 14 years; P < 0.05) and were more likely to be male (57.6 versus 76.9 versus 84.7%; P < 0.001). Furthermore, these patients had lower estimated glomerular filtration rates (83 ± 27 versus 74 ± 23 versus 59 ± 24 mL/minute/1.73 m2; P < 0.001) and lower left ventricular ejection fractions (58 ± 14 versus 57 ± 14 versus 53 ± 15%; P < 0.001). During the median 4-year follow-up, there were 158 incidents of all-cause death. Patients in the top quintile, followed by patients in the bottom quintile, had greater all-cause mortality compared with patients in the middle quintile (16.5 versus 11.4 versus 23.8%; P < 0.001). When the middle of the 3 quintiles was assigned as the reference group, the adjusted hazard ratios for all-cause mortality for the top and bottom quintiles were 1.72 (95% confidence interval [CI] 1.16-2.53, P < 0.05) and 1.57 (95% CI 1.03-2.36, P < 0.05), respectively. These results demonstrate that UA levels upon admission in patients with ACS who underwent PCI exhibited a 'J-shaped' association with all-cause mortality.
Mutant cardiac ryanodine receptor channels (RyR2) are "leaky," and spontaneous Ca2+ release through these channels causes delayed afterdepolarizations that can deteriorate into ventricular fibrillation. Some patients carrying RYR2 mutations in type 1 catecholaminergic polymorphic ventricular tachycardia exhibit QT prolongation and are initially diagnosed with long QT syndrome. However, none have been reported to cause drug-induced ventricular fibrillation in patients with RYR2 variants. We describe the first case of an elderly woman with drug-induced QT prolongation and ventricular fibrillation who carried a novel RYR2 variant but no other mutations related to long QT syndrome. Oral adrenergic agents might induce QT prolongation and subsequent ventricular fibrillation in patients carrying an RYR2 variant. Screening for RYR2 could be valuable in patients with suspected drug-induced long QT syndrome.
Heart failure and frailty share aging as a strong risk factor. The prevalence of frailty has been shown to be particularly high in elderly patients with heart failure. Moreover, it is important not to confine frailty to physical aspects. Rather, it should be considered to consist of multiple domains, including physical disability, psychiatric disorders, cognitive impairment, depression, and social disconnection. Development of interventions that can improve frailty domains are not well established, although observational studies have evaluated the association of various frailty domains and their prognostic impact. Some interventions, including resistance exercise, functional exercise, and respiratory muscle training have been demonstrated to hold potential for improving physical frailty. In terms of cognitive dysfunction, previous studies have demonstrated that exercise therapy is also effective for cognitive dysfunction. The social domain of frailty is one of the least investigated domains, particularly in patients with heart failure. However, heart failure is also strongly associated with physical frailty and cognitive impairment and has a poor prognosis in old patients. The prevalence of social frailty in elderly patients who need hospitalization due to heart failure is higher than previously thought. Very few studies have tested interventions targeting social frailty. Frailty and heart failure affect each other, and both are becoming increasingly important in society. In this article, we review the physical, cognitive, and social domains of frailty and the possible interventions to improve them in patients with heart failure.
Electrical storm (ES), defined by 3 or more occurrences of ventricular arrhythmias within 24 hours, has been shown to be associated with an increased risk of mortality; however, detailed information remains lacking. We aimed to examine the incidence and determinants of ES and its impact on mortality in patients enrolled in the nationwide implantable cardioverter-defibrillator (ICD) registry.
We studied 1,256 patients (age 65 ± 12 years) who had structural heart disease with an ICD. The patients were classified into reduced ejection fraction (EF < 35%; 657 (52%) patients) and preserved or moderately reduced EF (EF ≥ 35%; 599 (48%) patients).
ES occurred in 49 (7%) and 36 (6%) patients in the EF < 35% and EF ≥ 35% groups (log-rank P = 0.297) during the median follow-up of 2.3 years. ICD with resynchronization therapy was associated with a lower incidence of ES in patients with EF < 35%. Non-ischemic heart disease and diuretics were associated with ES in patients with EF ≥ 35%. During the follow-up, 10/49 (20%) patients with ES and 80/608 patients (13%) without ES died in patients with EF < 35%, while 7/36 (19%) patients with ES and 38/563 patients (7%) without ES died in those with EF ≥ 35%. We have created 4 Cox multivariate models. All models showed approximately 2-fold higher hazard ratios in patients with EF ≥ 35% compared to EF < 35%.
Our study showed that the determinants of ES differed between EF < 35% and EF ≥ 35%. The impact of ES for mortality was numerically higher in EF ≥ 35% than in EF < 35%, although a significant interaction was not detected.
Kenji Nagashio, Kazuko Tajiri, Kimi Sato, Masaki Ieda
Erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor, is a targeted drug used for the treatment of non-small cell lung cancer (NSCLC). Erlotinib is considered relatively safe and generally well-tolerated, with rarely reported cardiac side effects. Herein, we report a case of cardiomyopathy that developed during erlotinib treatment for NSCLC. Two months after erlotinib initiation, our 70 year-old female patient complained of progressive dyspnea, and a diagnostic endomyocardial biopsy confirmed non-specific cardiomyopathy, indicating erlotinib-induced cardiomyopathy. We believed that continued administration of erlotinib would exacerbate her heart failure, while treatment of the heart failure with intensive monitoring would allow the administration of erlotinib to be continued. This case report highlights the potential cardiotoxic effects of erlotinib and suggests the need for close clinical and echocardiographic follow-up of patients receiving erlotinib.
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.
Jiefang Zhang, Xia Sheng, Yiwen Pan, Min Wang, Guosheng Fu
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.
Yu Kang, Hui Wang, Hong Chen, Bo Wang, Yingying Yang, Xuan Zhao, Qihui Ran, Jiafu Wei
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.
Yuki Shirakawa, Shinichi Niwano, Jun Oikawa, Daiki Saito, Tetsuro Sato, Gen Matsuura, Yuki Arakawa, Shuhei Kobayashi, Ryo Nishinarita, Ai Horiguchi, Naruya Ishizue, Jun Kishihara, Hidehira Fukaya, Junya Ako
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.