Endotyping is an emerging concept in which diseases are classified into distinct subtypes based on underlying molecular mechanisms. Heart failure (HF) is a complex clinical syndrome that encompasses multiple endotypes with differential risks of adverse events, and varying responses to treatment. Identifying these distinct endotypes requires molecular-level investigation involving multi-“omics” approaches, including genomics, transcriptomics, proteomics, and metabolomics. The derivation of these HF endotypes has important implications in promoting individualized treatment and facilitating more targeted selection of patients for clinical trials, as well as in potentially revealing new pathways of disease that may serve as therapeutic targets. One challenge in the integrated analysis of high-throughput omics and detailed clinical data is that it requires the ability to handle “big data”, a task for which machine learning is well suited. In particular, unsupervised machine learning has the ability to uncover novel endotypes of disease in an unbiased approach. In this review, we will discuss recent efforts to identify HF endotypes and cover approaches involving proteomics, transcriptomics, and genomics, with a focus on machine-learning methods.

With the rapid development of artificial intelligence (AI) and machine learning (ML), as well as the arrival of the big data era, technological innovations have occurred in the field of cardiovascular medicine. First, the diagnosis of cardiovascular diseases (CVDs) is highly dependent on assistive examinations, the interpretation of which is time consuming and often limited by the knowledge level and clinical experience of doctors; however, AI could be used to automatically interpret the images obtained in auxiliary examinations. Second, some of the predictions of the incidence and prognosis of CVDs are limited in clinical practice by the use of traditional prediction models, but there may be occasions when AI-based prediction models perform well by using ML algorithms. Third, AI has been used to assist precise classification of CVDs by integrating a variety of medical data from patients, which helps better characterize the subgroups of heterogeneous diseases. To help clinicians better understand the applications of AI in CVDs, this review summarizes studies relating to AI-based diagnosis, prediction, and classification of CVDs. Finally, we discuss the challenges of applying AI to cardiovascular medicine.

Background:This study evaluated the prevalence and prognostic impact of lung function abnormalities in patients with acute decompensated heart failure (ADHF) with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF).

Methods and Results:Of the 1,012 consecutive patients who were admitted to Nara Medical University with ADHF between 2011 and 2018, 657 routinely underwent spirometry (pulmonary function test [PFT]) before discharge. Lung function was classified as normal or abnormal (restrictive, obstructive, or mixed). Abnormal PFTs were seen in 63.0% of patients with ADHF (36.7%, 13.1%, and 13.2% for restrictive, obstructive, and mixed, respectively). The prevalence of abnormal PFT increased with age (P<0.001). Overall, abnormal PFT was an independent predictor of the composite endpoint of cardiovascular mortality or hospitalization for HF (adjusted hazard ratio [HR] 1.402; 95% confidence interval [CI] 1.039–1.914; P=0.027). Abnormal PFT (adjusted HR 2.294; 95% CI 1.368–4.064; P=0.001), as well as the restrictive (HR 2.299; 95% CI 1.322–4.175; P=0.003) and mixed (HR 2.784; 95% CI 1.399–5.581; P=0.004) patterns, were predictive of the composite endpoint in HFpEF, but not in HFrEF.

Conclusions:Abnormal PFT was prevalent and associated with poor outcomes in ADHF. Spirometry may be a useful tool in patients with ADHF, especially in those with HFpEF, to identify those at higher risk of a poorer outcome.

Background:With aging population, the prevalence and incidence of heart failure (HF) have been increasing worldwide. However, the characteristics and outcomes of patients with HF in an era of aging are not well established in Japan.

Methods and Results:The Japanese Registry Of Acute Decompensated Heart Failure (JROADHF), a retrospective, multicenter, nationwide registry, was designed to study the clinical characteristics and outcomes of patients hospitalized with HF throughout Japan in 2013. One hundred and twenty-eight hospitals were selected by cluster random sampling and 13,238 hospitalized patients with HF were identified by medical record review. Demographics, medical history, severity, treatment, and in-hospital and long-term outcome data were collected from the Diagnostic Procedure Combination and medical charts. Data were analyzed using univariate and multivariate logistic regression or Cox regression analysis. The mean age of registered patients was 78.0±12.5 years and 52.8% were male. Elderly patients (age >75 years) accounted for 68.9%, and HF with preserved ejection fraction (HFpEF) accounted for 45.1%. Median length of hospital stay was 18 days and in-hospital mortality was 7.7%. The median follow-up period was 4.3 years, and the incidence rates for cardiovascular death and rehospitalization for HF were 7.1 and 21.1 per 100 person-years, respectively.

Conclusions:A contemporary nationwide registry demonstrated that hospitalized HF patients were very elderly, HFpEF was common, and their prognosis was still poor in Japan.

Background:Since the international consensus on primary graft dysfunction (PGD) following heart transplantation (HT) was reported in 2014, few clinical studies have been reported. We aimed to analyze the incidence, predictive factors, and clinical implications of PGD following the International Society of Heart and Lung Transplant criteria in a single center.

Methods and Results:This study enrolled 570 consecutive adult patients undergoing isolated HT between November 1992 and December 2017. Under a new set of criteria, PGD-left ventricle (PGD-LV) occurred in 35 patients (6.1%; mild, n=1 [0.2%]; moderate, n=14 [2.5%]; severe, n=20 [3.5%]), whereas PGD-right ventricle (PGD-RV) occurred in 3 (0.5%). Multivariable analysis demonstrated that preoperative admission (odds ratio [OR] 4.20; 95% confidence interval [CI] 1.24–14.26; P=0.021), preoperative extracorporeal membrane oxygenation (OR 4.03; 95% CI 1.75–9.26; P=0.001), and prolonged total ischemic time (OR 1.09; 95% CI 1.02–1.15; P=0.006) were significant predictors of moderate to severe PGD-LV. Moderate to severe PGD-LV was an independent and significant risk factor for early death (OR 55.64; 95% CI 11.65–265.73; P<0.001), with its effects extending up to 3 months after HT.

Conclusions:Moderate to severe PGD-LV, as defined by the new guidelines, is an important predictor of early mortality, with effects extending up to 3 months after HT. Efforts to reduce the occurrence of moderate to severe PGD-LV may lead to better outcomes.

Background:Implantable left ventricular assist devices (LVAD) have improved quality of life and survival in patients with advanced heart failure. However, LVAD-specific infections and predicting which patients will develop infections remain challenging. This study investigated whether changes in body mass index (BMI) during hospitalization following LVAD implantation are associated with LVAD-specific infections within 1 year of implantation.

Methods and Results:Patients (n=135) undergoing LVAD implantation were retrospectively divided into 2 groups based on changes in BMI from LVAD implantation to discharge: those with and without decreases in BMI. Each group was further subdivided according to baseline albumin concentrations (high [>3.7 g/dL] and low [≤3.7 g/dL]). Twenty patients developed LVAD-specific infections within 1 year. Receiver operating characteristic curve analysis resulted in a ∆BMI cut-off of less than −0.128 kg/m². In multivariate analysis, younger patients and those with decreases in BMI had significantly higher rates of LVAD-specific infection (P=0.010 and P=0.035, respectively). LVAD-specific infection rates were significantly higher for patients with low albumin and decreases in BMI than for patients with low albumin but no decrease in BMI.

Conclusions:Decreases in BMI during hospitalization after LVAD implantation and younger age were independently associated with LVAD-specific infection within 1 year. Strict patient management may be needed to avoid decreases in BMI during hospitalization after LVAD implantation, particularly in patients with low baseline albumin concentrations.

Background:Dilated cardiomyopathy (DCM) is an important cause of heart failure and cardiac transplantation. This study determined the prevalence of DCM-associated genes and evaluated the genotype-phenotype correlation in Vietnamese patients.

Methods and Results:This study analyzed 58 genes from 230 patients. The study cohort consisted of 64.3% men; age at diagnosis 47.9±13.7 years; familial (10.9%) and sporadic DCM (82.2%). The diagnostic yield was 23.5%, 44.0% in familial and 19.6% in sporadic DCM.TTNtruncating variants (TTNtv) were predominant (46.4%), followed byTPM1,DSP,LMNA,MYBPC3,MYH6,MYH7,DES,TNNT2,ACTC1,ACTN2,BAG3,DMD,FKTN,PLN,TBX5,RBM20,TCAP(2–6%). Familial DCM, genotype-positive andTTNtv-positive patients were younger than those with genotype-negative and sporadic DCM. Genotype-positive patients displayed a decreased systolic blood pressure and left ventricular wall thickness compared to genotype-negative patients. Genotype-positive patients, particularly those withTTNtv, had a family history of DCM, higher left atrial volume index and body mass index, and lower right ventricle-fractional area change than genotype-negative patients. Genotype-positive patients reached the combined outcomes more frequently and at a younger age than genotype-negative patients. Major cardiac events occurred more frequently in patients positive with genes other thanTTNtv.

Conclusions:The study findings provided an overview of Vietnamese DCM patients’ genetic profile and suggested that management of environmental factors may be beneficial for DCM patients.

Background:Alcohol septal ablation (ASA) is a treatment option in patients with drug-refractory symptomatic hypertrophic obstructive cardiomyopathy (HOCM). In many patients, right bundle branch block (RBBB) develops during ASA because septal branches supply the right bundle branch. However, the clinical significance of procedural RBBB is uncertain.

Methods and Results:We retrospectively reviewed 184 consecutive patients with HOCM who underwent ASA. We excluded 40 patients with pre-existing RBBB (n=10), prior pacemaker implantation (n=15), mid-ventricular obstruction type (n=10), and those lost to follow-up (n=5), leaving 144 patients for analysis. Patients were divided into 2 groups according to the development (n=95) or not (n=49) of procedural RBBB. ASA conferred significant decreases in the left ventricular pressure gradient (LVPG) in both the RBBB and no-RBBB group (from 74±48 to 27±27 mmHg [P<0.001] and from 75±45 to 31±33 mmHg [P<0.001], respectively). None of the RBBB patients developed further conduction system disturbances. The percentage reduction in LVPG at 1 year after the procedure was significantly greater in the RBBB than no-RBBB group (66±24% vs. 49±45%; P=0.035). Procedural RBBB was not associated with pacemaker implantation after ASA, but was associated with reduction in repeat ASA (odds ratio 0.34; 95% confidence interval 0.13–0.92; P=0.045).

Conclusions:Although RBBB frequently occurs during the ASA procedure, it does not adversely affect clinical outcomes.

Background:Wild-type transthyretin-related amyloidosis (ATTRwt) and degenerative aortic stenosis (AS) are both age-related. Diagnosis of cardiac amyloidosis (CA) among patients with AS may be difficult due to overlapping morphological and functional criteria. The aim of this study was to describe an echocardiographic longitudinal strain (LS) pattern among patients with AS with and without ATTRwt.

Methods and Results:Patients who have AS with ATTRwt (n=30), AS without ATTRwt (n=50) and ATTRwt without AS (n=31) underwent two-dimensional speckle-tracking echocardiography. Transthyretin CA was based on positive bone scintigraphy without monoclonal gammopathy. All patients showed a gradual decrease in LS from the base to the apex resulting in a decrease of the global LS. A cut-off value of 1.0 for relative apical LS (average apical LS/[average basal LS+mid-LS]) was sensitive (88%) but less specific (68%) in differentiating ATTRwt among patients with severe AS. The best cut-off value for relative apical LS for identifying patients with ATTRwt among the whole population was 0.9 (sensitivity 74%, specificity 66%); however, 35%, 25% and 11% of patients who have ATTRwt without AS, with moderate AS and with severe AS, respectively, did not reach this threshold.

Conclusions:A decrease of global and relative apical LS is common in patients with AS, even in the absence of ATTRwt. ATTRwt CA can be present even in the absence of relative apical sparing of LS.

Background:Infective endocarditis (IE) in patients with adult congenital heart disease (ACHD) remains a diagnostic challenge due to difficulties in detecting endocardial lesions by echocardiography. ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) positron emission tomography/computed tomography (PET/CT) has shown good diagnostic performance in prosthetic valve IE. This study aimed to assess its additional diagnostic value in ACHD-associated IE and to characterize its advantages.

Methods and Results:Overall, 22 patients with ACHD and clinical suspicion of IE were retrospectively studied. ¹⁸F-FDG PET/CT was performed in addition to conventional assessment based on the modified Duke criteria. The final IE diagnosis was determined by an expert team during a 3-month clinical course, resulting in 18 patients diagnosed with IE. Seven patients (39%) were diagnosed with definite IE only by initial echocardiography. An ¹⁸F-FDG PET/CT assessment revealed endocardial involvement in the other 9 patients, resulting in the diagnosis of definite IE in 16 in total (88%). Right-sided endocardial lesions were more common (n=12, 67%) but rarely identified by echocardiography, whereas ¹⁸F-FDG PET/CT revealed right-sided lesions in 9 patients. A negative ¹⁸F-FDG PET/CT (n=7, 39%) assessment was associated with a native valve IE (71% vs. 0%). In 4 patients who were identified with not-IE, neither echocardiography nor ¹⁸F-FDG PET/CT detected any suspicious cardiac involvement.

Conclusions:In the diagnosis of ACHD-associated IE, characterized by right-sided IE, ¹⁸F-FDG PET/CT assessment should be useful.

Background:Stent implantation for vascular stenosis associated with congenital heart diseases is commonly performed as an off-label procedure in Japan because there is no officially approved stent for any congenital heart disease.

Methods and Results:We analyzed data from the Japanese Society of Congenital Interventional Cardiology Registry collected from January 2016 to December 2018. Patients who underwent stent implantation were enrolled in the present analysis. During the study period, there were 470 procedures, 443 sessions, and 391 cases. Of 443 sessions, 427 (96.4%) succeeded procedurally. There were no differences in the procedural success rates among age groups. In all, 416 sessions (367 patients; 94%) resulted in survival to 30 days after catheter intervention. Of 392 admissions, 357 patients (91%) survived to discharge. Only 4 deaths were directly related to stent implantation. Some in-hospital complications were observed during 55 of 443 sessions. Both hospital deaths and serious complications were significantly more frequent in the group with various preoperative risk factors.

Conclusions:Although not officially approved for congenital heart diseases in Japan, stent implantation in congenital heart diseases has been widely and routinely performed for many years with safety and efficacy. The aim of stenting was variable and broad because of many different applications and morphological variations. These data may facilitate approval of such an important device in Japan.

Background:Percutaneous atrial septal defect (ASD) closure is the treatment of choice for patients with a suitable ASD anatomy; however, the procedural characteristics and outcomes in children aged <6 years are unclear. The feasibility and safety of percutaneous ASD closure in children aged <6 years was evaluated and the predictors of procedural failure and challenging cases were identified.

Methods and Results:Patients from a single center between 2006 and 2018 (n=407) were retrospectively evaluated. There were 265 (65.1%) female patients. The median age at the time of the procedure and ASD size were 3.4 (0.9–5.9) years and 13.3 (3.8–27.0) mm, respectively. Medical records and echocardiographic images were analyzed. A challenging case was indicated by the use of non-conventional techniques. The procedure was completed in 399 patients (98.0%). Post-procedural acute complications occurred in 5 patients, including 1 with device embolization. Two patients underwent surgical device removal. During the follow up (30.3 [3.6–140.8] months), aggravated mitral regurgitation occurred in 5 patients. A multivariate logistic regression revealed large-sized ASD as a predictor of procedural failure (odds ratio=1.828, 95% confidence interval: 1.139–2.934, P=0.012) and challenging cases (odds ratio=1.371, 95% confidence interval: 1.180–1.593, P<0.001).

Conclusions:Percutaneous ASD closure is feasible and safe in children aged <6 years; however, patients with large-sized ASD are at high risk of procedural failure and becoming a challenging case.

Background:Rising blood pressure (BP) in the morning, known as the morning BP surge (MBPS), is known to pose a risk for cardiovascular events in hypertensive individuals. It was not known whether the MBPS was associated with a worse prognosis in patients with heart failure (HF) with a reduced (HFrEF) or preserved (HFpEF) ejection fraction.

Methods and Results:We performed a prospective, observational cohort study of hospitalized HF patients who underwent ambulatory BP monitoring (ABPM). The MBPS was calculated by subtracting the mean systolic BP (SBP) during the 1 h that included the lowest sleep BP from the mean SBP during the 2 h after waking. The MBPS group was defined as the top decile of MBPS (>40 mmHg). In all, 456 hospitalized HF patients (mean [±SD] age 68±13 years, 63.9% male) were followed-up for a median of 1.67 years. There were 90 events (16.3 per 100 person-years) of the composite outcome (all-cause mortality and worsening HF) in the HFrEF group, compared with 53 events (19.6 per 100 person-years) in the HFpEF group. Multivariate Cox regression analysis showed that MBPS was a significant predictor of outcome (hazard ratio 2.84, 95% confidence interval 1.58–5.10, P<0.01) in the HFrEF but not HFpEF group.

Conclusions:MBPS was found to be a novel predictor of worsening HF in patients with HFrEF.

Background:To examine the association of low educational attainment with incident heart failure (HF) and explore potential behavioral mediators of the causal pathway.

Methods and Results:A total of 12,109 participants in the Atherosclerosis Risk in Communities Study (ARIC) were included. Educational attainment was measured at baseline, and the risk of HF across educational attainment groups was assessed by Cox proportional hazards models. Using mediation analysis, we evaluated the mediating role of behavioral factors in the causal pathway between educational attainment and HF. During a median follow-up of 25.1 years, 2,407 cases (19.9%) of HF occurred. Educational attainment showed an inverse association with HF risk (hazard ratio (HR), 1.41; 95% confidence interval (CI), 1,26–1.57 for low educational attainment; HR, 1.13; 95% CI, 1.02–1.25 for medium educational attainment). In the mediation analysis, the association between educational attainment and HF was partially mediated by income, waist-to-hip ratio, current smoking, body mass index, current drinking, sports and physical activity, which explained 24.3%, 20.2%, 13.8%, 10.1%, 7.7%, 7.3% and 4.5%, respectively, of the relationship. In total, all mediators contributed 56.3% of the total effect.

Conclusions:Low educational attainment was associated with increased risk for HF. Income, obesity and current smoking mediated a great proportion of the total effect of educational attainment on HF. Our results provide underlying insights for the development of targeted public health interventions to reduce educational disparities on HF incidence.

Background:Many heart failure (HF) guidelines recommend sodium restriction for patients with HF, but the outcome of sodium restriction counseling (SRC) for HF patients is still unknown. We wanted to clarify whether SRC reduces cardiac events in patients with HF.

Methods and Results:Overall, 800 patients (77±12 years) who were hospitalized for HF were enrolled. During HF hospitalization, patients received SRC; patients were required to have a salt intake of <6 g/day. After discharge, death or HF rehospitalization events were investigated. During a mean follow-up of 319±252 days, 83 patients died, and 153 patients were rehospitalized for HF. SRC significantly decreased all-cause death (odds ratio, 0.42; 95% confidence interval [CI], 0.23–0.76; P<0.01), especially cardiac death of hospitalized HF patients after discharge. In the multivariate analysis adjusted for age, sex, SRC, body mass index, hypertension, dyslipidemia, β-blockers, and mineralocorticoid receptor antagonist intake, cardiac rehabilitation, and the type of HF, SRC remained a significant predictor of death. Kaplan-Meier analysis showed that SRC significantly reduced deaths and the combined outcome of HF rehospitalization and death. In patients with reduced left ventricular ejection fraction, SRC significantly decreased the mortality rate (odds ratio, 0.27; 95% CI, 0.10–0.71; P<0.01).

Conclusions:SRC reduced the mortality rate after discharge of hospitalized HF patients.

Background:The purpose of this study was to clarify the current status and issues of community collaboration in heart failure (HF) using a nationwide questionnaire survey.

Methods and Results:We conducted a survey among hospital cardiologists and general practitioners (GPs) using a web-based questionnaire developed with the Delphi method, to assess the quality of community collaboration in HF. We received responses from 46 of the 47 prefectures in Japan, including from 281 hospital cardiologists and 145 GPs. The survey included the following characteristics and issues regarding community collaboration. (1) Hospital cardiologists prioritized medical intervention for preventing HF hospitalization and death whereas GPs prioritized supporting the daily living of patients and their families. (2) Hospital cardiologists have not provided information that meets the needs of GPs, and few regions have a community-based system that allows for the sharing of information about patients with HF. (3) In the transition to home care, there are few opportunities for direct communication between hospitals and community staff, and consultation systems are not well developed.

Conclusions:The current study clarified the real-world status and issues of community collaboration for HF in Japan, especially the differences in priorities for HF management between hospital cardiologists and GPs. Our data will contribute to the future direction and promotion of community collaboration in HF management.

Background:It is well acknowledged that left ventricular (LV) contractile performance affects LV relaxation via LV elastic recoil. Accordingly, we aimed to investigate whether global longitudinal strain (GLS), particularly longitudinal strain at LV apical segments at end-systole (ALS), obtained by 2-dimensional speckle-tracking echocardiography could be used to assess LV relaxation.

Methods and Results:We enrolled 121 patients with suspected or definite coronary artery disease in whom echocardiography and diagnostic cardiac catheterization were performed on the same day. We obtained conventional echo-Doppler parameters and GLS, as well as ALS prior to catheterization. LV functional parameters were obtained from the LV pressure recorded using a catheter-tipped micromanometer. In all patients, GLS and ALS were significantly correlated with the time constant τ of LV pressure decay during isovolumetric relaxation (r=0.63 [P<0.001] and r=0.66 [P<0.001], respectively). Receiver operating characteristic curve analysis for identifying impaired LV relaxation (τ ≥48 ms) revealed that ALS greater than −22.3% was an optimal cut-off value, with 81.7% sensitivity and 82.4% specificity. Even in patients with preserved LV ejection fraction, the same ALS cut-off value enabled the identification of impaired LV relaxation with 70% sensitivity and 87.5% specificity.

Conclusions:The findings indicate that contractile dysfunction at LV apical segments slows LV relaxation via loss of LV elastic recoil, even in patients with preserved LVEF.