Heart failure with preserved ejection fraction phenogroup classification using machine learning.

AIMS: Heart failure (HF) with preserved ejection fraction (HFpEF) is a complex syndrome with a poor prognosis. Phenotyping is required to identify subtype-dependent treatment strategies. Phenotypes of Japanese HFpEF patients are not fully elucidated, whose obesity is much less than Western patients. This study aimed to reveal model-based phenomapping using unsupervised machine learning (ML) for HFpEF in Japanese patients. METHODS AND RESULTS: We studied 365 patients with HFpEF (left ventricular ejection fraction >50%) as a derivation cohort from the Nara Registry and Analyses for Heart Failure (NARA-HF), which registered patients with hospitalization by acute decompensated HF. We used unsupervised ML with a variational Bayesian-Gaussian mixture model (VBGMM) with common clinical variables. We also performed hierarchical clustering on the derivation cohort. We adopted 230 patients in the Japanese Heart Failure Syndrome with Preserved Ejection Fraction Registry as the validation cohort for VBGMM. The primary endpoint was defined as all-cause death and HF readmission within 5 years. Supervised ML was performed on the composite cohort of derivation and validation. The optimal number of clusters was three because of the probable distribution of VBGMM and the minimum Bayesian information criterion, and we stratified HFpEF into three phenogroups. Phenogroup 1 (n = 125) was older (mean age 78.9 ± 9.1 years) and predominantly male (57.6%), with the worst kidney function (mean estimated glomerular filtration rate 28.5 ± 9.7 mL/min/1.73 m2 ) and a high incidence of atherosclerotic factor. Phenogroup 2 (n = 200) had older individuals (mean age 78.8 ± 9.7 years), the lowest body mass index (BMI; 22.78 ± 3.94), and the highest incidence of women (57.5%) and atrial fibrillation (56.5%). Phenogroup 3 (n = 40) was the youngest (mean age 63.5 ± 11.2) and predominantly male (63.5 ± 11.2), with the highest BMI (27.46 ± 5.85) and a high incidence of left ventricular hypertrophy. We characterized these three phenogroups as atherosclerosis and chronic kidney disease, atrial fibrillation, and younger and left ventricular hypertrophy groups, respectively. At the primary endpoint, Phenogroup 1 demonstrated the worst prognosis (Phenogroups 1-3: 72.0% vs. 58.5% vs. 45%, P = 0.0036). We also successfully classified a derivation cohort into three similar phenogroups using VBGMM. Hierarchical and supervised clustering successfully showed the reproducibility of the three phenogroups. CONCLUSIONS: ML could successfully stratify Japanese HFpEF patients into three phenogroups (atherosclerosis and chronic kidney disease, atrial fibrillation, and younger and left ventricular hypertrophy groups).

Validity of Diagnostic Algorithms for Cardiovascular Diseases in Japanese Health Insurance Claims.

BACKGROUND: We aimed to validate a claims-based diagnostic algorithm to identify hospitalized patients with acute major cardiovascular diseases (CVDs) from health insurance claims in Japan.Methods and Results: This retrospective multicenter validation study was conducted at 4 institutes, including Japanese Circulation Society-certified and uncertified hospitals in Japan. Data on patients with CVDs in departmental lists or with International Classification of Diseases, 10th Revision (ICD-10) codes for CVDs hospitalized between April 2018 and March 2019 were extracted. We examined the sensitivity and positive predictive value of a diagnostic algorithm using ICD-10 codes, medical examinations, and treatments for acute coronary syndrome (ACS), acute heart failure (HF), and acute aortic disease (AAD). We identified 409 patients with ACS (mean age 70.6 years; 24.7% female), 615 patients with acute HF (mean age 77.3 years; 46.2% female), and 122 patients with AAD (mean age 73.4 years; 36.1% female). The respective sensitivity and positive predictive value for the algorithm were 0.86 (95% confidence interval [CI] 0.82-0.89) and 0.95 (95% CI 0.92-0.97) for ACS; 0.74 (95% CI 0.70-0.77) and 0.79 (95% CI 0.76-0.83) for acute HF; and 0.86 (95% CI 0.79-0.92) and 0.83 (95% CI 0.76-0.89) for AAD. CONCLUSIONS: The validity of the diagnostic algorithm for Japanese claims data was acceptable. Our results serve as a foundation for future studies on CVDs using nationwide administrative data.

Incidence and prognostic impact of the calcified nodule in coronary artery disease patients with end-stage renal disease on dialysis.

Coronary artery calcification is frequently observed in coronary artery disease (CAD) patients with end-stage renal disease (ESRD). Calcified nodule (CN) is recognized as one of the vulnerable plaque characteristics responsible for acute coronary syndrome (ACS). Although CN is a cause of ACS in only 10%, its prevalence may be higher in elderly patients and/or ESRD. The aim of this study is to investigate incidence, clinical characteristics, and prognostic impact of CN in CAD patients with ESRD on dialysis. A total of 51 vessels from 49 CAD patients with ESRD on dialysis were enrolled in this study. CN was defined as a high-backscattering mass protruding into the lumen with a strong signal attenuation and an irregular surface by optical coherence tomography. Incidence, clinical characteristics and prognosis of patients with CN were studied. Major adverse cardiac events (MACE) were defined as a composite of all-cause death, non-fatal myocardial infarction, target vessel revascularization (TVR) and stroke. CNs were observed in 30 vessels from 29 patients (59.2%). Duration of dialysis was significantly longer in CN group than in non-CN group (P = 0.03). Overall, all-cause death, cardiac death, TVR and MACE occurred in 7 (14.3%), 3 (6.1%), 11 (22.4%) and 16 (32.7%) patients during follow-up (median 826 days), respectively. Kaplan-Meier survival analysis revealed that MACE-free survival was significantly lower in patients with CN compared with those without CN (Log-rank, P = 0.036).In conclusion, CN was observed in about 60% of the CAD patients with ESRD and was associated with duration of dialysis and worse prognosis.

Detection of myocardial bridge by optical coherence tomography.

Myocardial bridge (MB) is less commonly documented by angiography than autopsy. Optical coherence tomography (OCT) may be useful to detect angiographically undetectable MB. To investigate OCT characteristics of MB, 86 LAD vessels were imaged by OCT. MB was defined as presence of intermediate optical intensity, "fine" layer surrounding coronary artery by OCT. Frequency and characteristics of the angio-detectable and angio-undetectable but OCT-detectable MB were investigated. In a subset of patients with angio-detectable MB, cyclic changes in coronary arterial dimensions were analyzed. OCT detected MB in 44 of 86 (51%). Arc of the MB was significantly larger (334.8 ± 58.5° vs. 268.4 ± 92.1°, P = 0.008) and length was significantly longer (22.6 ± 11.7 mm vs. 14.5 ± 8.1 mm, P = 0.014) in angio-detectable MB than OCT-detectable but angio-undetectable MB. Both vessel (6.8 ± 1.5 to 5.3 ± 1.0 mm2, P = 0.035) and lumen area (4.4 ± 1.5 to 3.1 ± 0.7 mm2, P = 0.040) decreased significantly from diastole to systole. Adventitial (0.08 ± 0.03 to 0.08 ± 0.02 mm, P = 0.828) and intima + plaque thickness (0.12 ± 0.05 to 0.10 ± 0.03 mm, P = 0.398) did not change significantly during cardiac cycle. On the other hand, medial thickness increased significantly from diastole to systole (0.08 ± 0.03 to 0.12 ± 0.03 mm, P = 0.022). In conclusion, MB is frequently detected as intermediate intensity, fine layer by OCT. During systole, vessel and lumen size decrease with increased medial thickness. Therefore, we should be careful for OCT interpretation of the coronary arteries with MB.

Incidence and Characteristics of Incomplete Stent Apposition in Calcified Lesions: An Optical Coherence Tomography Study.

BACKGROUND: Persistent or late acquired incomplete stent apposition (ISA) may be associated with late or very late stent thrombosis following drug-eluting stent implantation. Presence of calcium at the target lesion may increase the risk of ISA even after rotational atherectomy (RA) followed by stenting with high pressure balloon inflation. The aim of this study is to examine the incidence and characteristics of ISA in heavily calcified lesions. METHODS: A total of 52 heavily calcified coronary artery lesions requiring RA plus stenting were selected and studied. After successful ablation followed by stent implantation, optical coherence tomography (OCT) was performed to assess stent expansion and apposition. Presence or absence of ISA was examined and maximal stent strut to vessel wall distance (max SV distance) was measured. In lesions with repeated OCT at follow-up, serial changes in ISA were investigated. RESULTS: ISA was documented in 51 of 52 (98%) lesions. Mean max SV distance was 713 ± 371 µm. In lesions with serial OCT images (n = 11), max SV distance decreased significantly (692.1 ± 420.2 to 462.5 ± 387.0 µm, P < 0.01) but persisted in all but 2 lesions (82%). CONCLUSIONS: ISA is frequently documented in heavily calcified lesions requiring RA. Significant ISA still persisted with minimal improvement in SV distance at follow-up. Prognostic impact of the persistent ISA in such calcified lesions needs further investigations.

Clinical Impact of Irregular Protrusion Angle After Coronary Stenting at Culprit Lesions With ST-Elevation Myocardial Infarction　- An Intravascular Optical Coherence Tomography Study.

Background: A recent optical coherence tomography (OCT) registry showed that the presence of irregular protrusion (IP) after coronary stenting was a predictor of worse 1-year cardiovascular events. This study evaluated the clinical impact of OCT-detected IP after coronary stenting at ST-elevation myocardial infarction (STEMI) culprit lesions. Methods and Results: In all, 139 consecutive STEMI patients with OCT-detected IP after stenting were analyzed retrospectively. The maximum IP angles were measured and patients with IP were divided into 2 groups (large IP, maximum IP angle ≥180°; small IP, 0°

Prognostic Impact of Calcified Plaque Morphology After Drug Eluting Stent Implantation　- An Optical Coherence Tomography Study.

BACKGROUND: Optical coherence tomography (OCT) has the potential to characterize the detailed morphology of calcified coronary plaques. This study examined the prognostic impact of calcified plaque morphology in patients with coronary artery calcification (CAC) who underwent newer-generation drug-eluting stent (DES) implantation.Methods and Results:In all, 251 patients with moderate to severe CAC who underwent OCT-guided DES implantation were reviewed retrospectively and divided into 3 groups according to OCT findings of the target lesion: 25 patients (10.0%) with calcified nodules (CN), 69 patients (27.5%) with calcified protrusion (CP) without CN, and 157 patients (62.5%) with superficial calcific sheet (SC) without CN and CP. The primary endpoint was major adverse cardiac events (MACE), defined as a composite of cardiac death, myocardial infarction, and target lesion revascularization (TLR). Kaplan-Meier survival analysis revealed that, among the 3 groups, the rates of MACE-free survival (log-rank test, P=0.0117), myocardial infarction (log-rank test, P=0.0103), and TLR (log-rank test, P=0.0455) were significantly worse in patients with CN. Multivariate Cox proportional hazards analysis demonstrated that CN was an independent predictor of MACE (hazard ratio 4.41; 95% confidence interval 1.63-10.8; P=0.0047). CONCLUSIONS: Target lesion CN was associated with higher cardiac event rates in patients who underwent newer-generation DES implantation for lesions with moderate to severe CAC.

Post-Stent Optical Coherence Tomography Findings at Index Percutaneous Coronary Intervention　- Characteristics Related to Subsequent Stent Thrombosis.

BACKGROUND: The association between unfavorable post-stent optical coherence tomography (OCT) findings and subsequent stent thrombosis (ST) remains unclear. This study investigated the ST-related characteristics of post-stent OCT findings at index percutaneous coronary intervention (PCI).Methods and Results:Fifteen patients with ST onset after OCT-guided PCI (ST group) were retrospectively enrolled. Post-stent OCT findings in the ST group were compared with those in 70 consecutive patients (reference group) without acute coronary syndrome onset for at least 5 years after OCT-guided PCI. The incidence of acute myocardial infarction (AMI) was higher in the ST than reference group (60.0% vs. 17.1%, respectively; P=0.0005). The incidence of incomplete stent apposition (93.3% vs. 55.7%; P=0.0064), irregular protrusion (IP; 93.3% vs. 62.8%; P=0.0214), and thrombus (93.3% vs. 51.4%; P=0.0028) was significantly higher in the ST than reference group. The maximum median (interquartile range) IP arc was significantly larger in the ST than reference group (265° [217°-360°] vs. 128° [81.4°-212°], respectively; P<0.0001). In AMI patients, the incidence of a maximum IP arc >180° was significantly higher in the ST than reference group (100% vs. 58.3%, respectively; P=0.0265). CONCLUSIONS: IP with a large arc was a significant feature on post-stent OCT in patients with ST.

Predominant subtype of heart failure after acute myocardial infarction is heart failure with non-reduced ejection fraction.

AIMS: Patients who survive acute myocardial infarction (AMI) are at risk of being rehospitalized owing to the occurrence of acute decompensated heart failure (HF). However, the clinical characteristics of HF after AMI, especially the frequency of each HF subtype, are unclear. METHODS AND RESULTS: We retrospectively studied 1055 patients with AMI. We excluded 257 patients, who were admitted >48 h after the onset of AMI, died during hospitalization or after discharge, and whose echocardiogram data at index hospitalization and follow-up data were missing. The remaining 798 patients (mean age: 66.5 ± 11.7 years) were investigated for a mean follow-up period of 4.9 years. All patients underwent emergency coronary angiography. The mean maximum creatine kinase levels were 2898 ± 2627 IU/L, and mean left ventricular ejection fraction (LVEF) was 58.9 ± 10.2%. Eighty-one patients (10.2%) were rehospitalized because of unexpected worsening of HF. Echocardiography data were available for 74 of the 81 patients during the acute phase of the second hospitalization, of which 30, 20, and 24 patients (41%, 27%, and 32%, respectively) were diagnosed as having HF with preserved LVEF (LVEF ≥ 50%), HF with mid-range LVEF (40% ≤ LVEF < 50%), and HF with reduced LVEF (LVEF < 40%), respectively. The ejection fraction during index hospitalization was 58.3 ± 9.7% in the HF with preserved LVEF group, 53.3 ± 10.2% in the HF with mid-range LVEF group, and 43.3 ± 10.5% in the HF with reduced LVEF group (P < 0.001). CONCLUSIONS: The predominant subtypes of HF after AMI were HF with mid-range ejection fraction and preserved ejection fraction, or HF with non-reduced ejection fraction.

Effects of Fatty Acid Therapy in Addition to Strong Statin on Coronary Plaques in Acute Coronary Syndrome: An Optical Coherence Tomography Study.

BACKGROUND Vascular healing response associated with adjunctive n-3 polyunsaturated fatty acid therapy therapy in patients receiving strong statin therapy remains unclear. The aim of this study was to evaluate the effect of polyunsaturated fatty acid therapy with eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) in addition to strong statin therapy on coronary atherosclerotic plaques using optical coherence tomography. METHODS AND RESULTS This prospective multicenter randomized controlled trial included 130 patients with acute coronary syndrome treated with strong statins. They were assigned to either statin only (control group, n=42), statin+high-dose EPA (1800 mg/day) (EPA group, n=40), statin+EPA (930 mg/day)+DHA (750 mg/day) (EPA+DHA group, n=48). Optical coherence tomography was performed at baseline and at the 8-month follow-up. The target for optical coherence tomography analysis was a nonculprit lesion with a lipid plaque. Between baseline and the 8-month follow-up, fibrous cap thickness (FCT) significantly increased in all 3 groups. There were no significant differences in the percent change for minimum FCT between the EPA or EPA+DHA group and the control group. In patients with FCT <120 µm (median value), the percent change for minimum FCT was significantly higher in the EPA or EPA+DHA group compared with the control group. CONCLUSIONS EPA or EPA+DHA therapy in addition to strong statin therapy did not significantly increase FCT in nonculprit plaques compared with strong statin therapy alone, but significantly increased FCT in patients with thinner FCT. Registration URL: https://www.umin.ac.jp/ctr/; Unique identifier: UMIN 000012825.

Plasma Renin Activity Is an Independent Prognosticator in Patients With Myocardial Infarction.

BACKGROUND: Plasma renin activity (PRA) is associated with cardiovascular events in patients with heart failure (HF), but its prognostic role in acute myocardial infarction (AMI) is unclear.Methods and Results:A total of 878 patients with information on baseline PRA on admission were selected from 1,055 AMI patients who underwent emergency coronary angiography between 2007 and 2016. The patients were divided into 2 groups according to their median PRA (2.0 ng/mL/h). The primary endpoint was major adverse cardiac events (MACE), defined as a composite of cardiovascular death and hospitalization because of HF. During follow-up (median 4.5±3.1 years), MACE occurred in 108 patients. Kaplan-Meier analysis showed that the high PRA group had significantly lower MACE-free survival than the low PRA group (log-rank P=0.0009). By multivariate analysis, high PRA was an independent predictor of MACE (hazard ratio (HR) 1.573; 95% confidence interval (CI) 1.049-2.396, P=0.0282). Similarly, among 580 patients who had not been previously treated with renin-angiotensin system inhibitors or ß-blockers on admission, high PRA was an independent predictor of MACE (HR 1.732; 95% CI 1.010-3.047, P=0.0460). CONCLUSIONS: In the studied AMI patients, elevated levels of PRA were independently associated with poor prognosis.

Usefulness of longitudinal reconstructed optical coherence tomography images for predicting the need for the reverse wire technique during coronary bifurcation interventions.

OBJECTIVES: The aim is to investigate the usefulness of longitudinal reconstructed optical coherence tomography (OCT) images in selecting the reverse wire (RW) technique for inserting a guidewire into a side branch (SB). BACKGROUND: It is sometimes necessary to protect the SB with a guidewire to prevent SB complications in PCI for bifurcation lesions. The RW is a novel method for guidewire insertion into an extremely angulated SB when the standard antegrade wire (AW) approach is difficult. METHODS: This retrospective study included 46 consecutive patients who underwent OCT-guided PCI in bifurcation lesions with significant SB stenosis. Patients were divided into two groups: 36 patients with successful guidewire crossing using the AW (AW group) and 10 patients with unsuccessful AW but successful RW guidewire crossing (RW group). SB angle and branch point (BP) slope, defined as the angle between the line connecting the proximal and distal BPs and the vertical, were measured using longitudinal reconstructed OCT images. RESULTS: The RW group had a significantly larger SB angle and higher BP slope than the AW group (108.7 ± 11.4° vs. 76.2 ± 14.9°; P < 0.0001, 128.7 ± 31.6° vs. 82.9 ± 33.6°; P = 0.0004, respectively). Receiver operating characteristic curve analysis indicated that SB angle ≥ 100° and BP slope ≥ 120° are optimal cutoff values for predicting the need for RW (area under the curve 0.97, sensitivity 90.0%, specificity 91.7%; area under the curve 0.83, sensitivity 80.0%, specificity 86.1%, respectively). CONCLUSIONS: Longitudinal reconstructed OCT is useful for selecting the wiring technique for bifurcation lesions.

Refractory high output heart failure in a patient with primary mitochondrial respiratory chain disease.

A 40-year-old man who was referred to our hospital due to dyspnea was found to have high output cardiac failure on Swan-Ganz catheterization. An endomyocardial biopsy revealed cardiomyocyte hypertrophy with a vacuolar structure consistent with mitochondrial disease (MD). The patient was discharged, then readmitted for high output cardiac failure with hypotension and hyperlactacidemia. Treatment with cardiopulmonary support and hemodiafiltration gradually improved his general condition, although it resulted in ischemic necrosis of the right leg. The hyperlactacidemia completely resolved after amputation, and the high output cardiac failure has not recurred for two years. High output cardiac failure is rare in MD patients and is related to myocardial abnormalities and hyperlactacidemia.