Time-dependent change of relative apical longitudinal strain index in patients with wild-type transthyretin amyloid cardiomyopathy.

Aim: This study was conducted to investigate the meaning of left ventricular (LV) apical sparing in patients with wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM). Methods and results: 165 patients who were diagnosed with ATTRwt-CM at Kumamoto University Hospital from January 2002 to December 2020 and had sufficient data for two-dimensional speckle tracking echocardiography were enrolled. Of these, 86 patients (52 %) had LV apical sparing (relative apical longitudinal strain index (RapLSI) > 1.0). Multivariable logistic regression analysis revealed the following variables were significantly associated with LV apical sparing: interventricular septal thickness in diastole (odds ratio (OR), 1.19; 95 % confidence interval (CI), 1.01-1.41; p < 0.05); E/e' ratio (OR, 1.06; 95 % CI, 1.00-1.11; p < 0.05); and heart-to-contralateral ratio by 99mTc-labeled pyrophosphate scintigraphy (OR, 3.40; 95 % CI, 1.07-10.83; p < 0.05).Next, we compared RapLSI at the time of diagnosis with that during the follow-up period (396 days (346-458) after diagnosis) in 92 patients. RapLSI increased significantly during the follow-up period compared with RapLSI at diagnosis in the non-LV apical sparing group (0.89 ± 0.32 vs 0.74 ± 0.18, p < 0.01) but not in the LV apical sparing group (1.33 ± 0.53 vs 1.39 ± 0.45, p = 0.46). A total of 12 patients (29 %) in the non-LV apical sparing group developed LV apical sparing and 11 patients (22 %) in LV apical sparing group diminished LV apical sparing during the follow-up period. Conclusion: Approximately half of ATTRwt-CM patients did not have LV apical sparing at diagnosis. Because RapLSI in ATTRwt-CM significantly changed over time, repeated two-dimensional speckle tracking analysis is important for suspected ATTR-CM patients.

Prognostic value of right ventricular global longitudinal strain in transthyretin amyloid cardiomyopathy.

BACKGROUND: This study was performed to investigate whether right ventricular global longitudinal strain (RV-GLS) provides prognostic information in patients with wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM). METHODS AND RESULTS: Among 129 patients who were diagnosed with ATTRwt-CM at Kumamoto University Hospital from December 2002 to December 2019, 111 patients who had enough information for two-dimensional speckle tracking imaging were retrospectively analyzed. During a median follow-up of 615 days, 26 cardiovascular deaths occurred. Compared with patients in the non-event group, those in the cardiovascular death group were significantly older (81.1 ±â€¯7.4 years vs. 78.2 ±â€¯6.2 years, p = 0.009) and had significantly higher interventricular septal thickness in diastole (16.6 ±â€¯3.1 mm vs. 15.3 ±â€¯2.4 mm, p = 0.048), lower RV-GLS (10.9 ±â€¯2.7% vs. 12.8 ±â€¯3.5%, p = 0.010), and lower right ventricular free wall longitudinal strain (RVFWLS) (13.1 ±â€¯3.3% vs. 15.5 ±â€¯3.8%, p = 0.004). In the univariate Cox proportional hazard analysis, age, left atrial volume index (LAVI), RV-GLS, and RVFWLS were significantly associated with cardiovascular death [age, hazard ratio (HR), 1.10; 95% confidence interval (CI), 1.02-1.19, p = 0.010; LAVI, HR, 1.02; 95% CI, 1.00-1.03, p = 0.009; RV-GLS, HR, 0.86; 95% CI, 0.75-0.97, p = 0.017; RVFWLS, HR 0.89; 95% CI, 0.79-1.00; p = 0.041]. Multivariable Cox proportional hazard analysis showed RV-GLS was significantly and independently associated with cardiovascular death in patients with ATTRwt-CM (HR, 0.86; 95% CI, 0.74-0.99; p = 0.038). Receiver operating characteristic analysis showed that the area under the curve of RV-GLS for cardiovascular death was 0.668 and that the best cut-off value of RV-GLS was 11.59% (sensitivity, 69.2%; specificity, 63.5%). In the Kaplan-Meier analysis, patients with ATTRwt-CM who had low RV-GLS (<11.59%) had a significantly higher probability of total cardiovascular death (p = 0.004) and heart failure-related hospitalization (p = 0.013). CONCLUSION: RV-GLS has significant prognostic value in patients with ATTRwt-CM and provides greater prognostic power than conventional echocardiographic findings.

Cardiac computed tomography-derived myocardial tissue characterization after anthracycline treatment.

AIMS: Understanding cardiac function after anthracycline administration is very important from the perspective of preventing the onset of heart failure. Although cardiac magnetic resonance and echocardiography are recognized as the 'gold standard' for detecting cardiotoxicity, they have many shortcomings. We aimed to investigate whether cardiac computed tomography (CCT) could replace these techniques, assessing serial changes in cardiac tissue characteristics as determined by CCT after anthracycline administration. METHODS AND RESULTS: We prospectively investigated 15 consecutive breast cancer patients who were scheduled to receive anthracycline therapy. We performed echocardiography and CCT before and 3, 6, and 12 months after anthracycline treatment. The mean cumulative administered anthracycline dose was 269.9 ± 14.6 mg/m2 (doxorubicin-converted dose). Of the 15 enrolled patients who received anthracycline treatment for breast cancer, none met the definition of cardiotoxicity. The CCT-derived extracellular volume fraction tended to continue to increase after anthracycline treatment and had relatively similar dynamics to the left ventricular ejection fraction and global longitudinal strain as determined by echocardiography. CONCLUSIONS: Our findings indicated that CCT could provide adequate information about the characteristics of myocardial tissue after anthracycline administration. CCT may improve the understanding of cardiotoxicity by compensating for the weaknesses of echocardiography. This technique could be useful for understanding cardiac tissue characterization as a 'one-stop shop' evaluation, providing new insight into cardiooncology.

Increased soluble programed cell death-ligand 1 is associated with acute coronary syndrome.

BACKGROUND: Programmed cell death (PD)-1 and its ligand (PD-L1) plays crucial roles in T-cell tolerance as immune checkpoint. Previous studies reported that increased serum levels of soluble PD-L1 (sPD-L1) reflect myocardial and vascular inflammation. However, little is known about the clinical relationship between sPD-L1 and acute coronary syndrome (ACS). We investigated the relation of sPD-L1 and ACS. METHODS: We prospectively measured serum levels of sPD-L1 using a commercially available enzyme-linked immunosorbent assay kit in patients with coronary artery disease (CAD) and continuous non-CAD admitted to Kumamoto University Hospital between December 2017 and June 2019. All malignant diseases, patients who underwent hemodialysis, active collagen diseases, and severe infectious diseases were excluded. RESULTS: Totally, 446 CAD patients [ACS, n = 124; chronic coronary syndrome (CCS), n = 322] and 24 non-CAD patients were analyzed. The levels of sPD-L1 were significantly higher in patients with ACS than those both with non-CAD and CCS {ACS, 188.7 (111.0-260.8) pg/mL, p < 0.001 vs. non-CAD [83.5 (70.8-130.4) pg/mL]; and p = 0.009 vs. CCS [144.2 (94.8-215.5) pg/mL], respectively}. Univariate logistic regression analysis identified that sPD-L1 was significantly associated with ACS [odds ratio (OR): 1.459, 95% confidence interval (CI): 1.198-1.778, p < 0.001]. Multivariable logistic regression analysis with nine significant factors identified from the univariate analysis revealed that sPD-L1 was significantly and independently associated with ACS (OR: 1.561, 95% CI: 1.215-2.006, p < 0.001). CONCLUSIONS: This is the first clinical study to demonstrate the increased level of sPD-L1 in patients with CAD, and the significant association with ACS.

HFA-PEFF scores: prognostic value in heart failure with preserved left ventricular ejection fraction.

BACKGROUND/AIMS: The Heart Failure Association (HFA)-PEFF score is recognized as a simple method to diagnose heart failure (HF) with preserved ejection fraction (HFpEF). This study aimed to evaluate the relationship between HFA-PEFF scores and cardiovascular outcomes in HFpEF patients. METHODS: A total of 502 consecutive HFpEF patients were prospectively observed for up to 1,500 days. Cardiovascular outcomes were compared between two groups of patients, defined by their HFA-PEFF scores: those who scored 2-4 (the intermediate-score group) and those who scored 5-6 group (the high-score group). Overall, 236 cardiovascular events were observed during the follow-up period (median, 1,159 days). RESULTS: Kaplan-Meier analysis showed that there were significant differences in composite cardiovascular events and HF-related events between the intermediate-score group and the high-score group (p = 0.003 and p < 0.001, respectively). Multivariate Cox proportional hazards analysis showed that the HFA-PEFF scores significantly predicted future HF-related events (hazard ratio, 1.66; 95% confidence interval [CI], 1.11 to 2.50; p = 0.014); receiver operating characteristic analysis confirmed this relationship (area under the curve, 0.633; 95% CI, 0.574 to 0.692; p < 0.001). The cutoff HFA-PEFF score for the identification of HF-related events was 4.5. Decision curve analysis revealed that combining the HFA-PEFF score with conventional prognostic factors improved the prediction of HF-related events. CONCLUSION: HFA-PEFF scores may be useful for predicting HF-related events in HFpEF patients.

The usefulness of C-reactive protein to predict improving left ventricular function after aortic valve replacement in patients with aortic regurgitation.

Background: We aimed to clarify the predictive factors for left ventricular (LV) function after aortic valve replacement (AVR) in patients with aortic regurgitation (AR). Methods and results: Among 555 patients who underwent AVR at our institution from January 2015 to December 2020, we enrolled 44 patients for whom only AVR (or AVR + aortic replacement) was performed. We defined LV dysfunction under any of the following criteria: LV ejection fraction (LVEF) <50 %, LV diastolic dimension >65 mm, LV systolic dimension (LVDs) >50 mm, or LVDs/body surface area > 25 mm/m2. Multivariable logistic regression analysis revealed high natural logarithm (ln) C-reactive protein (CRP) and low LVEF in the pre-AVR period significantly associated with LV dysfunction after AVR (ln CRP: odds ratio [OR] 4.15, 95 % confidence interval [CI] 1.44-11.98, p < 0.01; LVEF: OR 0.79, 95%CI 0.65-0.97, p < 0.05). Receiver-operating characteristic analysis revealed an area under curve of CRP and LVEF in the pre-AVR period for LV dysfunction after AVR of 0.84 and 0.83, respectively. Upon dividing the patients into four groups according to cutoff values of CRP (0.13 mg/dL) and LVEF (50 %) in the pre-AVR period, no patients (0/19) had LV dysfunction in the low CRP (<0.13 mg/dL) and high LVEF (≥50 %) group, and all patients (5/5) in the high CRP (≥0.13 mg/dL) and low LVEF (<50 %) group had LV dysfunction after AVR. Conclusion: High CRP level was significantly and independently associated with LV dysfunction after AVR. Combination of CRP and LVEF values might be useful for predicting improvement in LV function after AVR.

Prognostic value of left atrial strain in patients with wild-type transthyretin amyloid cardiomyopathy.

AIMS: This study was performed to investigate whether left atrial (LA) strain by echocardiography provides prognostic information in patients with wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM). METHODS AND RESULTS: Among 129 patients who were diagnosed with ATTRwt-CM at Kumamoto University Hospital from December 2002 to December 2019, 113 patients who had enough information for two-dimensional speckle tracking echocardiography were enrolled in this study. During a median follow-up of 668 days, 28 cardiovascular deaths occurred. Compared with patients in the non-event group, those in the cardiovascular death group were significantly older (81.5 ± 7.4 vs. 78.1 ± 6.1 years, P < 0.01), had a lower incidence of carpal tunnel syndrome (21% vs. 47%, P < 0.05), and had a higher high-sensitivity cardiac troponin T [0.085 (0.063-0.105) vs. 0.049 (0.036-0.079) ng/mL, P < 0.01] and B-type natriuretic peptide concentrations [419 (239-541) vs. 271 (155-462) pg/mL, P < 0.01] and lower estimated glomerular filtration rate (41.8 ± 15.4 vs. 53.4 ± 14.6 mL/min/1.73 m2 , P < 0.01). Electrocardiography showed higher rate of a V1-V3 QS pattern (52% vs. 24%, P < 0.01) and complete left bundle branch block (27% vs. 6%, P < 0.01), and echocardiography showed a significantly lower peak LA strain rate during the contraction phase (0.16 ± 0.13 vs. 0.28 ± 0.27 S-1 , P < 0.05), LA strain during the reservoir phase (LASr) (5.84 ± 2.41 vs. 8.22 ± 4.05%, P < 0.01), and peak LA strain rate during the reservoir phase (0.26 ± 0.09 vs. 0.33 ± 0.15 S-1 , P < 0.05) in the cardiovascular death group than in non-event group. By contrast, conventional echocardiographic findings were not significantly different between these two groups. After adjusting for conventional predictive factors of ATTRwt-CM (age, high-sensitivity cardiac troponin T and B-type natriuretic peptide concentrations, and estimated glomerular filtration rate), multivariable Cox proportional hazard analyses showed that LASr was significantly and independently associated with cardiovascular death in patients with ATTRwt-CM (odds ratio, 0.84; 95% confidence interval, 0.72-0.98; P < 0.05). After adjusting for age and echocardiographic findings associated with cardiovascular death (LA volume index and peak LA strain rate during the contraction phase), LASr was significantly and independently associated with cardiovascular death in patients with ATTRwt-CM (odds ratio, 0.83; 95% confidence interval, 0.70-0.98; P < 0.05). Receiver operating characteristic curve analysis showed that the area under the curve of LASr for cardiovascular death was 0.686 and that the best cut-off value of LASr was 6.69% (sensitivity, 62.4%; specificity, 64.3%). In the Kaplan-Meier analysis, patients with low LASr (<6.69%) had a significantly higher probability of total cardiovascular death (P < 0.05) and heart failure-related hospitalization (P < 0.05). CONCLUSIONS: Left atrial strain during the reservoir phase provides significant prognostic value in patients with ATTRwt-CM even after adjusting for conventional predictive factors.

Prognostic significance of liver stiffness assessed by fibrosis-4 index in patients with heart failure.

BACKGROUND: Heart failure (HF)-related congestive hepatopathy is a well-recognized problem in management of HF. The fibrosis-4 (FIB4) index calculated by [age × aspartate aminotransferase (IU/L)/platelet count (109 /L) × square root of alanine aminotransferase (IU/L)] is useful for evaluating liver stiffness. We aimed to investigate the impact of the FIB4 index on prognosis in patients with HF. METHODS AND RESULTS: Consecutive HF patients referred for hospitalization at Kumamoto University Hospital, Japan, were registered between 2006 and 2015. We observed cardiovascular outcomes in each type of HF [HF with reduced left ventricular ejection fraction (LVEF) (HFrEF), HF with mid-range LVEF (HFmrEF) and with preserved LVEF (HFpEF)] according to their FIB4 index; Group 1 (FIB4 index <1.3), Group 2 (FIB4 index: 1.3-2.67), and Group 3 (FIB4 index >2.67). This study enrolled 83 HFrEF patients, 117 HFmrEF patients, and 504 HFpEF patients. In HFpEF patients, the Kaplan-Meier curve revealed that Group 3 had a significantly higher rate of total cardiovascular events compared with the other two groups. By contrast, the occurrences of total cardiovascular events were not different among three groups in HFrEF and HFmrEF patients. Multivariate Cox proportional hazard analysis with significant factors in univariate analysis identified that the FIB4 index as an independent and significant predictor for future total cardiovascular events in HFpEF patients (hazard ratio: 1.09, 95% confidence interval: 1.03-1.15, P = 0.001). CONCLUSIONS: The FIB4 index was a significant predictor for total cardiovascular events in HFpEF.

Cardiac computed tomography-derived extracellular volume fraction in late anthracycline-induced cardiotoxicity.

Cardiotoxicity in the late phase after anthracycline drugs administration remains to be defined. Of the 44 patients who received anthracycline treatment, 7 were found to have cancer therapeutics-related cardiac dysfunction (CTRCD). The global longitudinal strain determined by echocardiography and myocardial extracellular volume fraction (ECV) determined by cardiac computed tomography (CCT) of the CTRCD(+) group were significantly higher than those of the control group and CTRCD(-) group, whereas there were no significant differences between the control and CTRCD(-) groups. Our findings indicated that CCT may be a tool comparable to echocardiography, indicating the effective evaluation of CTRCD by CCT.

Elevated C-reactive protein is significantly associated with left ventricular dysfunction in patients with aortic regurgitation and concomitant collagen disease.

BACKGROUND: Collagen disease is an important cause of aortic regurgitation (AR). Although aortic valve surgery is recommended for patients with AR and depressed left ventricular (LV) function, there have been few reports about risk factors for LV dysfunction in patients with AR concomitant with collagen disease. METHODS AND RESULTS: We conducted this study at Kumamoto University Hospital in Japan. A total of 41 patients who had moderate to severe AR and concomitant collagen disease between January 2014 and December 2019 were enrolled. With regard to baseline characteristics, there were no significant differences in the type of collagen disease or El Khoury class between patients with preserved LV function and those with reduced LV function. B-type natriuretic peptide (375.2 [257.9-3852.6]pg/ml vs. 64.0 [33.3-133.6]pg/ml, p < 0.01), C-reactive protein (CRP) levels (2.00 [1.24-9.14]mg/dl vs. 0.19 [0.06-0.52]mg/dl, p < 0.01) and neutrophil-to-lymphocyte ratio (7.94 [3.30-9.98] vs. 3.94 [1.83-5.58], p < 0.05) were significantly higher, and hemoglobin level (10.7 ± 1.6 g/dl vs. 12.2 ± 1.8 g/dl, p < 0.05) was significantly lower in patients with reduced LV function than in those with preserved LV function. There were no significant differences in any variables associated with severity and features of AR. Multivariable logistic regression analysis showed that high CRP levels (≥1.0 mg/dl) were independently and significantly associated with LV dysfunction in patients with AR and collagen disease, even after adjusting for the severity of AR (odds ratio: 95.7; 95% confidence interval: 4.6-1990.4, p < 0.01). CONCLUSIONS: Uncontrolled inflammation, represented as high CRP levels, is an important marker for LV dysfunction in patients with AR and collagen disease.

The controlling nutritional status score predicts outcomes of cardiovascular events in patients with heart failure with preserved ejection fraction.

BACKGROUNDS: The relationship between cardiovascular outcomes and the Controlling Nutritional Status (CONUT) score in heart failure (HF) with preserved ejection fraction (HFpEF) patients is unknown. This study aimed to evaluate the relationship between the score and cardiovascular outcomes in HFpEF patients. METHODS AND RESULTS: A total of 506 consecutive HFpEF patients were prospectively observed for up to 1500 days or until the occurrence of cardiovascular events. The mean age was 71.6 ± 9.4 years. Cardiovascular outcomes were compared between the CONUT score 0-1 group with a normal nutritional state (normal group), the CONUT score 2-4 group with a light degree of undernutrition (light group), and the CONUT score 5-8 group with a moderate degree of undernutrition (moderate group). In this study, there were no patients who scored 9-12, which was defined as a severe state of undernutrition. Overall, 238 cardiovascular events were observed during the follow-up period (median: 1159 days). Kaplan-Meier analysis showed that the moderate group was at higher risk of composite cardiovascular events than the normal group (P < 0.001) and the light group (P = 0.031). The analysis also showed that the light group was at higher risk of composite cardiovascular events than the normal group (P = 0.038). Multivariable Cox proportional hazards analysis with the significant factors from the univariate analysis showed that the CONUT score (hazard ratio: 1.12, 95% confidence interval: 1.03-1.21, P = 0.005) significantly predicted future cardiovascular events. CONCLUSION: Nutritional screening using the CONUT score may be useful for predicting cardiovascular events in HFpEF patients.

Temporal Change in Longitudinal Strain After Domino Liver Transplantation With Liver Grafts Explanted From Patients With Hereditary Amyloidogenic Transthyretin Amyloidosis.

Background: Using transthoracic echocardiography, including 2D speckle tracking imaging (STI), this study examined cardiac function after domino liver transplantation (DLT) with liver grafts explanted from patients with hereditary amyloidogenic transthyretin amyloidosis. Methods and Results: In all, 14 patients who underwent DLT at Kumamoto University Hospital and for whom 2D STI information was available were enrolled in the study; time-dependent echocardiographic changes were evaluated in 7. Although left ventricular (LV) systolic and diastolic function did not differ between the pre- and post-DLT periods (mean [±SD] 5.4±1.0 years after DLT), there were significant (P<0.05 for all) increases in the post- vs. pre-DLT period in basal longitudinal strain (LS; -13.4±2.3 vs. -19.3±4.4), relative apical LS index (=apical LS/[basal LS+mid LS]; 0.75±0.20 vs. 0.58±0.08), and LV ejection fraction/global LS (3.91±0.58 vs. 3.06±0.44). Age at the time of DLT was significantly higher in the group with impaired (>-14%) than preserved basal LS (57.2±3.5 vs. 39.6±16.0 years; P<0.05). When control subjects (n=14) were added to the enrolled DLT recipients, multivariable logistic regression analysis revealed that a history of DLT was significantly associated with impaired basal LS (>-14%; odds ratio 28.39, 95% confidence interval 1.89-427.45, P<0.05). Conclusions: LV systolic and diastolic function was preserved in the long term after DLT. However, 2D STI revealed subtle cardiac dysfunction in DLT recipients, which may be an early manifestation of cardiac amyloidosis.

Clinical Features of Patients With Acute Aortic Dissection After an Earthquake: Experience from the Kumamoto Earthquake 2016.

BACKGROUND: While there is a concern about the increase in the occurrence of acute aortic dissection (AAD) caused by the worsening of hypertension, mental stress, etc., there is a lack of data regarding the influence of disasters on this event. The aim of this study was to address this issue in the acute-subacute phase after the Kumamoto Earthquake occurred on 14 April 2016. METHODS: We retrospectively investigated the impacts of the Kumamoto Earthquake on various cardiovascular diseases, including AAD, utilizing the medical records of patients in 16 hospitals in Kumamoto Prefecture during the period from 14 April to 30 June (78 days) in 2014, 2015, 2016, and 2017. RESULTS: The occurrence of heart failure and venous thromboembolism increased significantly in the acute-subacute phase after the earthquake. When comparing the earthquake year (2016) to the non-earthquake years (2014, 2015, and 2017), the difference in the occurrences and mortalities of AADs were not significant. When other characteristics of the patients were compared between the earthquake year and the non-earthquake years, there were no differences. CONCLUSIONS: It might be possible that the Kumamoto Earthquake did not affect the incidence of AAD or deaths from AAD, possibly because the climate was mild and the preventive efforts based on previous experience were successful. REGISTRATION: University Hospital Medical Information Network (UMIN)-CTR (http://www.umin.ac.jp/ctr/). IDENTIFIER: UMIN000023864. PUBLIC ACCESS INFORMATION: Opt-out materials were available at the following website: http://www.kumadai-junnai.com/home/wp-content/uploads/shinsai.pdf.