Left ventricular reverse remodeling following initiation of sacubitril/valsartan for heart failure with reduced ejection fraction and low blood pressure.

Sacubitril/valsartan has become an important first-line drug for symptomatic heart failure (HF) patients, especially with left ventricular (LV) ejection fraction (LVEF) < 50%. However, the impact of sacubitril/valsartan on cardiovascular outcomes, especially LV reverse remodeling for such patients with low blood pressure, remains uncertain. We retrospectively studied 164 HF patients with LVEF < 50% who were treated with sacubitril/valsartan from two institutions. Echocardiography was performed before and 9.5 ± 5.1 months after initiation of maximum tolerated dose of sacubitril/valsartan. The maximum tolerated dose of sacubitril/valsartan was lower for the low blood pressure group (≤ 100 mmHg in systole) than for the non-low blood pressure group (> 100 mmHg in systole) (165 ± 106 mg vs. 238 ± 124 mg, P = 0.017). As expected, significant LV reverse remodeling was observed in the non-low blood pressure group after initiation of sacubitril/valsartan. It was noteworthy that significant LV reverse remodeling was also observed in the low blood pressure group after initiation of sacubitril/valsartan (LV end-diastolic volume: 177.3 ± 66.0 mL vs. 137.7 ± 56.1 mL, P < 0.001, LV end-systolic volume: 131.6 ± 60.3 mL vs. 94.6 ± 55.7 mL, P < 0.001, LVEF: 26.8 ± 10.3% vs. 33.8 ± 13.6%, P = 0.015). Relative changes in LV volumes and LVEF after initiation of sacubitril/valsartan were similar for the two groups. In conclusion, significant LV reverse remodeling occurred after initiation of sacubitril/valsartan, even in HF patients with LVEF < 50% and systolic blood pressure ≤ 100 mmHg.

Left atrial volume index as a predictor for left atrial appendage thrombus in patients with non-valvular atrial fibrillation receiving appropriate oral anticoagulation therapy: A prospective multi-center study.

OBJECTIVES: We previously reported a higher left atrial volume index (LAVI) was independently associated with left atrial (LA) appendage (LAA) thrombus formation in 737 patients with non-valvular atrial fibrillation (NVAF) receiving appropriate oral anticoagulation therapy. Since our previous study was a retrospective single-center study, we designed and conducted a prospective multi-center study to verify our findings for LAVI as a predictor of LAA thrombus in patients with NVAF receiving appropriate oral anticoagulation therapy. METHODS: This prospective multi-center study comprised 746 consecutive patients with NVAF recruited between December 2021 and March 2023 from eight institutions in Japan, who were receiving appropriate oral anticoagulation therapy, had undergone transthoracic echocardiography and transesophageal echocardiography (TEE). RESULTS: LAA thrombi were observed in 21 patients (2.8%). The prevalence of LAA thrombus formation in patients with paroxysmal AF (PAF) was significantly lower than that in patients with non-PAF (0.7% vs. 4.1%, p = .006). LAA thrombus formation was detected in none (0/171) of the patients with normal size LA (LAVI ≤ 34 mL/m2 ). The prevalence of LAA thrombus formation in patients with mildly dilated LA (LAVI: 34-49.9 mL/m2 ) was 2.1% (6/283), but that in PAF patients was low at 1.0% (1/104). Furthermore, this prevalence in patients with severely dilated LA (LAVI ≥ 50 mL/m2 ) was high at 5.1% (15/292). CONCLUSIONS: The findings of this prospective multi-center study are consistent with those of our previous study. Thus, the need for TEE prior to catheter ablation or electrical cardioversion can be determined by the level of LAVI.

Impact of Tafamidis on Echocardiographic Cardiac Function of Patients With Transthyretin Cardiac Amyloidosis.

BACKGROUND: The efficacy of a therapy for patients with transthyretin amyloid cardiomyopathy (ATTR-CM) has not been proven, but tafamidis has been associated with favorable outcomes. However, echocardiographic details of the association of tafamidis with cardiac morphology remain undetermined. Moreover, whether the efficacy of tafamidis varies with the degree of cardiac involvement remains unknown. Using echocardiography, this study investigated the impact of tafamidis on the cardiac morphology of patients with ATTR-CM.Methods and Results: Of 52 consecutive patients with biopsy-proven ATTR-CM at Kobe University Hospital, we included 41 for whom details of follow-up echocardiographic examinations after the administration of tafamidis were available. All patients underwent standard and speckle-tracking echocardiography before and a mean (±SD) of 16±8 months after the administration of tafamidis. No significant changes were observed in any representative echocardiographic parameters after the administration of tafamidis. Furthermore, there were no significant changes observed in subgroup analyses (e.g., left ventricular [LV] ejection fraction ≥50% vs. <50%; LV mass index <150 vs. ≥150 g/m2; New York Heart Association Class I-II vs. Class III; age ≥80 vs. <80 years). CONCLUSIONS: Tafamidis may prevent worsening of various representative echocardiographic parameters of patients with ATTR-CM. This effect is also seen in patients with relatively advanced disease and in those who are elderly.

Identification of factors associated with progression of left atrial enlargement in patients with atrial fibrillation.

Left atrial (LA) enlargement frequently occurs in atrial fibrillation (AF) patients, and this enlargement is associated with the development of heart failure, thromboembolism, or atrial functional mitral regurgitation (AFMR). AF patients can develop LA enlargement over time, but its progression depends on the individual. So far, the factors that cause progressive LA enlargement in AF patients have thus not been elucidated, so that the aim of this study was to identify the factors associated with the progression of LA enlargement in AF patients. We studied 100 patients with persistent or permanent AF (aged: 67 ± 2 years, 40 females). Echocardiography was performed at baseline and 12 (5-30) months after follow-up. LA size was evaluated as the LA volume index which was calculated with the biplane modified Simpson's method from apical four-and two-chamber views, and then normalized to the body surface area (LAVI). The deterioration of AFMR after follow-up was defined as a deterioration in severity of mitral regurgitation (MR) by a grade of 1 or more. Multivariate regression analysis demonstrated that hypertension (p = .03) was an independently associated parameter of progressive LA enlargement, as was baseline LAVI. In addition, the Kaplan-Meier curve indicated that patients with hypertension tended to show greater deterioration of AFMR after follow-up than those without hypertension (log-rank p = .08). Hypertension proved to be strongly associated with progression of LA enlargement over time in patients with AF. Our findings provide new insights for better management of patients with AF to prevent the development of AFMR.

Effect of heart rate on left ventricular longitudinal myocardial function in type 2 diabetes mellitus.

BACKGROUND: Left ventricular (LV) longitudinal myocardial dysfunction is considered a marker of preclinical LV dysfunction in patients with type 2 diabetes mellitus (T2DM). High heart rate (HR) is associated with cardiovascular outcomes, but the effect of HR on LV longitudinal myocardial function in T2DM patients is uncertain. METHODS: We studied 192 T2DM patients with preserved LV ejection fraction (LVEF), and 81 age-, sex-, and LVEF-matched healthy volunteers. HR was measured as the average HR during echocardiography, and high HR was defined as resting HR ≥ 70 beats/minute. LV longitudinal myocardial function was assessed as global longitudinal strain (GLS). The predefined cutoff for subclinical LV dysfunction was set at GLS < 18%. RESULTS: GLS in T2DM patients with high HR was significantly lower than that in T2DM patients with low HR (16.3% ± 4.2% vs. 17.8% ± 2.8%; P = 0.03), whereas GLS in normal subjects with high and low HR was similar (20.3 ± 1.7% vs. 20.3 ± 2.0%; P = 0.99). Multivariable logistic regression analysis showed that high HR (odds ratio: 1.04; 95% confidence interval: 1.01-1.07; P = 0.01) was independently associated with GLS < 18% in T2DM patients as well as HbA1c, T2DM duration, LVEF, body mass index, and mitral inflow E and mitral e' annular velocity ratio. One sequential logistic model evaluating the associations between GLS < 18% and clinical variables in T2DM patients showed an improvement with the addition of LVEF and E/e' (P < 0.001) and a further improvement with the addition of high HR (P < 0.001). CONCLUSION: Compared with normal subjects, resting HR was associated with LV longitudinal myocardial function in asymptomatic T2DM patients with preserved LVEF. Our findings provide new insights on the management of T2DM patients.

Association of left ventricular longitudinal myocardial function with subclinical right ventricular dysfunction in type 2 diabetes mellitus.

BACKGROUND: Left ventricular (LV) involvement in diabetic cardiomyopathy has been reported; however, only limited data exist on right ventricular (RV) involvement. Therefore, our purpose was to investigate RV systolic dysfunction and its association with LV longitudinal myocardial dysfunction in patients with type 2 diabetes mellitus (T2DM) and preserved LV ejection fraction (LVEF). METHODS: We studied 177 T2DM patients with preserved LVEF and 79 age-, sex-, and LVEF-matched healthy volunteers. LV longitudinal myocardial function was assessed as global longitudinal strain (GLS), and RV systolic function was assessed as RV free-wall strain, and predefined cutoff values for subclinical dysfunction were set at GLS < 18% and RV free-wall strain < 20%, respectively. RESULTS: RV free-wall strain in T2DM patients was significantly lower than that in normal controls (19.3% ± 4.8% vs. 24.4% ± 5.1%; P < 0.0001). RV free-wall strain in T2DM patients and LV longitudinal dysfunction was similar compared to that in T2DM patients without (19.0 ± 4.5% vs. 19.6 ± 5.0%, P = 0.40). Furthermore, multivariate logistic regression analyses showed that GLS was independently associated with RV systolic dysfunction as well as mitral inflow E and mitral e' annular velocities ratio (odds ratio, 1.16; 95% confidence interval: 1.03-1.31; P < 0.05). Sequential logistic models evaluating the association of RV systolic dysfunction in T2DM patients showed an improvement in clinical variables (χ2 = 6.2) with the addition of conventional echocardiographic parameters (χ2 = 13.4, P < 0.001) and a further improvement with the addition of GLS (χ2 = 20.8, P < 0.001). CONCLUSION: RV subclinical systolic dysfunction was observed in T2DM patients with preserved LVEF and was associated with LV longitudinal myocardial dysfunction. Our findings may provide additional findings for the management of T2DM patients.

Left Ventricular Longitudinal Myocardial Function of Heart Failure Patients With Transition From Reduced to Preserved Ejection Fraction and of Those With Preserved Ejection Fraction.

Background: Left ventricular (LV) longitudinal myocardial function is associated with the outcomes of heart failure (HF) patients. HF with improved ejection fraction (EF), known as HFimpEF, which is defined as current LVEF >40% but any previously documented LVEF ≤40%, has favorable outcomes compared with HF with preserved EF (HFpEF). However, LV longitudinal myocardial function in patients with previously reduced LVEF (<50%) but improved LVEF to within the normal range (≥50%) (HFnorEF) and its association with cardiovascular events remain unclear. Methods and Results: We studied 70 patients with HFpEF and 65 with HFnorEF. LV longitudinal myocardial function was assessed as global longitudinal strain (GLS). The primary endpoint was defined as cardiovascular death or HF hospitalization during follow-up of 5.6±3.1 years. The GLS of HFpEF patients was significantly lower than that of HFnorEF patients (13.6±3.5% vs. 14.8±2.2%, P=0.02) even when the LVEF was similar. Multivariate Cox proportional hazards analysis showed that GLS was independently associated with cardiovascular events. Furthermore, of the entire study population, patients with GLS >15.0% had fewer cardiovascular events than those without (log-rank P=0.014) among all the patients. Conclusions: LV longitudinal myocardial dysfunction was more frequently observed in patients with HFpEF than in those with HFnorEF, even when LVEF was similar, and was independently associated with cardiovascular events for HF patients with current LVEF ≥50%.

Association of acute improvement in left ventricular longitudinal function after transcatheter aortic valve implantation with outcomes for severe aortic stenosis and preserved ejection fraction.

BACKGROUND: Global longitudinal strain (GLS) is reportedly a sensitive marker for early subtle abnormalities in left ventricular (LV) performance of asymptomatic patients with severe aortic stenosis (AS) and preserved LV ejection fraction (LVEF). For symptomatic patients with severe AS and preserved LVEF, however, the association of immediate improvement in GLS after transcatheter aortic valve implantation (TAVI) with long-term outcomes remains uncertain. METHODS: This study concerned 151 symptomatic patients with severe AS and preserved LVEF who had undergone TAVI. Echocardiography was performed before TAVI and 7 (7-9) days after TAVI. GLS was determined by means of a two-dimensional speckle-tracking strain using current guidelines. The primary endpoint was defined as a composite endpoint comprising cardiovascular death or re-hospitalization for HF after TAVI over a median follow-up period of 27.7 (11.9-51.4) months. RESULTS: Mean LVEF and GLS were 65 ±â€¯7 % and 12.8 ±â€¯3.4 %, respectively. The Kaplan-Meier curve indicated that patients with acute improvement in GLS after TAVI experienced fewer cardiovascular events than those without such improvement (log-rank P = 0.02). Multivariate analysis showed that non-acute improvement in GLS after TAVI was independently associated with worse outcomes as well as deterioration of the mean transaortic pressure gradient. CONCLUSION: Assessment of GLS immediately after TAVI is a valuable additional parameter for better management of symptomatic patients with severe AS and preserved LVEF who are scheduled for TAVI.

Effect of increase in heart rate after anthracycline chemotherapy on subsequent left ventricular dysfunction.

BACKGROUND: Anthracycline chemotherapy-related cardiac dysfunction is believed to be refractory to conventional pharmacological therapy and is associated with a poor prognosis. Increased heart rate (HR) is a known marker of cardiovascular outcomes for various categories of heart failure (HF). However, little interest has been expressed regarding increased HR after anthracycline chemotherapy. Aim of this study was to investigate the effect of increased HR soon after completion of anthracycline chemotherapy on subsequent left ventricular (LV) ejection fraction (LVEF) in cancer patients. METHODS: We studied 172 patients with breast cancer and malignant lymphoma with preserved LVEF (≥ 50 %) and sinus rhythm treated with anthracyclines. Electrocardiography was performed before and soon after completion of anthracycline chemotherapy (2.3 months), and echocardiography before and late after completion of anthracycline chemotherapy (10.5 months). RESULTS: HR significantly increased from 74.2 ±â€¯14.2 bpm to 75.9 ±â€¯13.2 bpm (P = 0.05) soon after completion of anthracycline chemotherapy, while LVEF subsequently significantly decreased from 65.3 ±â€¯5.5 % to 62.4 ±â€¯6.1 % (P < 0.01) late after completion of anthracycline chemotherapy. Patients whose HR increased ≥10 bpm subsequently showed a significantly greater decrease in LVEF than those whose HR increased <10 bpm [-4.9 % (-32.7 % - 10.8 %) vs. -2.2 % (-21.2 % - 12.9 %), p = 0.04]. Multivariable logistic regression analysis showed that an increase in HR soon after completion of anthracycline chemotherapy was independently associated with a subsequent decrease in LVEF (odds ratio: 1.022, 95 % confidential interval; 1.008-1.037, P = 0.002). CONCLUSIONS: Our findings may have a novel effect on the management of cancer patients scheduled for anthracycline chemotherapy.

A novel small compound that promotes nuclear translocation of YB-1 ameliorates experimental hepatic fibrosis in mice.

Transforming growth factor-ß (TGF-ß) is considered to be a major factor contributing to liver fibrosis. We have previously shown that nuclear translocation of YB-1 antagonizes the TGF-ß/Smad3 signaling in regulating collagen gene expression. More recently, we have demonstrated that the novel small compound HSc025 promotes nuclear translocation of YB-1, resulting in the improvement of skin and pulmonary fibrosis. Here, we presented evidence as to the mechanism by which HSc025 stimulates nuclear translocation of YB-1 and the pharmacological effects of HSc025 on a murine model of hepatic fibrosis. A proteomics approach and binding assays using HSc025-immobilized resin showed that HSc025 binds to the amino acid sequence within the C-tail region of YB-1. In addition, immunoprecipitation experiments and glutathione S-transferase pulldown assays identified poly(A)-binding protein (PABP) as one of the cytoplasmic anchor proteins of YB-1. HSc025 directly binds to YB-1 and interrupts its interaction with PABP, resulting in accelerated nuclear translocation of YB-1. Transfection of cells with PABP siRNA promoted nuclear translocation of YB-1 and subsequently inhibited basal and TGF-ß-stimulated collagen gene expression. Moreover, HSc025 significantly suppressed collagen gene expression in cultured activated hepatic stellate cells. Oral administration of HSc025 to mice with carbon tetrachloride-induced hepatic fibrosis improved liver injury as well as the degree of hepatic fibrosis. Altogether, the results provide a novel insight into therapy for organ fibrosis using YB-1 modulators.

Association between diabetic nephropathy and left ventricular longitudinal myocardial function in type 1 diabetes mellitus patients with preserved ejection fraction.

Left ventricular (LV) longitudinal myocardial dysfunction can be observed even in type 2 diabetes mellitus (DM) (T2DM) patients with preserved LV ejection fraction (LVEF), and is considered the earliest marker of DM-related cardiac dysfunction. Furthermore, diabetic nephropathy (DN), a common complication in DM, is strongly associated with LV longitudinal myocardial function in T2DM patients, but its association with type 1 DM (T1DM) has not been fully investigated. We studied 125 asymptomatic T1DM patients with preserved LVEF, and 75 age-, gender-, LVEF-matched non-diabetic healthy controls. Two-dimensional speckle-tracking strain LV was used to assess longitudinal myocardial function as global longitudinal strain (GLS). GLS of T1DM patients was significantly lower than that of normal controls (19.7 ± 3.6% vs. 20.6 ± 1.8%, P = 0.049). GLS of T1DM patients with DN was significantly lower that of T1DM patients without DN (17.3 ± 3.7% vs. 20.2 ± 3.5%, P < 0.001), but that of T1DM patients without DN was similar compared to normal controls (20.6 ± 1.8% vs. 20.2 ± 3.5%, P = 0.37). Moreover, multiple regression analysis identified DN the independent determinant parameters for GLS of T1DM patients also correlated significantly with duration of T1DM. Impaired LV longitudinal myocardial function was observed in asymptomatic T1DM patients with preserved LVEF, and DN was associated with LV longitudinal myocardial dysfunction. These findings are clinically useful for better management of T1DM patients to prevent impending development of cardiovascular disease.

Characteristics of non-valvular atrial fibrillation with left atrial appendage thrombus who are undergoing appropriate oral anticoagulation therapy.

We investigated the characteristics of patients with non-valvular atrial fibrillation (NVAF) and left atrial (LA) appendage (LAA) thrombus who had been given appropriate oral anticoagulation therapy. We studied 737 NVAF patients who were scheduled for catheter ablation or electrical cardioversion. All patients received appropriate oral anticoagulation therapy for at least 3 weeks prior to echocardiography in accordance with the guidelines. Whether LAA thrombus was present or absent on transesophageal echocardiography (TEE) was determined by at least three senior echocardiologists. LAA thrombi were observed in 22 patients (3.0%). Multivariate logistic regression analysis showed that LAA flow and LA volume index were both independent predictors of LAA thrombus formation; however, LAA flow (≤ 18 cm/s) was indicated as a more powerful predictor. Moreover, the prevalence of LAA thrombus formation in patients with NVAF without LA enlargement (LA volume index ≤ 34 mL/m2) was extremely rare (0.4%). LAA thrombus formation in patients with a mildly dilated LA volume index of 34-49.9 mL/m2 and paroxysmal AF was also extremely rare (0.0%). LAA flow is strongly associated with LAA thrombus formation, even in NVAF patients treated with appropriate oral anticoagulation therapy. Augmented oral anticoagulation therapy or transcatheter or surgical LAA closure should be considered for such patients, especially for those with an LAA flow < 18 cm/s. Furthermore, TEE for evaluating LAA thrombus before catheter ablation or electrical cardioversion may be unnecessary for NVAF patients who are undergoing appropriate oral anticoagulation therapy, depending on LA size.

Clinical Features of Spontaneous Isolated Dissection of Abdominal Visceral Arteries.

BACKGROUND: Spontaneous isolated dissection of abdominal visceral arteries without aortic dissection is rare and its pathology and prognosis are not yet clear; therefore, therapeutic strategies for this disease have not been established. The present multi-institution investigational study analyzed the clinical features of patients with spontaneous isolated dissection of abdominal visceral arteries. METHODS: A total of 36 patients diagnosed as spontaneous isolated dissection of abdominal visceral arteries from January 2010 to October 2016 were enrolled. The medical data of the patients were retrospectively reviewed. Imaging characteristics were evaluated. Spontaneous isolated dissection of abdominal visceral arteries was detected on upper abdominal computed tomography examination in almost patients, and was detected on magnetic resonance imaging in one patient. RESULTS: Of the 36 cases, 26 cases involved the superior mesenteric artery dissection, nine involved the celiac artery, two involved the splenic artery, one involved the common hepatic artery, one involved the gastroduodenal artery and one involved the left gastric artery. Among the 36 patients, 20 had hypertension and 14 were current smokers. Additionally, only one patient had diabetes and four patients had dyslipidemia. Moreover, 32 cases complained of pain including abdominal pain and back pain, one had cough and three had no symptoms. Of the 36 patients, 34 cases (94.4%) were treated conservatively, and two (5.6%) required intravascular treatment. All patients were discharged without complications. CONCLUSIONS: Our findings indicate that hypertension and smoking might be closely involved in the pathogenesis of spontaneous isolated dissection of abdominal visceral arteries, whereas dyslipidemia and diabetes might be less involved. Additionally, few asymptomatic patients were accidentally diagnosed, indicating that the absence of symptoms cannot be used to rule out the presence of this disease. Randomized clinical trials cannot be performed because a considerable number of cases are required. Therefore, detailed descriptions of clinical features, as provided in our report, are important.

Antimalarial activity of novel 5-aryl-8-aminoquinoline derivatives.

In an attempt to separate the antimalarial activity of tafenoquine (3) from its hemolytic side effects in glucose-6-phosphate dehydrogenase (G6PD) deficiency patients, a series of 5-aryl-8-aminoquinoline derivatives was prepared and assessed for antimalarial activities. The new compounds were found metabolically stable in human and mouse microsomal preparations, with t(1/2) > 60 min, and were equal to or more potent than primaquine (2) and 3 against Plasmodium falciparum cell growth. The new agents were more active against the chloroquine (CQ) resistant clone than to the CQ-sensitive clone. Analogues with electron donating groups showed better activity than those with electron withdrawing substituents. Compounds 4bc, 4bd, and 4be showed comparable therapeutic index (TI) to that of 2 and 3, with TI ranging from 5 to 8 based on IC(50) data. The new compounds showed no significant causal prophylactic activity in mice infected with Plasmodium berghei sporozoites, but are substantially less toxic than 2 and 3 in mouse tests.

Antitumor agents. Part 218: Cappamensin A, a new In vitro anticancer principle, from Capparis sikkimensis.

A new inhibitor of in vitro tumor cell replication, cappamensin A (1) (2H-1,4-benzoxazin-3(4H)-one, 6-methoxy-2-methyl-4-carbaldehyde), was isolated from the roots of Capparis sikkimensis subsp. formosana using bioactivity-guided fractionation. The structure of 1 was established by spectroscopic methods, including 2D NMR analyses. Compound 1 displayed significant in vitro anticancer activity against ovarian (1A9), lung (A549), ileocecal (HCT-8), breast (MCF-7), nasopharyngeal (KB), and vincristine resistant (KB-VIN) human tumor cell lines with ED(50) values