Rationale and Design of Prospective, Multicenter, Double-Arm Clinical Trial to Investigate the Efficacy of Tofogliflozin on Left Ventricular Diastolic Dysfunction in Patients with Heart Failure with Preserved Ejection Fraction and Type 2 Diabetes Mellitus (TOP-HFPEF Trial).

BACKGROUND: Recent large clinical trials have revealed that sodium-glucose cotransporter 2 (SGLT2) inhibitors improve cardiovascular outcomes not only in patients with heart failure with reduced ejection fraction, but also in patients with heart failure with mildly reduced or preserved ejection fraction (HFpEF). However, the effect of SGLT2 inhibitors on left ventricular (LV) diastolic function is still controversial. METHODS AND RESULTS: The TOP-HFPEF trial (Efficacy of Tofogliflozin on Left Ventricular Diastolic Dysfunction in Patients with Heart Failure with Preserved Ejection Fraction and Type 2 Diabetes Mellitus) is a multicenter, double-arm, open-label, confirmatory, investigator-initiated clinical study to investigate the effect of SGLT2 inhibitor on LV diastolic function in patients with HFpEF and type 2 diabetes mellitus. The participants are randomly assigned (1:1) to the tofogliflozin group (20 mg once daily) or the control group (administration or continuation of antidiabetic drugs other than SGLT2 inhibitors). The estimated number of patients to be enrolled in this trial is 90 in total (45 in each group). The participants are followed up for 52 weeks with tofogliflozin or control drugs. The primary endpoint is the change in E/e' assessed by echocardiography from the baseline to the end of this study (52 weeks). This trial will also evaluate the effects of tofogliflozin on cardiovascular events, biomarkers, other echocardiographic parameters, the occurrence of atrial fibrillation, and renal function. CONCLUSIONS: The TOP-HFPEF trial will clarify the efficacy of an SGLT2 inhibitor, tofogliflozin, on LV diastolic function in patients with HFpEF and type 2 diabetes mellitus.

Atrial ectopy after pulmonary vein isolation and left heart reverse remodeling in patients with atrial fibrillation.

BACKGROUND: Maintenance of sinus rhythm after pulmonary vein isolation (PVI) for atrial fibrillation (AF) is associated with left atrial (LA) and ventricular (LV) reverse remodeling, although the degree varies among individuals. We hypothesized that frequent premature atrial complex (PAC) after PVI may attenuate the left heart reverse remodeling benefited from maintenance of sinus rhythm. METHODS: We included 82 AF patients who underwent first-time PVI and 24-h Holter recordings at 6 months after PVI. All patients had no AF recurrence before this time. The number of PAC was categorized into tertiles: <90, 90-488 and >488 PACs/day. All patients underwent two-dimensional echocardiography and serum plasma B-type natriuretic peptide (BNP) measurement before and 6 months after PVI. LA reverse remodeling was defined as ≥15% decrease in LA volume index. RESULTS: There was no significant difference in the baseline characteristics among the PAC tertiles except for sex. Six months after PVI, LA volume index, LV mass index, and serum BNP levels were significantly decreased in lower and middle PAC tertiles (all P < .05), whereas no significant changes were observed in upper PAC tertile. Frequency of LA reverse remodeling was significantly lower in upper tertile of PAC compared with middle and lower tertiles (22.2%, 57.1%, and 59.3%, P < .001). Baseline LA volume index, changes in LV mass index, and the frequency of PAC were independently associated with LA reverse remodeling (all P < .05). CONCLUSIONS: Frequent PAC after PVI was associated with less left heart reverse remodeling in AF patients even without AF recurrence.

High-sensitive cardiac troponin T as a novel predictor for recurrence of atrial fibrillation after radiofrequency catheter ablation.

AIMS: We aimed to determine whether elevated serum high-sensitive cardiac troponin T (hs-TnT) levels predict atrial fibrillation (AF) recurrence after pulmonary vein isolation (PVI). METHODS AND RESULTS: We included 125 consecutive patients with AF (paroxysmal, n = 79; persistent, n = 46) who underwent first-time PVI. Serum hs-TnT, high-sensitive C-reactive protein (hs-CRP), atrial natriuretic peptide, and plasma B-type natriuretic peptide levels were measured in venous samples collected before PVI. Elevated hs-TnT was diagnosed in patients with levels ≥0.014 µg/L. All patients underwent multidetector computed tomographic examinations before PVI to measure left atrial volume (LAV) and left ventricular (LV) mass, which were indexed to body surface area. Arrhythmia recurrence was defined as AF/atrial tachycardia episodes lasting for ≥30 s after a 2-month blanking period from the PVI procedure. Elevated hs-TnT levels were observed in 22 (17.6%) patients. Age, diabetes mellitus, LV mass index, estimated glomerular filtration rate, and hs-CRP were independently associated with serum hs-TnT levels (all P < 0.05). During a mean follow-up of 12.9 ± 8.5 months after a single PVI procedure, the clinical recurrence rate was 33% (n = 41). Multivariate Cox proportional hazard analysis revealed that a greater LAV index (P = 0.01) and elevated serum hs-TnT level (P = 0.01) were significant predictors of AF recurrence after PVI. CONCLUSION: This study demonstrated that elevated serum hs-TnT levels are associated with AF recurrence independent of traditional risk factors and left atrial enlargement.

Pre-Procedural Serum Atrial Natriuretic Peptide Levels Predict Left Atrial Reverse Remodeling After Catheter Ablation in Patients With Atrial Fibrillation.

OBJECTIVES: This study aimed to investigate the role of atrial natriuretic peptide (ANP) levels to predict left atrial (LA) reverse remodeling in atrial fibrillation (AF) patients. BACKGROUND: Although LA reverse remodeling after radiofrequency catheter ablation (RFCA) for AF was reported to be associated with favorable outcomes and improvement of LA and left ventricular function, the predictor has not been extensively evaluated. METHODS: This study included 104 consecutive patients who underwent RFCA for AF. All patients underwent multidetector computed tomography examination and laboratory tests, including measurement of ANP, plasma B-type natriuretic peptide (BNP), and high-sensitivity C-reactive protein (hs-CRP) levels before and 6 months after RFCA. The study population was divided according to the extent of the decrease in the LA volume index at follow-up; responders were defined as patients who exhibited a ≥15% decrease in the LA volume index. RESULTS: At follow-up, 49 patients (47%) were classified as responders. Pre-procedural serum ANP and BNP levels were significantly higher in the responders than in the nonresponders (both p < 0.01). In the responders, a significant decrease was observed in the log ANP, log BNP, and log hs-CRP levels from baseline to follow-up (all p < 0.01). Multivariate linear regression analysis revealed that log ANP levels before RFCA and maintenance of sinus rhythm during follow-up were independent predictors of LA reverse remodeling (both p < 0.01). CONCLUSIONS: In this study, 47% of the patients exhibited LA reverse remodeling after RFCA for AF, with a concomitant improvement in serum ANP, BNP, and hs-CRP levels. The pre-procedural ANP level and maintenance of sinus rhythm were independently associated with LA reverse remodeling.

Comparison of determinations of left atrial volume by the biplane area-length and Simpson's methods using 64-slice computed tomography.

OBJECTIVES: There is increasing evidence that left atrial (LA) size is an important predictor of adverse cardiovascular outcomes such as atrial fibrillation, stroke, and congestive heart failure. The aim of this study was to determine whether there is a difference in results of quantification of LA volume by the area-length and Simpson's methods using multislice computed tomography (MSCT). METHODS AND RESULTS: The study population consisted of 51 patients with sinus rhythm (sinus group) and 20 patients with atrial fibrillation (af group) clinically indicated for MSCT angiography for evaluation of coronary arteries. Maximum LA volume, obtained at end-systole from the phase immediately preceding mitral valve opening, was measured using the area-length and Simpson's methods. In the sinus group, the mean LA volumes, indexed to body surface area, were 48.4+/-17.9 ml/m(2) with the area-length method and 48.3+/-17.0 ml/m(2) with the Simpson's method. In the af group, the mean indexed LA volumes with the area-length method and the Simposon's method were 91.5+/-47.5 ml/m(2) and 90.3+/-45.9 ml/m(2), respectively. LA volumes calculated by the area-length method exhibited a strong linear relationship and agreement with those calculated using Simpson's method in both the groups (sinus group: r=0.99, P<0.0001, af group: r=0.99, P<0.0001). CONCLUSIONS: The area-length method is a simple and reproducible means of assessment of LA volume. Standardization of LA volume assessment using MSCT is important for serial follow-up and meaningful communication of results of testing among institutions and physicians.

Assessment of aortic atheromatous plaque and stiffness by 64-slice computed tomography is useful for identifying patients with coronary artery disease.

BACKGROUND: With multislice computed tomography (MSCT) it is possible to visualize the coronary arteries, as well as the aorta, in a single computed tomography scan. Using MSCT, atherosis and sclerosis of the descending thoracic aorta (DTA) were quantified and differences between patients with and without coronary artery disease (CAD) were analyzed. METHODS AND RESULTS: The population comprised 89 patients who underwent ECG-gated MSCT: 40 patients with suspected CAD by MSCT underwent invasive coronary angiography, and had documented significant stenoses (CAD group), 49 patients did not have significant stenoses (control group). Twenty cross-sectional images of DTA were reconstructed every 5% (0-95%) of the RR interval, and the largest and smallest luminal areas were traced. Atheromatous score and stiffness beta of DTA were quantified; both were significantly higher in the CAD group than in the controls. Multivariate analysis revealed that the average atheromatous score was an independent factor associated with CAD (p<0.005). CONCLUSION: This study demonstrates that atherosis and sclerosis of DTA are associated with CAD. In cases with image quality that is unsatisfactory for interpretation of coronary stenoses, additional assessment of atherosclerosis of the DTA will be useful for identifying patients with CAD.

Small coronary calcium deposits and elevated plasma levels of oxidized low density lipoprotein are characteristic of acute myocardial infarction.

AIM: Predictions of the onset of acute myocardial infarction (AMI) in high risk individuals are of great clinical importance. Among various risk factors, elevated levels of oxidized low density lipoprotein (ox-LDL) in plasma have been shown to reflect unstable coronary plaques. Coronary calcification is a common finding in the elderly, however, its clinical implications as a risk factor for plaque rupture are controversial. This study was designed to investigate the clinical implications of plasma ox-LDL levels and coronary calcification detected by electron-beam computed tomography (EBCT), by comparing patients with AMI with those with stable angina pectoris (SAP). METHODS: We measured plasma ox-LDL levels in AMI (n=34) and SAP (n=49) patients. In addition, a coronary calcium score was quantified with the Agatston system. The total coronary calcium score (TCS) was defined as the sum of the scores for each lesion. RESULTS: TCS and total calcium area were significantly smaller in patients with AMI than in those with SAP. On the other hand, plasma ox-LDL levels were significantly higher in AMI patients than in SAP patients (p<0.0005). CONCLUSION: These results suggest that a combined assessment of coronary calcium and plasma ox-LDL levels may be useful for screening patients with unstable coronary plaques.

Morphological but not functional changes of the carotid artery are associated with the extent of coronary artery disease in patients with preserved left ventricular function.

BACKGROUND AND PURPOSE: The atherosclerotic process is associated with both morphological and functional changes in the carotid artery. We evaluated the relationship between these parameters of the carotid artery and the extent of coronary artery disease (CAD) in patients with preserved left ventricular function. METHODS: The study population consisted of 104 stable patients with CAD who had preserved left ventricular function (left ventricular ejection fraction >or=45%). All patients underwent carotid ultrasound for evaluation of carotid artery plaque score defined by the sum of plaque thickness, maximum percent area stenosis, and carotid arterial stiffness index beta calculated by a combination of changes in carotid arterial diameter and blood pressure. RESULTS: Plaque score and percent area stenosis correlated with the extent of CAD defined as the number of diseased coronary vessels (P<0.001 and 0.002, respectively), but arterial stiffness beta did not (P=0.39). Using logistic regression analyses adjusting for confounding coronary risk factors and arterial stiffness beta, plaque score and percent area stenosis were independently correlated with multivessel CAD (P=0.001 and 0.004, respectively). CONCLUSIONS: Carotid artery plaque burden, but not arterial stiffness, is associated with the extent of CAD, suggesting morphological rather than functional changes in the carotid artery may be a more accurate predictor of the extent of CAD and multivessel CAD independent of left ventricular function.

Elevated plasma levels of oxidized low-density lipoprotein relate to the presence of angiographically detected complex and thrombotic coronary artery lesion morphology in patients with unstable angina.

BACKGROUND: Increased levels of oxidized low-density lipoprotein (ox-LDL) are related to plaque instability, so the aim of the present study was to investigate whether there is a relationship between angiographic coronary plaque morphology in patients with unstable angina pectoris (UAP) and the level of ox-LDL. METHODS AND RESULTS: Plasma ox-LDL levels were measured in 149 patients with UAP and in 88 control subjects, using a highly sensitive enzyme-linked immunosorbent assay method. Angiographic morphology of the culprit lesion was classified as either simple or complex based on the Ambrose classification. Plasma ox-LDL levels in patients with Braunwald class III were significantly higher than in patients with class I (p<0.0001) or in control subjects (p<0.0001). In each of the 3 Braunwald classes, plasma ox-LDL levels in patients with a complex lesion were significantly higher than in patients with a simple lesion. Multivariate logistic regression analysis revealed that ox-LDL level and Braunwald class III were independent factors associated with angiographically detected complex lesions. CONCLUSION: In each Braunwald class of UAP, elevated plasma levels of ox-LDL closely relate to the presence of angiographically detected complex and thrombotic lesion morphology.

Risk stratification in patients with Brugada syndrome: analysis of daily fluctuations in 12-lead electrocardiogram (ECG) and signal-averaged electrocardiogram (SAECG).

INTRODUCTION: Risk stratification between symptomatic and asymptomatic patients with Brugada syndrome is not yet established. We compared daily fluctuations in 12-lead electrocardiogram (ECG) and signal-averaged ECG (SAECG) characteristics between symptomatic and asymptomatic patients with Brugada syndrome to identify new markers for distinguishing between high- and low-risk patients. METHODS AND RESULTS: Thirty-five patients with Brugada syndrome underwent ECG and SAECG simultaneously at least 4 times every 3 months. We evaluated daily fluctuations (differences between maximum and minimum values) in ECG and SAECG characteristics and compared them between symptomatic (N = 11), and asymptomatic (N = 24) patients. On ECG, the daily fluctuations in r-J interval (interval from QRS onset to J point) in leads V1, V2, and V6 were significantly larger in symptomatic than in asymptomatic patients (V1; 20 +/- 6 vs 10 +/- 8 msec, P < 0.01, V2; 22 +/- 8 vs 11 +/- 4 msec, P < 0.01, and V6; 24 +/- 7 vs 14 +/- 7 msec, P < 0.01). On SAECG, daily fluctuations in filtered QRS (f-QRS) duration and LAS40 were significantly larger in symptomatic than in asymptomatic patients (f-QRS; 15 +/- 7 vs 9 +/- 4 msec, P < 0.05, and LAS40; 21 +/- 7 vs 10 +/- 6 msec, P < 0.05). CONCLUSIONS: Instability of depolarization appears to be related to the risk of fatal ventricular arrhythmias in patients with Brugada syndrome. Daily fluctuations in ECG and SAECG characteristics could be useful for distinguishing between high- and low-risk patients with Brugada syndrome.

Method analysis for optimal continuous imaging using intravascular optical coherence tomography.

OBJECTIVES: Optical coherence tomography(OCT)is a high-resolution imaging method that can clearly visualize vessels through the displacement of blood with flushing agents. Continuous imaging methods have not been established. This study investigated optimal methods for continuous OCT imaging. METHODS: Thirty-four arteries with stent implantation (24 peripheral and 10 coronary arteries)in 14 pigs were examined using OCT with a motorized pullback device. Two imaging methods (flush alone by liquid substance and flush with occlusion) were compared. Adequate image acquisition was defined as the entire circumferential intimal layer being detectable within continuous segments. To investigate factors that could influence image quality, stented regions were divided into 4-5 mm segments. RESULTS: The flush with occlusion method provided better OCT images compared to flush alone (flush with occlusion: 60.9%, flush alone: 8.7%, p = 0.0002). Using the flush with occlusion method, the rate of adequate image acquisition was 64.4% and visualization of > 75% intimal circumference was 83.5%. Intravascular ultrasound could detect all stented regions. Segmental analyses found more adequate images were detected in smaller vessels (adequate segment: 3.8 +/- 0.4 mm, inadequate segment: 4.2 +/- 0.8 mm, p < 0.0001) or with centered image wire position (adequate segment: center 35%, inadequate segment: center 14%, p = 0.003). In addition, side branches did not affect image quality. CONCLUSIONS: To acquire continuous OCT images, the flush with occlusion method was more effective compared to flush alone. Moreover, image quality is affected by vessel size and imaging wire position. These results suggest that optimized OCT imaging can provide continuous vessel detection.

Comparison of levels of serum matrix metalloproteinase-9 in patients with acute myocardial infarction versus unstable angina pectoris versus stable angina pectoris.

Matrix metalloproteinases (MMPs) are important for resorption of extracellular matrixes and may degrade the fibrous cap of an atherosclerotic plaque, thus contributing to coronary plaque rupture. Histologic studies have shown MMP expression in lesions of acute coronary syndrome. In this study, we evaluated the relation between plaque morphology as obtained by intravascular ultrasound before percutaneous coronary intervention and serum MMP levels in patients who had coronary artery disease. We enrolled consecutive 47 patients who had acute myocardial infarction (AMI), 23 who had unstable angina pectoris (UAP), and 19 who had stable effort angina pectoris and underwent intravascular ultrasound before percutaneous coronary intervention followed by successful primary percutaneous coronary intervention. Peripheral blood was obtained from all patients before angiography and serum levels of MMP-1,-2, and -9 were analyzed. Serum levels of MMP-9 in the AMI and UAP groups were significantly higher than that in the stable effort angina pectoris group (p = 0.007 and 0.04, respectively). From the intravascular ultrasound findings before percutaneous coronary intervention, plaque rupture was detected in 26 patients (55%) in the AMI group and in 11 patients (48%) in the UAP group. In these 2 groups, patients with plaque rupture had significantly higher levels of MMP-9 than patients who did not have plaque rupture (p = 0.03 and 0.01, respectively). Multiple logistic regression analysis showed that MMP-9 was the only independent predictor of plaque rupture (p = 0.004). In conclusion, high levels of MMP-9 in patients who have AMI and UAP are related to the presence of plaque rupture in the culprit lesion.

Acute myocardial infarction: clinical characteristics and plaque morphology between expansive remodeling and constrictive remodeling by intravascular ultrasound.

BACKGROUND: According to recent intravascular ultrasound (IVUS) studies, expansive remodeling (ER) at the culprit lesion has been observed in almost 50% of patients with acute coronary syndrome and constrictive remodeling (CR) in 30%. The purpose of this study is to investigate the difference between ER and CR at the culprit lesion in patients with acute myocardial infarction (AMI). METHODS AND RESULTS: Preinterventional IVUS images of 73 patients with AMI were identified. The remodeling index (RI) was defined as the ratio of the external elastic membrane (EEM) areas at the culprit lesion to the EEM areas at the proximal reference site. Expansive remodeling was defined as an RI > 1.05; CR, as an RI < 0.95. In patients with AMI, 40 patients (55%) showed ER on IVUS, whereas CR was observed in 18 patients (25%). Patients with ER were significantly older than those with CR (P < .005). The frequency of the presence of calcifications was higher in patients with ER than in those with CR (P < .0005). In patients with AMI with ER, soft plaque with small calcium was the most frequent (58%). Multivariate analysis revealed that age and the presence of calcifications remained as independent predictors of ER. CONCLUSIONS: These findings suggest that ER relates to old age and calcification, and CR may contribute to early plaque progression than ER in patients with AMI.

Spotty calcification typifies the culprit plaque in patients with acute myocardial infarction: an intravascular ultrasound study.

BACKGROUND: Calcification is a common finding in human coronary arteries; however, the relationship between calcification patterns, plaque morphology, and patterns of remodeling of culprit lesions in a comparison of patients with acute coronary syndromes (ACS) and those with stable conditions has not been documented. METHODS AND RESULTS: Preinterventional intravascular ultrasound (IVUS) images of 178 patients were studied, 61 with acute myocardial infarction (AMI), 70 with unstable angina pectoris (UAP), and 47 with stable angina pectoris (SAP). The frequency of calcium deposits within an arc of less than 90 degrees for all calcium deposits was significantly different in culprit lesions of patients with AMI, UAP, and SAP (P<0.0001). Moreover, the average number of calcium deposits within an arc of <90 degrees per patient was significantly higher in AMI than in SAP (P<0.0005; mean+/-SD, AMI 1.4+/-1.3, SAP 0.5+/-0.8). Conversely, calcium deposits were significantly longer in SAP patients (P<0.0001; mean+/-SD, AMI 2.2+/-1.6, UAP 1.9+/-1.8, and SAP 4.3+/-3.2 mm). In AMI patients, the typical pattern was spotty calcification, associated with a fibrofatty plaque and positive remodeling. In ACS patients showing negative remodeling, no calcification was the most frequent observation. Conversely, SAP patients had the highest frequency of extensive calcification. CONCLUSIONS: Our observations show that IVUS allows the identification of vulnerable plaques in coronary arteries, not only by identifying a fibrofatty plaque and positive remodeling, but also by identifying a spotty pattern of calcification.

Impact of HMG-CoA reductase inhibitors for non-treated coronary segments.

BACKGROUND: HMG-CoA reductase inhibitors (statin) have been reported to decrease coronary artery events in several angiographic studies. However, the mechanism by which statin achieve this is still unclear. The purpose of this study was to identify the effect of statin on coronary plaque using serial intravascular ultrasound analysis. METHODS AND RESULTS: In this study, 48 patients with 48 lesions were divided into the prescribed group (statin group, n = 22) or the non-prescribed group (control group, n = 26) after successful coronary artery stenting. IVUS images were obtained at consecutive 5 mm segments, 5 mm from the proximal stent edge, immediately after stenting and at 6 months follow up. External elastic membrane volume (EEMV), lumen volume (LV) and plaque volume (PV) were measured using Simpson's method. The control group revealed no significant serial change in EEMV, PV, and LV during 6 months. On the other hand, the statin group revealed significant reductions of PV (35.5 +/- 12.7 mm3 vs 30.9 +/- 15.6 mm3, p = 0.001), resulting in increase of LV (47.7 +/- 19.8 mm3 vs 52.5 +/- 22.2 mm3, p = 0.003) without EEMV change (82.8 +/- 21.8 mm3 vs 83.9 +/- 25.7 mm3, p = NS). Although percent EEMV and percent LV changes showed no differences between the two groups, a larger percent PV change was observed in the statin group compared to the control group (control; 5.8 +/- 20.3% vs statin; -20.4 +/- 21.8%, p = 0.02). CONCLUSION: The results of this study suggest that statin administration for 6 months reduces coronary plaque without positive vessel remodeling.

Marked improvement of left ventricular function after parathyroidectomy in a hemodialysis patient with secondary hyperparathyroidism and left ventricular dysfunction.

A 52-year-old woman, a hemodialysis patient, was admitted because of exertional dyspnea. Echocardiography showed left ventricular (LV) dilatation and reduced contraction. Coronary angiography showed no fixed stenosis. She had elevated levels of parathyroid hormone (PTH) as a result of secondary hyperparathyroidism with advanced renal failure. After parathyroidectomy, marked improvement of LV function following immediate decrease of blood levels of PTH was observed. It is suggested that PTH might have a significant role in the pathogenesis of LV dysfunction and that parathyroidectomy might be effective as a therapy for heart failure in some patients with secondary hyperparathyroidism and LV dysfunction.