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Background: It remains controversial whether a cancer history increases the risk of cardiovascular (CV) events among patients with myocardial infarction (MI) who undergo revascularization.Methods and Results: Patients who were confirmed as type 1 acute MI (AMI) by coronary angiography were retrospectively analyzed. Patients who died in hospital or those not undergoing revascularization were excluded. Patients with a cancer history were compared with those without it. A cancer history was examined in the in-hospital cancer registry. The primary outcome was a composite of cardiac death, recurrent type 1 MI, post-discharge coronary revascularization, heart failure hospitalization, and stroke. Among 551 AMI patients, 55 had a cancer history (cancer group) and 496 did not (non-cancer group). Cox proportional hazards model revealed that the risk of composite endpoint was significantly higher in the cancer group than in the non-cancer group (adjusted hazard ratio [HR]: 1.78; 95% confidence interval [CI]: 1.13-2.82). Among the cancer group, patients who were diagnosed as AMI within 6 months after the cancer diagnosis had a higher risk of the composite endpoint than those who were diagnosed as AMI 6 months or later after the cancer diagnosis (adjusted HR: 5.43; 95% CI: 1.55-19.07)., Conclusions: A cancer history increased the risk of CV events after discharge among AMI patients after revascularization.

Objectives: To assess geriatric nutritional risk index (GNRI) in patients with chronic limb-threatening ischemia (CLTI)., Background: The prevalence of CLTI continues to rise, with major amputation and mortality remaining prominent. Frailty is a vital risk factor for adverse outcomes in cardiovascular care. The GNRI is a nutrition-based surrogate for frailty that has been utilized in Southeast Asia to predict adverse events in CLTI. It has not yet been evaluated in a primarily Western population, nor in the context of wound healing., Methods: Between 8August 2017 and April 2019, we identified patients undergoing endovascular interventions for CLTI at our institution, categorized into low GNRI (≤ 94, frail) versus normal GNRI (> 94, reference). We analyzed the risks of major adverse limb events (MALE), its individual components [mortality, major amputation, and target vessel revascularization (TVR)], amputation free survival (AFS), and wound healing using Kaplan-Meier and multivariate cox-proportional hazard regression analyses., Results: A total of 255 patients were included in the analysis, with follow up of 14 ± 9.1 months. Lower GNRI was associated with higher cumulative event rates for MALE (71.0% vs. 43.3%, p <  0.001), mortality (34.3% vs. 15.2%, p < 0.001), major amputation (31.2% vs. 15.8%, p = 0.002), and freedom from AFS (56.0% vs. 28.2%, p < 0.001). There was a trend toward lower TVR and higher wound healing with higher GNRI score., Conclusions: Our single-center, retrospective evaluation of GNRI (as a surrogate for frailty) correlated with increased risks of MALE, mortality, and major amputation. Future directions should focus not only on the recognition of these patients, but risk-factor modification to optimize long-term outcomes., (© 2021 Wiley Periodicals LLC.)

Objective  Although blood thrombogenicity seems to be one of the determinant factors for the development of acute myocardial infarction (MI), it has not been dealt with in-depth. This study aimed to investigate blood thrombogenicity and its change in acute MI patients. Methods and Results  We designed a prospective, observational study that included 51 acute MI patients and 83 stable coronary artery disease (CAD) patients who underwent cardiac catheterization, comparing thrombogenicity of the whole blood between: (1) acute MI patients and stable CAD patients; and (2) acute and chronic phase in MI patients. Blood thrombogenicity was evaluated by the Total Thrombus-Formation Analysis System (T-TAS) using the area under the flow pressure curve (AUC 30 ) for the AR-chip. Acute MI patients had significantly higher AUC 30 than stable CAD patients (median [interquartile range], 1,771 [1,585-1,884] vs. 1,677 [1,527-1,756], p  = 0.010). Multivariate regression analysis identified acute MI with initial TIMI flow grade 0/1 as an independent determinant of high AUC 30 ( β  = 0.211, p  = 0.013). In acute MI patients, AUC 30 decreased significantly from acute to chronic phase (1,859 [1,550-2,008] to 1,521 [1,328-1,745], p  = 0.001). Conclusion  Blood thrombogenicity was significantly higher in acute MI patients than in stable CAD patients. Acute MI with initial TIMI flow grade 0/1 was significantly associated with high blood thrombogenicity by multivariate analysis. In acute MI patients, blood thrombogenicity was temporarily higher in acute phase than in chronic phase., Competing Interests: Conflict of Interest None declared., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. ( https://creativecommons.org/licenses/by/4.0/ ).)

Purpose: To identify lower limb 2-dimensional (2D) perfusion angiographic parameters that are related to skin perfusion pressure (SPP), a predictor of wound healing in patients with chronic limb-threatening ischemia (CLTI) undergoing below-the-knee (BTK) endovascular treatment (EVT). Materials and Methods: Thirty-three consecutive patients (mean age 74.5 years; 18 men) with 47 isolated BTK lesions in 33 limbs (Rutherford category 3-5) underwent EVT. Dorsal and plantar SPPs were measured before EVT and the day after. The indexed blood flow below the ankle was measured using 2D perfusion angiography before and after EVT to determine changes in perfusion parameters [arrival time (AT), time to peak, wash-in rate, mean transit time, and width and area under the time-density curve] at rest vs during hyperemia induced with a 20-mg intra-arterial papaverine infusion. Correlations between the 2D perfusion parameters and SPPs were assessed using the Pearson coefficient. The cutoff points to predict mean SPPs >40 mm Hg were analyzed using a receiver operating characteristic curve; outcomes are reported as the area under the curve (AUC) with 95% confidence interval (CI). Results: After EVT at rest and during hyperemia, only AT was significantly changed, although hyperemia produced significant changes in all the pre-/post-EVT 2D perfusion parameters except the wash-in rate. Dorsal and plantar SPPs after EVT were significantly increased and correlated with hyperemic AT and the AT ratio (hyperemia/at rest values) below the ankle. Hyperemic ATs <6.3 seconds and AT ratios <0.78 were predictive factors for a mean SPP >40 mm Hg, with AUCs of 0.83 (95% CI 0.67 to 0.99) and 0.78 (95% CI 0.61 to 0.95), respectively. Conclusion: Hyperemic ATs <6.3 seconds or AT ratios <0.78 below the ankle may be essential to obtain sufficient SPPs for limb salvage in BTK lesions. Thus, the use of 2D perfusion angiography enabled the monitoring of lower limb tissue perfusion throughout EVT and may thereby optimize treatment of CLTI.

Background: In superficial femoral artery (SFA) stenosis, stenosis resistance may increase, but the relationship between stenosis resistance and stenotic severity remains to be seen. This study aimed to investigate the physiological response, through a hyperemic condition, and the pathophysiological significance of Doppler flow and stenosis resistance in SFA. Methods: Twenty-four limbs with focal stenosis of the SFA were analyzed. We assessed the fractional flow reserve (FFR), hyperemic stenosis resistance (h-SR), and vascular flow reserve (VFR) of the SFA with a pressure/Doppler flow sensor-tipped combination guidewire before and after endovascular therapy (EVT). Results: FFR, h-SR, and VFR changed significantly after EVT. h-SR was more strongly correlated with % area stenosis, measured by intravascular ultrasound than FFR (FFR: r=-0.716, h-SR: r=0.741, p<0.0001, respectively). However, VFR was not associated with % area stenosis. A receiver operating characteristic curve showed cut-offs h-SR >0.36 mmHg·sec/cm, and FFR <0.88 predicted >75% area stenosis with area under curves of 0.883 and 0.828, respectively. Conclusion: h-SR can indicate stenotic severity in an SFA focal lesion more prominently than FFR and may be a new physiological index to determine indication for EVT. VFR was not feasible for assessment in SFA focal stenosis., Competing Interests: Disclosure StatementAll authors have no conflict of interest, (Copyright © 2019 Annals of Vascular Diseases.)

Background: We previously reported that an index of afterload-related left ventricular diastolic function, operant diastolic elastance (Ed)/effective arterial elastance (Ea) = E/e'/(0.9 × systolic blood pressure), was significantly higher in elderly hypertensive women. We aimed to determine sex-related differences in the E/e'-related indices for left ventricular diastolic function and their related factors during admission in patients with heart failure with preserved ejection fraction (HFpEF)., Hypothesis: Elderly HFpEF women exhibit severe left ventricular diastolic dysfunction associated with different left atrioventricular volume ratio., Methods: We divided 267 patients with HFpEF (men/women, 116/151) into two groups by age (≥75 years, n = 212; <75 years, n = 55). We examined the alterations of E/e', E/e'/stroke volume index = Ed, and Ed/Ea, and cardiac structure during admission., Results: Ed and Ea were significantly higher in women than in men, at admission, especially in patients ≥75 years. Before discharge, not only Ed and Ea but also Ed/Ea was significantly higher in women than in men, especially in patients ≥75 years. Elderly female patients had larger left atrial than left ventricular volume., Conclusions: Higher afterload-related left ventricular diastolic elastance, Ed/Ea, in association with higher arterial elastance, Ea, accompanied by left atrioventricular volume mismatch was observed in elderly HFpEF women., (© 2018 Wiley Periodicals, Inc.)

Aim: Maximal hyperemic response, leading to examination of microvascular resistance in lower-limb lesions is not well understood. This study aimed to investigate the infrainguinal arterial physiological response through a hyperemic condition and the pathophysiological significance of microvascular resistance in peripheral artery disease., Methods: Sixteen limbs with focal stenosis of the superficial femoral artery (SFA) and 16 control limbs were analyzed. We assessed the fractional flow reserve (FFR), vascular flow reserve (VFR), and hyperemic microvascular resistance (h-MR) of the SFA with a pressure/Doppler flow sensor-tipped combination guidewire before and after endovascular therapy (EVT). Skin perfusion pressure (SPP) on both the dorsal and the plantar sides of the foot was measured at baseline before and after the endovascular procedures., Results: FFR (p＜0.05) and VFR (p＜0.05), but not h-MR, improved after EVT. There was no association between h-MR and FFR or VFR before EVT. h-MR was negatively correlated with the dorsal SPP before EVT (r=－0.589, p＜0.05). h-MR in patients with high h-MR before EVT significantly decreased after EVT (p＜0.05). Patients with high, but not those with low, h-MR before EVT exhibited a significant increase in dorsal and plantar SPP after EVT (p＜0.05, each)., Conclusion: EVT for SFA stenosis improved FFR and VFR comprehensively, with no apparent change in h-MR. However, high h-MR before EVT may play a predictive role for limb perfusion improvement associated with h-MR reduction after EVT.

It is unclear whether arterial healing occurs beyond 1 year following paclitaxel-coated stent implantation in peripheral artery disease. An 81-year-old woman with superficial femoral artery disease underwent endovascular therapy with a paclitaxel-coated stent. An angiography 21 months later revealed peri-stent contrast staining in the superficial femoral artery, and optical frequency domain imaging demonstrated incomplete stent apposition with significant positive vascular remodeling. High-resolution angioscopy detected positive vascular wall remodeling and in-stent yellow plaque more clearly than conventional angioscopy. Refractory superficial femoral arterial wall healing was apparent more than 20 months after paclitaxel-coated stent implantation.

Background: In patients with atrial fibrillation, ablation decreases left atrial (LA) compliance, which may lead to left ventricular (LV) diastolic dysfunction. We aimed to examine serial changes in LV diastolic function after 2 ablation procedures and their related factors in patients with paroxysmal atrial fibrillation (PAF)., Hypothesis: LV diastolic function is different after 2 ablation procedures., Methods: We enrolled 132 patients with PAF (76 males, mean age 67 years; cryoballoon [CB] ablation/radiofrequency [RF] ablation 60/72) who underwent a single ablation procedure. The transthoracic echocardiographic parameters were obtained before, 3 days after, and 6 months after ablation., Results: The afterload-related index of LV diastolic function, Ed/Ea = E/e' / (0.9 × systolic blood pressure), increased significantly at 3 days after ablation, especially after CB ablation (P <0.05), although no differences were observed in age, sex, LA size, LV size, and E/e' before ablation between CB ablation and RF ablation. Creatine kinase release after ablation was significantly higher in CB ablation than in RF ablation (P <0.001). The increment of Ed/Ea after CB ablation was positively correlated with LV ejection fraction (LVEF) before ablation (r =0.416; P <0.05). The elderly (age ≥ 75 years), females, and patients with hypertension were more likely to show impaired LV diastolic function transiently after 3 days of ablation, but the diastolic index was restored to baseline level after 6 months., Conclusions: The increased Ed/Ea after CB ablation represented transient manifestation of underlying LV diastolic dysfunction in PAF patients with preserved LVEF with older age, female sex, and a history of hypertension., (© 2018 Wiley Periodicals, Inc.)

Background: The mechanisms of heart failure with preserved ejection fraction (HFpEF) need to be clarified immediately.Methods and Results:We examined diastolic function relative to arterial elasticity among hypertensive patients with preserved EF. Diastolic elastance (EdI)/effective arterial elastance (EaI), EdI/EaI=E/e'/(0.9×systolic blood pressure [SBP]) was significantly more impaired in women than in men among patients ≥75 years. The higher EdI/EaI value in elderly women implies they are intermittently exposed to higher left ventricular filling pressure relative to SBP during daily life., Conclusions: Highly fluctuating impairment of diastolic function relative to arterial elasticity may predispose elderly women to pulmonary edema.

The presence of spontaneous echo contrast (SEC) in the left atrium has been reported to be an independent predictor of thromboembolic risk in patients with atrial fibrillation (AF). Dabigatran was associated with lower rates of stroke and systemic embolism as compared with warfarin when administered at a higher dose. Between July 2011 and October 2015, nonvalvular AF patients treated with warfarin or dabigatran who had transesophageal echocardiography prior to ablation therapy for AF were enrolled. The intensity of SEC was classified into four grades, from 0 to 3. Univariate and multivariate analysis was performed to analyze factors associated with SEC. Sixty-five patients were on dabigatran and 65 were on warfarin, with the prothrombin time in therapeutic range. There were no significant differences in the age, CHADS2 score, left atrial dimension, and left atrial appendage flow between the two groups. However, there were more grade 2 or higher patients with left atrial SEC in the warfarin group (n = 20) than in the dabigatran group (n = 2) (p < 0.001). When multivariate regression analysis was performed, grade 2 or higher left atrial SEC was independently associated with no dabigatran usage in addition to high brain natriuretic peptide level and high incidence of diabetes mellitus or persistent AF. Thus, dabigatran exhibited low intensity of left atrial SEC in nonvalvular AF patients as compared with warfarin.

Patients with persistent atrial fibrillation (AF) and a large left atrium are at a high risk for thromboembolisms. Recently, direct oral anticoagulants (DOACs) have mainly been used for the prevention of cardiac embolisms caused by AF. Transesophageal echocardiography (TEE) is performed in order to exclude any left atrial appendage (LAA) thrombi. We herein report two cases of persistent AF, both of which were treated with rivaroxaban for more than two years. Since TEE identified mobile LAA thrombi with this treatment, we switched from rivaroxaban to the direct thrombin inhibitor dabigatran. Dabigatran resolved the LAA thrombi that had been refractory to rivaroxaban.

Aims: The prevalence of left ventricular diastolic dysfunction increases with age, particularly in hypertensive women. We aimed to determine the age- and sex-related differences in diastolic function, and its relation to alterations of cardiac dimensions in a hypertensive population., Methods and Results: We enrolled 479 hypertensive patients with a left ventricular ejection fraction (LVEF) ≥50% (men/women, 267/212) and their echocardiographic parameters regarding LV performance and vascular function were measured. Left atrial volume index (LAVI) and operant diastolic elastance (EdI: E/e'/stroke volume index), but not LV mass index (LVMI), correlated weakly with age in both sexes. The arterial elastance index (EaI) and EdI did not differ significantly between sexes in any of the three age groups (A, <65 years; B, ≥65 years but <75 years; C, age ≥75 years). The EdI indexed to EaI, EdI/EaI = E/e'/(0.9 × systolic blood pressure), was significantly more impaired in women than in men only in group C. There were significant differences in LAVI, LVMI, and EdI/EaI between groups B and C only in women., Conclusions: Impairment of diastolic function relative to arterial elasticity, EdI/EaI, occurred in elderly hypertensive women and was coincident with the alteration of cardiac dimensions. The coincidence with the changes in diastolic function and the alterations of cardiac dimensions occurred in a different time point between the sexes.

The origin and developmental mechanisms underlying coronary vessels are not fully elucidated. Here we show that myocardium-derived angiopoietin-1 (Ang1) is essential for coronary vein formation in the developing heart. Cardiomyocyte-specific Ang1 deletion results in defective formation of the subepicardial coronary veins, but had no significant effect on the formation of intramyocardial coronary arteries. The endothelial cells (ECs) of the sinus venosus (SV) are heterogeneous population, composed of APJ-positive and APJ-negative ECs. Among these, the APJ-negative ECs migrate from the SV into the atrial and ventricular myocardium in Ang1-dependent manner. In addition, Ang1 may positively regulate venous differentiation of the subepicardial APJ-negative ECs in the heart. Consistently, in vitro experiments show that Ang1 indeed promotes venous differentiation of the immature ECs. Collectively, our results indicate that myocardial Ang1 positively regulates coronary vein formation presumably by promoting the proliferation, migration and differentiation of immature ECs derived from the SV.

Treatment of refractory Takayasu arteritis (TA) remains an unresolved clinical issue. Patients usually respond to glucocorticoid (GC) therapy, but often relapse on tapering of the GC dose. The aim of the present study was to assess the safety and efficacy of the interleukin-6 (IL-6) receptor antibody tocilizumab (TCZ) in patients with TA refractory to conventional therapies including GC. Four patients with TA who had shown GC resistance received TCZ infusions (8 mg/kg) every 4 weeks a total of at least 24 times (range, 24 to 51). Clinical symptoms, the serum levels of acute phase proteins and IL-6, GC dosage necessary to maintain remission, and cross-sectional imaging by enhanced CT and MRI were assessed. All patients achieved good clinical response and rapid normalization of the acute phase proteins such as C-reactive protein and serum amyloid A during the therapy with TCZ. The mean dosage of prednisolone could be reduced from 21.3 mg/day to 1.5 mg/day. Although the serum IL-6 level was transiently elevated in all patients after several TCZ infusions, it gradually recovered to the initial level. Along with the decrease of serum IL-6, two patients exhibited significant reduction in thickened arterial lesions. No drug-related adverse effects were noted. In this small group of patients with refractory TA, TCZ therapy was effective and well-tolerated. Further larger studies should be conducted to confirm this finding.

Background: Docking protein Grb2-associated binder 1 (Gab1) has critical roles in signal transduction of various growth factors, cytokines, and numerous other molecules. Our previous reports show that Gab1 is essential for postnatal angiogenesis through the analysis of endothelium-specific Gab1 knockout (Gab1ECKO) mice. However, the role of Gab1 in atherosclerosis remains unknown. The aim of the present study was to elucidate the role of endothelial Gab1 in vascular inflammation and atherosclerosis., Methods and Results: We intercrossed Gab1ECKO mice with apolipoprotein E (ApoE) knockout (ApoEKO) mice. Six-month-old male ApoEKO/Gab1ECKO and littermate control (ApoEKO) mice were treated with angiotensin II (AngII) via an osmotic infusion mini-pump. After AngII treatment, ApoEKO/Gab1ECKO mice showed significantly enhanced atherosclerosis and aneurysm formation compared with control mice. The production of proinflammatory cytokines in the aorta was significantly enhanced in ApoEKO/Gab1ECKO mice compared with control mice. Furthermore, the expression levels of Krüppel-like factor (KLF) 2 (KLF2) and KLF4, key transcription factors for endothelial homeostasis, were significantly reduced in the aortic endothelium of ApoEKO/Gab1ECKO mice compared with those of control mice. Consistently, both vascular cell adhesion molecule-1 expression and macrophage infiltration on the aortic walls were enhanced in ApoEKO/Gab1ECKO mice compared with control mice., Conclusions: Collectively, endothelial Gab1 deletion accelerates AngII-dependent vascular inflammation and atherosclerosis on ApoE-null background presumably in association with downregulation of KLF2 and KLF4.

Objective: We investigated the role of the angiosome concept in endovascular therapy (EVT) for limb salvage., Background: The angiosome concept is clinically useful in bypass surgery for critical limbs ischemia (CLI). However, comparison with direct and indirect flow to the site of ulceration based on angiosome concept regarding freedom from amputation has not been systematically studied for the patient with CLI undergoing EVT., Methods: We analyzed 203 limbs in 177 consecutive patients (male = 127, age = 70 +/- 11 years) with ischemic ulceration that was Rutherford 5 or 6 (5 in 145 limbs and 6 in 58 limbs; pretreatment ankle-brachial index = 0.74 +/- 0.27), who underwent EVT alone without bypass surgery. We classified these patients into direct and indirect groups depending on whether feeding artery flow to the site of ulceration was successfully acquired or not acquired based on the angiosome concept. Freedom from amputation was compared between the direct and the indirect groups by Kaplan-Meier analysis., Results: The overall limb salvage rate was 82% (167/203). Skin perfusion pressure was significantly higher in the direct group (67 +/- 25 mm Hg) than in the indirect group (41 +/- 20 mm Hg, P = 0.002). The limb salvage rate was also significantly (P = 0.03) higher in the direct group (86%) than in the indirect group (69%) for up to 4 years after the procedure. The number of vessels with run-off flow did not influence the limb salvage rate in either the direct group (P = 0.84) or the indirect group (P = 0.90)., Conclusion: Acquiring direct flow based on the angiosome concept is important for limb salvage by EVT in patients with CLI., (Copyright 2010 Wiley-Liss, Inc.)

Background: Although in clinical practice endovascular therapy (EVT) with a nitinol stent for femoro-popliteal artery (FPA) lesions has been widely applied for TASC II A/B lesions, primary patency beyond 2 years remains unknown, as do the factors associated with restenosis., Methods and Results: A prospectively maintained database that included 189 limbs treated with nitinol stents for de novo TASC II A/B FPA lesions was retrospectively analyzed. The outcomes were overall primary and secondary patency during the follow-up period and predictors associated with restenosis. Primary patency overall with nitinol stents was 84%, 82%, 80%, 80% and secondary patency was 96%, 93%, 90%, 90% at 12, 24, 36, 48 months, respectively. Primary patency was not statistically different between the 2 types of nitinol stents (Luminexx vs S.M.A.R.T. Control. stent, P=0.37) during follow-up period. From the multivariate analysis, administration of cilostazol was the strongest independent factor associated with restenosis (P=0.0012)., Conclusions: Nitinol stent implantation for TASC II A/B FPA lesions is suitable and durable in sustaining freedom from restenosis through 4 years of follow-up.

Objectives: We investigated the time course of stent patency in the femoro-popliteal artery for as long as 4 years., Background: Stent fracture has been related to poor 2-year patency in the femoro-popliteal artery., Methods: We studied 239 consecutive patients who underwent provisional de novo stenting with nitinol stents for 333 limbs (Luminexx stent [C. R. Bard, Inc., Murray Hill, New Jersey] in 91 limbs; Smart stent [Cordis Corp., Miami Lakes, Florida] in 242 limbs) from April 2004 to December 2007. Stent fracture was determined by X-ray with multiple projections. Patency was assessed by duplex ultrasonography as peak systolic velocity ratio <2.4 or by angiography (% diameter stenosis <50%). Primary patency in those with and without stent fracture at follow-up was assessed along with factors influencing stent fracture., Results: Primary patency was 81%, 74%, 68%, and 65% at 1, 2, 3, and 4 years, respectively. Stent fracture occurred in 14% (78 of 544) per stent and 17% (55 of 333) per limbs. Stent fracture was significantly associated with multiple stent deployments (with fracture = 2.3 +/- 0.9 stents vs. without fracture = 1.5 +/- 0.7 stents, p < 0.001) and long lesions (with fracture = 208 +/- 84 mm vs. without fracture = 121 +/- 79 mm, p < 0.001). Primary patency was 68% with fracture versus 83% without fracture at 1 year, p = 0.03; 65% versus 75% at 2 years, p = 0.05; 61% versus 69% at 3 years, p = 0.06; and 61% versus 65% at 4 years, p = 0.07. Neither type 1 nor type 3 fracture affected patency, although type 2 showed the worst patency., Conclusions: Stent fracture worsened the patency during the first 2 years, but it did not apparently affect patency beyond 2 years. In particular, complete stent separation did not affect patency.