Peripheral artery disease (PAD) affects more than 200 million adults worldwide. Patients with lower extremity PAD have a heightened risk for cardiovascular events because of the systemic nature of atherosclerosis, and benefit from treatment with risk factor-modifying therapies. Limb symptoms in PAD include intermittent claudication and diminished walking ability. Arterial obstruction from atherosclerotic lesions initiates limb ischemia; however, decreased perfusion incompletely determines the clinical expression of PAD and its response to therapy. Potential mechanistic drivers of claudication in addition to arterial obstruction include inflammation, vascular dysfunction, reduced microvascular flow, impaired angiogenesis, and altered skeletal muscle function. An improved understanding of the pathophysiology of limb symptoms has the potential to accelerate development of novel therapeutic strategies to increase functional capacity in patients with PAD.

It is almost a quarter of century that a pioneering work of 2 researchers named Brugada brought the entire scientific community to understanding the molecular, clinical, and electrophysiological aspects of a distinctive syndrome. It affects mainly young adults with syncope and/or sudden cardiac death caused by polymorphic ventricular tachycardia or ventricular fibrillation in the absence of any sign of cardiac degeneration or alteration. Although the involvement of the epicardial layer of the right ventricular outflow tract, and the requirement of pharmacologic challenge for unveiling concealed forms, have been fully characterized, many areas of uncertainties remain to be elucidated, such as the unpredictable usefulness of programmed ventricular stimulation, the role of radiofrequency catheter ablation for reducing ST-segment elevation, and the value of risk stratification in patients diagnosed with upper displacement of right precordial leads. How much Brugada syndrome is an intense field of research is witnessed by 4 different consensus committees that took place in a relatively short period of time considering the recent discovery of this intricate arrhythmogenic disease. The main focus of this review is to describe the milestones in Brugada syndrome from its first phenotypic and genotypic appraisals to recent achievements in electrical therapies proposed for the management of this fascinating rhythm disturbance that, despite new diagnostic and therapeutic learnings, still predisposes to sudden cardiac death.

Background:Although there have been several reports on the risk factors associated with intima-media thickness (IMT), many questions remain. The purpose of this study was to investigate the association between IMT and cardiovascular risk factors in a Japanese general population.

Methods and Results:The study group consisted of 1,583 male subjects undergoing routine health checkups. IMT of the common carotid artery was measured by high-resolution ultrasonography. Brachial-ankle pulse wave velocity (baPWV) was measured using an automated device. Univariate analysis demonstrated that carotid IMT significantly associated with age, body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), baPWV, fasting glucose, low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and high-density lipoprotein cholesterol (HDL-C). Multiple logistic regression analysis for carotid atherosclerosis (carotid IMT ≥1.0 mm) was performed using obesity (BMI ≥25.0 kg/m²), high BP (SBP ≥130 mmHg or DBP ≥85 mmHg), dyslipidemia (LDL-C ≥140 mg/dL, TG ≥150 mg/dL, or HDL-C <40 mg/dL), impaired fasting glucose (IFG) (fasting glucose ≥110 g/dL), and high baPWV (≥1,400 cm/s). Carotid atherosclerosis was significantly associated with only high baPWV (OR: 2.22, 95% CI: 1.24–4.17, P<0.01).

Conclusions:High baPWV was a stronger predictor of early carotid atherosclerosis than high BP, dyslipidemia, or IFG in a Japanese general male population.

Background:Vascular calcification is a major complication in chronic kidney disease (CKD) that increases the risk of adverse clinical outcomes. Geriatric nutritional risk index (GNRI) is a simple nutritional assessment tool that predicts poor prognosis in elderly subjects. The purpose of the present study was to evaluate the correlation between GNRI and severity of vascular calcification in non-dialyzed CKD patients.

Methods and Results:We enrolled 323 asymptomatic CKD patients. To evaluate abdominal aortic calcification (AAC), we used aortic calcification index (ACI) determined on non-contrast computed tomography. The patients were divided into three groups according to GNRI tertile. Median ACI significantly decreased with increasing GNRI tertile (15.5%, 13.6%, and 7.9%, respectively; P=0.001). On multivariate regression analysis GNRI was significantly correlated with ACI (β=−0.15, P=0.009). We also investigated the combination of GNRI and C-reactive-protein (CRP) for predicting the severity of AAC. Low GNRI and high CRP were significantly associated with severe AAC, compared with high GNRI and low CRP (OR, 4.07; P=0.004).

Conclusions:GNRI was significantly associated with AAC in non-dialyzed CKD patients.

Background:Brugada-type ECG (Br-ECG) is occasionally observed during acute myocardial ischemia of the right ventricular outflow tract (RVOT). No studies have explored, however, the association of ventricular tachyarrhythmia and development of Br-ECG due to acute ischemia of the RVOT.

Methods and Results:The study included 13 consecutive patients with acute ischemia of the RVOT during coronary catheterization. Patients were divided into 2 groups: those with Br-ECG (group B) and those without (group N). The proportion of male patients was higher in group B than in group N (100% vs. 25%, P<0.01), and VT/VF developed in only patients with Br-ECG (group B). In group B, VT/VF was observed in patients without pre-existing organic change in the conus/right ventricular (RV) branch of the right coronary artery and no VT/VF was seen in patients with organic coronary stenosis despite Br-ECG.

Conclusions:Acute myocardial ischemia of the RVOT caused Br-ECG predominantly in male patients and subsequent development of VT/VF in some patients. VT/VF was seen in patients without any obstructive lesion but arrhythmic events were not observed in RVOT ischemia in the case of pre-existing coronary occlusion or stenosis of the conus or RV branch, suggesting the effects of precondition.

Background:The aim of this study was to compare early and late outcomes of tricuspid valve replacement (TVR) and tricuspid valve repair (TVr) for severe tricuspid regurgitation (TR).

Methods and Results:From 1994 to 2012, 360 patients (mean age, 58±13 years) with severe TR underwent TVR (n=97, 27%) or TVr (n=263, 73%). Among them, 282 patients (78%) had initial rheumatic etiology, and 307 patients (85%) had preoperative atrial fibrillation. The TVR group had higher total bilirubin, higher baseline central venous pressure, and higher incidence of previous cardiac operation. There was no difference in early mortality (TVR:TVr, 3.1%:3.4%, P=0.877). Ten-year overall survival (TVR:TVr, 72%:70%, P=0.532) and 10-year freedom from cardiac death (TVR:TVr, 76%:77%, P=0.715) were not significantly different between groups. After applying stabilized inverse probability of treatment weighting methods, there were still no significant differences in early mortality (P=0.293), overall survival (P=0.649) or freedom from cardiac death (P=0.870). Higher NYHA functional class, total bilirubin (>2 mg/dL), initial central venous pressure, and cardiopulmonary bypass time were independent predictors of early mortality. Older age, LV dysfunction (EF <40%), and hemoglobin <10 g/dL were independent predictors of late cardiac mortality.

Conclusions:Compared with TVr, TVR had acceptable early and late outcomes in patients with severe TR. TVR can be considered as a valid option with acceptable clinical outcomes in patients who are not suitable candidates for TVr.

Background:The neurohumoral and endothelial responses to the blood pressure (BP) lowering effects of heated water-based exercise (HEx) in resistant hypertension (HT) patients remain undefined.

Methods and Results:We investigated these in 44 true resistant HT patients (age 53.3±0.9 years, mean±SEM). They were randomized and allocated to 2 groups, 28 to a HEx training protocol, which consisted of callisthenic exercises and walking in a heated pool for 1 h, three times weekly for 12 weeks and 16 patients to a control group maintaining their habitual activities. Measurements made before and after 12 weeks of HEx included clinic and 24-h BP, plasma levels of nitric oxide, endothelin-1, aldosterone, renin, norepinephrine and epinephrine, as well as peak V̇O₂, and endothelial function (reactive hyperemia). After 12 weeks of HEx patients showed a significant decrease in clinic and 24-h systolic and diastolic BPs. Concomitantly, nitric oxide increased significantly (from 25±8 to 75±24 μmol/L, P<0.01), while endothelin-1 (from 41±5 to 26±3 pg/mL), renin (from 35±4 to 3.4±1 ng/mL/h), and norepinephrine (from 720±54 to 306±35 pg/mL) decreased significantly (P<0.01). Plasma aldosterone also tended to decrease, although not significantly (from 101±9 to 76±4 pg/mL, P=NS). Peak V̇O₂increased significantly after HEx (P<0.01), while endothelial function was unchanged. No significant change was detected in the control group.

Conclusions:The BP-lowering effects of HEx in resistant HT patients were accompanied by a significant reduction in the marked neurohumoral activation characterizing this clinical condition.

Background:Ultrasound measurements of the inferior vena cava (IVC) diameter (IVCD), together with its respiratory variation, provide a noninvasive estimate of right atrial pressure (RAP). However, there is a paucity of studies that have compared this technique with simultaneous catheterization. We explored the best cut-off values of IVC parameters for elevated RAP in comparison with RAP measured by catheterization.

Methods and Results:We prospectively enrolled 120 East Asian patients who were scheduled for catheterization. The IVCD and IVC collapsibility index (IVCCI) were measured according to the current guidelines. The optimal maximum IVCD (IVCDmax) and IVCCI cut-offs for detecting elevated RAP (RAP ≥10 mmHg) were 17 mm and 40%, respectively. When we combined both in proportion to the guidelines, the sensitivity and specificity for detecting elevated RAP were 75% and 94%, respectively. When the cut-off values from the current guidelines (>21 mm and <50%) were applied, the respective sensitivity and specificity were 42% and 99%. Interestingly, the cut-off value of the optimal IVCDmax indexed by body surface area (11 mm/m²) was similar to previous Western population data. When we combined both cut-off values (11 mm/m²and 40%), the sensitivity and specificity were 75% and 95%, respectively.

Conclusions:The optimal absolute IVCDmax and IVCCI cut-offs to detect elevated RAP were smaller than those in the current guidelines. Indexed IVCDmax may be an IVC parameter that can be used internationally.

Background:In patients with myocardial infarction (MI), microvascular obstruction (MVO) determined by cardiac magnetic resonance imaging (CMR) is associated with left ventricular (LV) remodeling and worse prognosis.

Methods and Results:In 71 patients with ST-segment elevation MI (STEMI) treated by primary percutaneous coronary intervention (PCI), speckle tracking echocardiography (STE) and CMR were performed early after PCI. All patients underwent CMR at 6 months after hospital discharge to assess the occurrence of LV remodeling. The values of 3-dimensional (3D)-circumferential strain (CS), area change ratio (ACR), and 2-dimensional (2D)-CS were significantly different for the transmural extent of infarct, whereas the values of 3D- and 2D- longitudinal strain (LS) were not significantly different. In transmural infarct segments, the values of 3D-CS and ACR were significantly lower in segments with MVO than in those without MVO. At 6-month follow-up, LV remodeling was observed in 22 patients. In multivariable logistic regression models, global 3D-CS and ACR were significant determinants of LV remodeling rather than the number of MVO segments.

Conclusions:Regional 3D-CS and ACR reflected the transmural extent of infarct and were significantly associated with the presence of MVO. In addition, global 3D-CS and ACR were preferable to the extent of MVO in the prediction of LV remodeling.

Background:The relationship between time of onset of acute myocardial infarction (MI) and long-term clinical outcome has not been completely understood. We hypothesized that morning onset acute MI may be associated with adverse cardiac events.

Methods and Results:This study involved 663 patients who underwent primary percutaneous coronary intervention (PCI). The main outcome measures were cardiac death, recurrent acute coronary syndrome (ACS), and re-hospitalization for heart failure. Major adverse cardiac events (MACE) were defined as a composite of individual adverse outcomes. Morning onset acute MI occurred in 212 patients (32.0%); they had higher rates of recurrent ACS (13% vs. 8%, P=0.03) and MACE (21% vs. 14%, P=0.012) than the patients with other times of onset. The PCI rate for progressive lesions was also higher than for patients with other times of onset (23% vs. 14%, P=0.013). On multivariate Cox regression analysis, morning onset was an independent predictor of recurrent ACS, MACE, and PCI for progressive lesions, with adjusted hazard ratios of 1.34 (95% CI: 1.06–2.92, P=0.030), 1.51 (95% CI: 1.02–2.23, P=0.038), and 1.58 (95% CI: 1.03–2.42, P=0.037), respectively.

Conclusions:Morning onset may be associated with increased risk of recurrent ACS and coronary atherosclerosis progression.

Background:The force-frequency relation (FFR) is a hemodynamic index of the chronotropic relationship between left ventricular (LV) systolic function (percent change in dP/dt_max) and elevation of heart rate. FFR is a marker of myocardial contractile reserve and follows an upward slope in healthy myocardium [monophasic FFR (MoF)], a pattern that becomes biphasic (BiF) under pathological conditions. However, it remains uncertain whether the FFR determines a patient’s prognosis. We investigated the promising role of the FFR as a predictor of cardiac events in the setting of hypertrophic cardiomyopathy (HCM).

Methods and Results:A total of 113 consecutive patients with HCM (New York Heart Association (NYHA) class I–II) were retrospectively evaluated; 27 (23.9%) had a BiF pattern and they experienced a higher incidence of cardiac events compared with those showing an MoF pattern (median follow-up, 4.7 years; P<0.001). Furthermore, Cox proportional hazard regression analysis revealed that the LV end-diastolic volume index (hazard ratio: 1.051, P=0.014) and BiF pattern (hazard ratio: 15.260, P=0.001) were independent predictors of primary cardiac events. Interestingly, abnormal reductions in myocardial regulatory molecules related to contractility (SERCA2α) were observed exclusively in the patients exhibiting a BiF pattern.

Conclusions:The FFR reflects latent myocardial abnormalities and predicts cardiac events in the setting of HCM, even during the asymptomatic stages of the disease.

Background:The impact of endovascular revascularization of the lower extremity arteries with atherectomy (AT) compared with percutaneous transluminal angioplasty (PTA) is still unclear. Therefore, the aim of the study was to compare long-term outcomes after percutaneous PTA and AT in patients requiring endovascular revascularization.

Methods and Results:This was a single-center, retrospective registry of obstructive and symptomatic PAD patients who underwent endovascular revascularization. PTA was performed in 215 patients, and AT in 204 (Silver Hawk, EV3, n=125; CSI 360°, n=66; Pathway Medical Technologies, n=13). There were no significant between-group differences in baseline characteristics except for increased CAD, dialysis and CLI prevalence in the PTA group. Following propensity score analysis 131 well-matched pairs were included in analysis. Bail-out stenting was more frequent in the reference group (PTA, 6.1% vs. AT, 0%; P=0.004). At 6- and 12-month follow-up there were no differences in TLR between the groups (PTA, 8.3% vs. AT, 5.3%; P=0.47; and PTA, 16.7% vs. AT, 13.7%; P=0.73, respectively). The difference was in favor of AT at 24-month follow-up (PTA, 29.0% vs. AT, 16.7%; P=0.05). No difference was observed in amputation rate (PTA, 0.7% vs AT, 1.5%; P=0.62). On Kaplan-Meier analysis there were no significant differences between groups in time to TLR, amputation or death.

Conclusions:AT was associated with lower risk of TLR, and this should be confirmed in randomized controlled trials.

Background:Patients with pulmonary arterial hypertension (PAH) are currently treated with combination therapy of PAH-targeted drugs. Reverse right ventricular (RV) remodeling after lung transplantation (LTx) in patients with end-stage PAH despite combination therapy of PAH-targeted drugs has not been fully elucidated.

Methods and Results:A total of 136 patients, including 32 with PAH, underwent LTx from 1998 to 2014. We enrolled 12 consecutive patients with PAH treated with combination therapy of PAH-targeted drugs who underwent LTx and retrospectively analyzed the temporal and serial changes in hemodynamics and echocardiography before LTx and at 3 and 12 months after LTx. Before LTx, the RV was markedly dilated with substantially reduced RV fractional area change (RVFAC). At 3 months after LTx, pulmonary artery pressure, pulmonary vascular resistance and RV stroke work index were significantly decreased, while left ventricular stroke work index was increased. RV size assessed by echocardiography also significantly decreased and RVFAC improved. At 12 months after LTx, RVFAC was further increased and RV wall thickness was decreased significantly.

Conclusions:Although severe RV dysfunction and dilation were observed in patients with end-stage PAH despite combination therapy of PAH-targeted drugs, RV function and morphology were improved after reduction of RV pressure load by LTx.

Background:In Japan, warfarin treatment at prothrombin time-international normalized ratio (PT-INR) of 1.60–2.60 is recommended for elderly patients with nonvalvular atrial fibrillation (NVAF). But it remains unknown whether PT-INR 1.60–1.99 has a similar effect on stroke severity as a value >2.0. The purpose of this study was to clarify the association between infarct volume and PT-INR levels.

Methods and Results:The 180 patients (mean age, 76 years [SD, 10 years], 53% male) selected from 429 consecutive ischemic stroke patients admitted within 48 h of onset between 2004 and 2014 with NVAF were included. We classified them into 4 groups according to their PT-INR values on admission: no warfarin (NW), 129 patients; PT-INR <1.60 (poor control: PC), 29 patients; PT-INR 1.60–1.99 (low-intensity control: LC), 14 patients; and PT-INR ≥2.00 (high-intensity control: HC), 8 patients. Median (interquartile range: IQR) of infarct volume was 55 mL (IQR 14–175) in the NW, 42 mL (IQR 27–170) in the PC, 36 mL (IQR 6–130) in the LC, and 11 mL (IQR 0–39) in the HC groups. The infarct volume of the HC group was significantly smaller than in the other 3 groups, but no difference existed between the LC and PC groups or the LC and NW groups.

Conclusions:Warfarin control at PT-INR of 1.60–1.99 is not effective for reducing the severity of ischemic stroke in NVAF patients.

Background:Dual antiplatelet therapy (DAPT) is commonly used after transcatheter aortic valve implantation (TAVI); however, the supporting evidence is limited. To determine if aspirin alone is a better alternative to DAPT, we compared the outcomes of patients treated with DAPT or aspirin alone after TAVI.

Methods and Results:We analyzed a total of 144 consecutive patients (92 females, mean age 83±6 years) who underwent implantation of a balloon-expandable transcatheter valve (SAPIEN or SAPIEN XT, Edwards Lifesciences). Patients were divided into DAPT (n=66) or aspirin-alone treatment groups (n=78). At 1 year after TAVI, the composite endpoint, which consisted of all-cause death, myocardial infarction, stroke, and major or life-threatening bleeding complications, occurred significantly less frequently (Kaplan-Meier analysis) in the aspirin-alone group (15.4%) than in the DAPT group (30.3%; P=0.031). Valve function assessed by echocardiography was similar between the 2 treatment groups with respect to effective orifice area (1.78±0.43 cm²in DAPT vs. 1.91±0.46 cm²in aspirin-alone group; P=0.13) and transvalvular pressure gradient (11.1±3.5 mmHg in DAPT vs. 10.3±4.1 mmHg in aspirin-alone group; P=0.31).

Conclusions:Treatment with aspirin alone after TAVI had greater safety benefits and was associated with similar valve function as DAPT. These results suggest that treatment with aspirin alone is an acceptable regimen for TAVI patients.

Background:Alamandine is a newly discovered component of the renin-angiotensin system, which regulates blood pressure. In this study, the effect of alamandine on cardiovascular parameters in two-kidney, one clip (2K1C) hypertensive rats and normotensive rats, and the possible roles of the angiotensin II type 1 receptor (AT1R) and the PD123319-sensitive receptors in mediating this effect was investigated.

Methods and Results:The cardiovascular parameters were monitored for 10 min before the infusion of the drugs or saline, and for 30 min afterward. In the 2K1C hypertensive rats, alamandine caused brief increases in mean arterial pressure (MAP), left-ventricular systolic pressure (LVSP) and maximum rate of pressure change in the left ventricle (dP/dt(max)). This was followed by decreases in these parameters, which extended throughout the remainder of the infusion period. Losartan, an AT1R blocker, abolished alamandine’s initial pressor effect and PD123319, which can block AT2R and Mas-related G protein-coupled receptor D (MrgD) receptors, partially decreased the late depressor effect. Left ventricular end-diastolic pressure (LVEDP) decreased during alamandine infusion; this effect was reduced by PD123319. In the normotensive rats, alamandine increased MAP, LVSP, dP/dt (max), and it decreased LVEDP during the infusion period. These effects of alamandine were reduced by losartan.

Conclusions:The results of this investigation suggest that, under normal conditions, alamandine acts via AT1R, but in pathological conditions such as hypertension, its effect on PD123319-sensitive receptors masks its effect on AT1R.