Tissue salvage of severely ischemic myocardium requires timely reperfusion by thrombolysis, angioplasty, or bypass. However, recovery of left ventricular function is rare. It may be absent or, even worse, reperfusion can induce further damage. Laboratory studies have shown convincingly that reperfusion can increase injury over and above that attributable to the pre-existing ischemia, precipitating arrhythmias, suppressing the recovery of contractile function (“stunning”) and possibly even causing cell death in potentially salvable ischemic tissue. The mechanisms of reperfusion injury have been widely studied and, in the laboratory, it can be attenuated or prevented. Disappointingly, this is not the case in the clinic, particularly after thrombolysis or primary angioplasty. In contrast, excellent results have been achieved by surgeons by means of cardioplegia and hypothermia. For the interventionist, the issue is more complex as, contrary to cardiac surgery where the cardioplegia can be applied before ischemia and the heart can be stopped, during an angioplasty the heart still has to beat to support the circulation. We analyze in detail all these issues.

Cardiovascular disease remains the leading cause of death worldwide and developing novel therapies to treat and cure the disease remains a high priority in the healthcare research community. Adult stem cells were successful in entering numerous clinical trials over the past 15 years in attempts to regenerate the heart. First-generation adult stem cell therapies for myocardial regeneration were highly promising in small animal models but realized benefits in humans were far more modest. Consequently, second-generation therapeutic approaches in early implementation phases have focused on enhancing cellular properties with higher survival and regenerative potential. Genetic programming dictates cellular fate, so understanding genetic composition and responses at the gene level to influence the outcome of the cell is essential for successful outcomes in regenerative medicine. Genetic editing is at the forefront of scientific innovation and as basic scientific research continues to expand upon understanding eukaryotic regenerative themes, a clearer vision of the possible future therapeutic approaches can be realized. Ultimately, enhancing biology and manipulating evolutional selection of cellular properties will be critical to achieving clinically relevant and biologically meaningful cardiac regeneration.

Background:Hematuria is a common and important complication in atrial fibrillation (AF) patients on oral anticoagulation therapy (OAT). This study evaluated the clinical significance of hematuria and its relationship with genitourinary disease in AF patients receiving OAT.

Methods and Results:Among 20,456 consecutive AF patients who visited a tertiary hospital from January 2005 to April 2015, 5,833 had hematuria. Of these 5,833 patients, 3,798 were on OAT (OAT(+) group) and 2,035 were not (OAT(–) group). A total of 1,785 patients from each group were then matched on propensity score analysis. The prevalence of cancer and other diseases in the genitourinary tract was evaluated. While there was no difference in the prevalence of genitourinary stones or urinary tract infection, genitourinary cancer was significantly more common in the OAT(+) group than in the OAT(–) group (1.6% vs. 0.7%, P=0.011). Bladder cancer was the most common genitourinary malignancy, and it was significantly more common in the OAT(+) group (1.2% vs. 0.5%, P=0.019). Subjects on warfarin were more likely to have bladder cancers of lower pathologic grade (63.6% vs. 33.3%, P=0.124).

Conclusions:OAT was associated with a higher prevalence and early detection of genitourinary cancer in AF patients with hematuria. Meticulous evaluation of the cause of hematuria is necessary in AF patients with hematuria receiving OAT.

Background:Tetralogy of Fallot (TOF) is one of the common congenital heart diseases (CHD) in implantable cardioverter defibrillator (ICD) recipients, but few studies have reported the long-term outcomes of and the anti-tachycardia pacing (ATP) efficacy in repaired TOF.

Methods and Results:Twenty-one repaired TOF patients with an ICD implanted between April 2003 and March 2015 were investigated retrospectively. ICD therapy and clinical outcome were analyzed. Mean patient age was 39±11 years; 62% were male; and mean age at repair surgery was 9.4±6.8 years. During a median follow-up of 5.6 years (range, 2.6–8.4 years), no patients died. Appropriate ATP were delivered in 11 patients (52%), with appropriate shocks in 5 patients (24%) and inappropriate shocks in 5 patients (24%). The success rate of ATP was 98% for fast ventricular tachycardia (VT; cycle length ≤320 ms) and 98% for slow VT (cycle length >320 ms). ATP effectiveness increased from 81.5% with the first ATP attempt to 93.7% with the second ATP attempt, to 97.5% with the third ATP attempt, and to 98.6% with the fourth or successive ATP attempt (P<0.0001, Cochran-Armitage trend test).

Conclusions:ATP was highly effective in repaired TOF regardless of VT cycle length. Multiple ATP attempts could have an important role in VT termination, and the novel subcutaneous ICD without ATP capability should be used carefully.

Background:Clinical outcome after pulmonary vein isolation (PVI) may be linked to both durability of PVI and the antral lesion size. Data on balloon-guided technologies are scarce. We investigated the size of the isolated surface area (ISA) acutely after PVI achieved by cryoballoon (CB) or laser balloon (LB), both using voltage mapping.

Methods and Results:In 40 patients (73% male, mean age 66±9 years), a bipolar voltage map before and after PVI in sinus rhythm was acquired to delineate the isolated antral surface area (IASA, contiguous area of low voltage <0.5 mV) and the ISA (relative size of the low-voltage area in relation to the whole antral surface area including the posterior wall). IASA (CB: 57±14 cm²vs. LB: 42±15 cm²; P=0.002) as well as ISA (65±8% vs. 54±10%; P=0.001) were significantly larger in the CB than in the LB group. No periprocedural complications occurred. During a mean follow-up of 326±142 days, 4/20 and 5/20 patients experienced an AF/AT recurrence in the CB and LB groups, respectively. No differences in clinical outcome were observed between patients with a large (≥55%) or small (<55%) ISA.

Conclusions:Balloon-guided PVI is associated with antral lesion formation. CB-guided PVI is associated with the largest ISA as compared with LB procedures. ISA size did not correlate with clinical outcome after a single procedure in the present study population.

Background:Only a few studies have addressed the optimal start time for oral anticoagulants (OACs) after acute ischemic stroke in patients with nonvalvular atrial fibrillation (NVAF). The aim of this retrospective study was to analyze the time of OAC administration after stroke onset.

Methods and Results:This study included 300 patients with NVAF who had acute ischemic stroke and were treated with OACs between April 2012 and March 2016. We investigated the time at which OACs were started by anticoagulant type and the relationship between the time of OAC administration and stroke severity (the National Institutes of Health Stroke Scale [NIHSS] score on admission). Of the 300 patients, 114 and 186 patients received warfarin and direct-acting OACs (DOACs), respectively. Patients in the DOAC group had OAC initiated therapy significantly sooner (3 days) than in the warfarin group (7 days; P<0.001). With regard to stroke severity (NIHSS score <8, mild; 8–16, moderate; >16, severe), the median time for starting therapy was 2, 7, and 11 days for mild, moderate, and severe stroke, respectively. Hemorrhagic events occurred in 3 patients in the warfarin group; however, no hemorrhagic events occurred in the DOAC group.

Conclusions:Our study revealed that neurologists began OACs earlier in patients with mild acute cerebral infarction. Even in patients with severe stroke, OACs were started earlier than expected.

Background:The prognostic impact of atrial fibrillation (AF) among patients at high risk for heart failure (HF) remains unclear. In addition, there is no risk estimation model for AF development in these patients.

Methods and Results:The present study included 5,382 consecutive patients at high risk of HF enrolled in the CHART-2 Study (n=10,219). At enrollment, 1,217 (22.6%) had AF, and were characterized, as compared with non-AF patients, by higher age, lower estimated glomerular filtration rate, higher B-type natriuretic peptide (BNP) level and lower left ventricular ejection fraction. A total of 116 non-AF patients (2.8%) newly developed AF (new AF) during the median 3.1-year follow-up. AF at enrollment was associated with worse prognosis for both all-cause death and HF hospitalization (adjusted hazard ratio (aHR) 1.31, P=0.027 and aHR 1.74, P=0.001, for all-cause death and HF hospitalization, respectively) and new AF was associated with HF hospitalization (aHR 4.54, P<0.001). We developed a risk score with higher age, smoking, pulse pressure, lower eGFR, higher BNP, aortic valvular regurgitation, LV hypertrophy, and left atrial and ventricular dilatation on echocardiography, which effectively stratified the risk of AF development with excellent accuracy (AUC 0.76).

Conclusions:These results indicated that AF is associated with worse prognosis in patients at high risk of HF, and our new risk score may be useful to identify patients at high risk for AF onset.

Background:Regional variations in health-care delivery, processes and spending have been reported across the world. Differences in revascularization procedures have been observed in the USA and Canada, but little is known about regional variation in revascularization procedures in Japan.

Methods and Results:Diagnostic procedure combination summary tables for 2013 issued by the Japanese government were used. The rates of percutaneous coronary intervention (PCI) per 100,000 population aged ≥40 years in each prefecture were summarized by angina and myocardial infarction (MI). Linear regression analysis was performed to investigate the factors associated with regional variation in the rate of PCI for angina. The mean PCI rates were 189 and 67 per 100,000 population for angina and MI, respectively. The ratios between the highest and lowest regions were 4.9-fold in angina and 1.8-fold in MI. The factor most associated with generating regional variation in the use of PCI for angina was the rate of coronary angiography (CAG; P<0.001).

Conclusions:Wide regional variation was observed in the use of PCI both for angina and for MI. The variation was larger for angina, in which PCI were mostly elective and positively associated with the use of CAG. Further research is needed to prevent overuse and underuse of PCI to ensure more appropriate health-care delivery and to control health-care expenditure.

Background:Cardiogenic shock (CS) is a strong predictor of mortality in patients with ST-elevation myocardial infarction (STEMI), but there is evidence that shock index (SI), taking into account both blood pressure and heart rate, is a more sensitive and powerful predictor. We investigated the independent impact of SI and CS on 30-day and 1-year mortality in patients with STEMI, treated by primary percutaneous coronary intervention (PCI).

Methods and Results:In 7,412 consecutive patients with STEMI treated with primary PCI, the predictive value of either SI or CS on 1-year mortality was assessed. Best cut-off value of SI, determined using receiver operating characteristic (ROC) curve, was 0.7, with an ROC AUC of 0.66 (95% CI: 0.65–0.67), compared with an ROC AUC of 0.60 (95% CI: 0.59–0.61) for CS (P<0.001). At admission, 387 patients (5.2%) had CS and 1,567 patients (21.1%) had SI ≥0.7. The adjusted hazard ratio of mortality in patients with SI ≥0.7 and in CS patients was, respectively, 3.3 (95% CI: 2.4–4.6) and 3.1 (95% CI: 2.1–4.6) after 30 days, and 2.3 (95% CI: 1.8–2.9) and 3.1 (95% CI: 2.2–4.2) after 1 year.

Conclusions:SI identifies more patients with increased risk of mortality, and seems to be a more sensitive prognostic predictor than CS in patients with STEMI treated by primary PCI.

Background:Constrictive pericarditis (CP) is characterized by impaired diastolic cardiac function leading to heart failure. Pericardiectomy is considered effective treatment for CP, but data on long-term clinical outcomes after pericardiectomy are limited.

Methods and Results:We retrospectively investigated 45 consecutive patients (mean age, 59±14 years) who underwent pericardiectomy for CP. Preoperative clinical factors, parameters of cardiac catheterization, and cardiac events were examined. Cardiac events were defined as hospitalization owing to heart failure or cardiac death.Median follow-up was 5.7 years. CP etiology was idiopathic in 16 patients, post-cardiac surgery (CS) in 21, tuberculosis-related in 4, non-tuberculosis infection-related in 2, infarction-related in 1, and post-radiation in 1. The 5-year event-free survival was 65%. Patients with idiopathic CP and tuberculosis-related CP had favorable outcomes compared with post-CS CP (5-year event-free survival: idiopathic, 80%; tuberculosis, 100%; post-CS, 52%). Higher age (hazard ratio: 2.51), preoperative atrial fibrillation (3.25), advanced New York Heart Association class (3.92), and increased pulmonary artery pressure (1.06) were predictors of cardiac events. Patients with postoperative right-atrial pressure ≥9 mmHg had lower event-free survival than those with right-atrial pressure <9 mmHg (39% vs. 75% at 5 years, P=0.013).

Conclusions:Long-term clinical outcomes after pericardiectomy among a Japanese population were related to the underlying etiology and the patient’s preoperative clinical condition. Postoperative cardiac catheterization may be helpful in the prediction of prognosis after pericardiectomy.

Background:Obesity has been correlated with various adverse events in patients who receive left ventricular assist devices (LVAD). In this study, we sought to further characterize the role of obesity in this patient population.

Methods and Results:We performed a retrospective analysis of 164 patients implanted with a HeartMate II from August 2008 to December 2014. Patients were categorized into 2 BMI groups based on WHO guidelines: BMI 18.5–30 kg/m²(n=99) and BMI >30 kg/m²(n=65). Patient demographics, adverse outcome and long-term survival were compared between the 2 groups. For any outcome associated with BMI groups, we performed a Cox regression to identify confounding comorbidities. Preoperative demographics and comorbidities were similar. Patients with BMI >30 were younger (P=0.01) and had a higher incidence of type 2 diabetes (P=0.01). While rate of pump thrombosis was higher among patients with BMI >30 (P=0.02), overall survival at 2 years did not differ. The most common cause of death was hemorrhagic stroke in the obese group. On multivariable cox regression analysis, BMI was an independent risk factor of pump thrombosis.

Conclusions:Higher BMI does not reduce survival after VAD implantation but it does appear to increase the risk of pump thrombosis. Further studies to characterize the role of BMI in survival and thrombosis rates are warranted.

Background:The cardiovascular prognosis of heart failure with preserved ejection fraction (HFpEF) has been shown to be similar to that of heart failure with reduced ejection fraction (HFrEF). It is unknown which factors predict cardiovascular outcome in HFpEF. We tested the hypothesis that the abnormal pattern of circadian blood pressure (BP) rhythm known as the riser BP pattern is associated with adverse outcomes in HFpEF.

Methods and Results:We performed a prospective, observational cohort study of hospitalized HF patients who underwent ambulatory BP monitoring (ABPM). Five hundred and sixteen hospitalized HF patients (age, 69±13 years; male, n=321 [62%]; female, n=195 [38%]) were followed up for a median 20.9 months. The composite outcome consisting of all-cause mortality and cardiovascular events was observed in 220 patients. On Kaplan-Meier analysis, the riser BP pattern subgroup had a significantly higher incidence of the composite outcome than the other subgroups of HFpEF patients (HR, 3.01; 95% CI: 1.54–6.08, P<0.01), but not the HFrEF patients.

Conclusions:The riser BP pattern was found to be a novel predictor of cardiovascular outcome in HFpEF patients.

Background:In the EMPA-REG OUTCOME^®trial, empagliflozin added to standard of care reduced the risk of 3-point major adverse cardiovascular (CV) events (3-point MACE: composite of CV death, non-fatal myocardial infarction, or non-fatal stroke) by 14%, CV death by 38%, hospitalization for heart failure by 35%, and all-cause mortality by 32% in patients with type 2 diabetes (T2DM) and established CV disease. We investigated the effects of empagliflozin in patients of Asian race.

Methods and Results:Patients were randomized to receive empagliflozin 10 mg, empagliflozin 25 mg, or placebo. Of 7,020 patients treated, 1,517 (21.6%) were of Asian race. The reduction in 3-point MACE in Asian patients was consistent with the overall population: 3-point MACE occurred in 79/1,006 patients (7.9%) in the pooled empagliflozin group vs. 58/511 patients (11.4%) in the placebo group (hazard ratio: 0.68 [95% confidence interval: 0.48–0.95], P-value for treatment by race interaction (Asian, White, Black/African-American): 0.0872). The effects of empagliflozin on the components of MACE, all-cause mortality, and heart failure outcomes in Asian patients were consistent with the overall population (P-values for interaction by race >0.05). The adverse event profile of empagliflozin in Asian patients was similar to the overall trial population.

Conclusions:Reductions in the risk of CV outcomes and mortality with empagliflozin in Asian patients with T2DM and established CV disease were consistent with the overall trial population.

Background:Sodium bicarbonate and ascorbic acid have been proposed to prevent contrast-induced nephropathy (CIN). The present study evaluated the effect of their combined use on CIN incidence.

Methods and Results:We prospectively enrolled 429 patients with chronic kidney disease (CKD: baseline estimated glomerular filtration rate <60 mL/min/1.73 m²) prior to elective coronary catheterization. CIN was defined as absolute (≥0.5 mg/dL) or relative (≥25%) increase in serum creatinine within 72 h. In the saline hydration (n=218) and combined sodium bicarbonate+ascorbic acid (n=211) groups, a total of 1,500–2,500 mL 0.9% saline was given before and after the procedure. In addition, the combination group received 20 mEq sodium bicarbonate and 3 g ascorbic acid i.v. before the procedure, followed by 2 g ascorbic acid after the procedure and a further 2 g after 12 h. There were no significant differences between the basic characteristics and contrast volume in the 2 groups. CIN occurred in 19 patients (8.7%) in the saline group, and in 6 patients (2.8%) in the combined treatment group (P=0.008).

Conclusions:Combined sodium bicarbonate and ascorbic acid could prevent CIN following catheterization in CKD patients.