Dipeptidyl peptidase IV (DPP-IV) is a complex enzyme that acts as a membrane-anchored cell surface exopeptidase and transmits intracellular signals through a small intracellular tail. DPP-IV exists in human blood in a soluble form, and truncates a large number of peptide hormones, chemokines, cytokines, and growth factors in vitro and in vivo. DPP-IV has gained considerable interest as a therapeutic target, and a variety of DPP-IV inhibitors that prolong the insulinotropic effects of glucagon-like peptide-1 (GLP-1) are widely used in clinical settings as antidiabetic drugs. Indeed, DPP-IV is upregulated in proinflammatory states, including obesity and cardiovascular disease with and without diabetes mellitus. Consistent with this maladaptive role, DPP-IV inhibitors seem to exert a protective role in cardiovascular disease. In addition to their GLP-1-dependent vascular protective actions, DPP-IV inhibitors exhibit GLP-1-independent beneficial effects on angiogenesis/neovascularization via several signaling pathways (e.g., stromal cell-derived factor-1α/C-X-C chemokine receptor type-4, vascular endothelial growth factor-A/endothelial nitric oxide synthase, etc.). This review focuses on recent findings in this field, highlighting the role of DPP-IV in therapeutic angiogenesis/neovascularization in ischemic heart disease and peripheral artery disease.
The 66thAnnual Scientific Sessions and Expo of the American College of Cardiology (ACC) were held at the Walter E. Washington Convention Center, Washington DC, from March 17thto 19th, 2017. This meeting offered 23 Late-Breaking Clinical Trial (LBCT) presentations, 17 Featured Clinical Research presentations with and without LBCT, and 2,572 abstracts presented in oral and poster sessions by over 2,000 experts. This report presents the highlights of this meeting, including the opening showcase, several important LBCTs and some international joint symposiums.
Background:Distinction of paroxysmal atrial fibrillation (PAF) from non-PAF is important in clinical practice, but this is often difficult at the time of first documented AF. Given that fibrillation cycle length (FCL) is longer in PAF than in non-PAF, the aim of this study was to compare various clinical parameters including FCL to establish a scoring system to distinguish PAF and non-PAF.
Methods and Results:The subjects consisted of 382 consecutive patients with AF on digital ECG at the present institute between 2008 and 2011. They were divided into PAF and non-PAF groups according to the following clinical course. Propensity score matching yielded 88 matched patient pairs with similar mean age and gender between the 2 groups. FCL was evaluated using customized fibrillation wave analyzer with fast Fourier transform analysis. On multivariate analysis, higher HR, longer FCL, and smaller LAD were independent predictors of PAF. For the scoring, cut-offs for each parameter were determined according to highest sensitivity and specificity on the ROC curves, and 1 point assigned for each parameter. Using this scoring system, 2 points detected PAF with 64% sensitivity and 84% specificity.
Conclusions:We propose a scoring system including FCL to distinguish PAF from non-PAF. Further studies are needed to validate the results.
Background:The characteristics and prognosis of implanted pacemaker-identified new-onset atrial fibrillation (AF) in Japanese people has not been well evaluated.
Methods and Results:A total of 395 consecutive patients with newly implanted pacemakers were retrospectively analyzed between January 2010 and December 2015 at Yokohama City University Hospital. Patients with a prior history of AF, VVI mode pacemaker, congenital heart disease, severe valvular heart disease, and cardiovascular surgery before pacemaker implantation were excluded. Among the remaining patients, 44 (21.3%) developed new AF during follow-up (mean follow-up, 1,115±651 days; range, 9–2,176 days). Patients with new-onset AF had a significantly higher CHADS2score (2.09±1.27 vs. 1.31±1.08, P<0.001) and CHA2DS2-VASc score (3.00±1.39 vs. 2.26±1.19, P<0.001) compared with those without new-onset AF. On Cox regression analysis only age at implantation was significantly correlated with new-onset AF. Interestingly, the incidence of hospitalization due to heart failure was significantly higher in the new-onset AF than in the without new-onset AF group.
Conclusions:A total of 21.3% of pacemaker-implanted patients with high CHADS2and CHA2DS2-VASc scores developed new-onset AF during a mean follow-up of 3.1 years; and pacemaker-identified AF was associated with an increased risk of worsening heart failure.
Background:Serum alkaline phosphatase (ALP) is related to vascular calcification. In a recent study on percutaneous coronary intervention (PCI) with a drug-eluting stent, higher ALP was associated with poor clinical outcomes in terms of mortality, myocardial infarction, and stent thrombosis. The aim of this study was to evaluate the relationship between preoperative ALP and clinical outcome of off-pump coronary artery bypass surgery (OPCAB).
Methods and Results:We retrospectively enrolled and reviewed a total of 1,335 patients who underwent OPCAB. Patients were divided into tertiles based on preoperative serum ALP (<60, 60–76, and >76 IU/L). As preoperative ALP increased, the HR of mortality remained constant after adjusting for confounders. On Cox proportional hazards regression analysis, there was no association between ALP and all-cause mortality. The adjusted HR for all-cause mortality for the middle tertile was 0.882 (95% CI: 0.592–1.314, P=0.537), and 0.915 (95% CI: 0.605–1.383, P=0.672) for the highest tertile. In addition, no associations between ALP and cardiovascular mortality, myocardial infarction, revascularization, or major adverse cardiac events were found.
Conclusions:Unlike after PCI, high ALP is not related to adverse clinical events, such as mortality, myocardial infarction, or revascularization after OPCAB. ALP might be considered when determining the optimal revascularization technique.
Background:New-onset diabetes mellitus (DM) can occur as a serious complication after heart transplantation, but the comparative data on its clinical impact on survival and on transplant-related adverse events are limited.
Methods and Results:We reviewed a total of consecutive 391 patients aged ≥17 years undergoing isolated orthotopic heart transplantation at the present institution from 1992 to 2013. The entire cohort was divided into 3 groups: (1) no diabetes (n=257); (2) pre-existing DM (n=46); and (3) new-onset DM (n=88). Early and long-term clinical outcomes were compared across the 3 groups. Early death occurred in 8 patients (2.0%). Of the 345 non-diabetic patients before transplantation, 88 (25.5%) developed new-onset DM postoperatively. During follow-up, 83 (21.2%) died. On time-varying Cox analysis, new-onset DM was associated with increased risk for overall death (HR, 2.11; 95% CI: 1.26–3.55) and tended to have a greater risk for severe chronic kidney disease (HR, 1.77; 95% CI: 0.94–3.44). Compared with the no-diabetes group, the new-onset DM group had a worse survival rate (P=0.035), but a similar survival rate to that of the pre-existing DM group (P=0.364).
Conclusions:New-onset DM has a negative effect on long-term survival and kidney function after heart transplantation. Further studies are warranted to evaluate the relevance of early diagnosis and timely control of new-onset DM to improve long-term survival.
Background:Door-to-balloon (DTB) time ≤90 min is an important quality indicator in the management of ST-elevation myocardial infarction (STEMI), but a considerable number of patients still do not meet this goal, particularly in countries outside the USA and Europe.
Methods and Results:We analyzed 2,428 STEMI patients who underwent primary PCI ≤12 h of symptom onset who were registered in an ongoing prospective multicenter database (JCD-KiCS registry), between 2008 and 2013. We analyzed both the time trend in DTB time within this cohort in the registry, and independent predictors of delayed DTB time >90 min. Median DTB time was 90 min (IQR, 68–115 min) during the study period and there were no significant changes with year. Predictors for delay in DTB time included peripheral artery disease, prior revascularization, off-hour arrival, age >75 years, heart failure at arrival, and use of IABP or VA-ECMO. Notably, high-volume PCI-capable institutions (PCI ≥200/year) were more adept at achieving shorter DTB time compared with low-volume institutions (PCI <200/year).
Conclusions:Half of the present STEMI patients did not achieve DTB time ≤90 min. Targeting the elderly and patients with multiple comorbidities, and PCI performed in off-hours may aid in its improvement.
Background:The goal of this study was to examine the association of serum γ-glutamyltransferase (GGT) levels with left ventricular (LV) diastolic dysfunction and LV hypertrophy.
Methods and Results:A cross-sectional study of 79,459 Korean men and women who underwent an echocardiography as part of a comprehensive health examination between March 2011 and December 2014. The presence of LV diastolic dysfunction and LV hypertrophy was determined using echocardiography. Of the subjects, 5,447 had LV diastolic dysfunction and 2,070 had LV hypertrophy. Both LV diastolic dysfunction and LV hypertrophy were associated with higher levels of serum GGT. Multivariable-adjusted odds ratios (95% confidence interval) for LV diastolic dysfunction comparing serum GGT quartiles 2–4 with quartile 1 were 1.25 (1.08–1.44), 1.65 (1.43–1.91) and 2.23 (1.92–2.58), respectively (P for trend <0.001). Multivariable-adjusted odds ratios (95% CI) for LV hypertrophy comparing serum GGT quartiles 2–4 with quartile 1 were 1.13 (0.94–1.36), 1.14 (0.93–1.40) and 1.33 (1.07–1.65), respectively (P for trend 0.01). These associations of serum GGT levels with LV diastolic dysfunction and LV hypertrophy were modified by age (P for interaction <0.05).
Conclusions:This study demonstrated a positive association between serum GGT levels and LV diastolic dysfunction and LV hypertrophy in a large cohort of middle-aged men and women independent of potential confounders.
Background:We reported less provoked spasm in the left circumflex artery (LCX) by acetylcholine testing compared with the left anterior descending artery (LAD) and right coronary artery (RCA), so we investigated the clinical characteristics of provoked spasm in the LCX by ergonovine (ER) testing.
Methods and Results:We retrospectively analyzed 1,185 consecutive cases of intracoronary ER testing during 25 years. Maximal ER dose was 64 μg into the left coronary artery (LCA) and 40 μg into the RCA. Positive spasm was defined as a transient ≥90% narrowing and usual chest symptoms or ischemic ECG changes. Positive provoked spasm was recognized in 347 patients (29.3%), including 207 RCA spasms, 166 LAD spasms, and 79 LCX spasms. Spasm was provoked in the LCX significantly less than in the other vessels (P<0.001). LCX-provoked spasm was obtained in 79 patients consisting of 16 patients (20.3%) with triple-vessel spasm, 38 patients (48.1%) with double-vessel spasm and 25 patients (31.6%) with single-vessel spasm. Less than 70% patients with LCX-provoked spasm had multiple spasms, whereas approximately 60% patients had single-vessel spasm in the RCA (64.3%) or LAD (59.6%). In 25 patients with LCX single-vessel spasm, 18 patients (72.0%) had a focal spasm.
Conclusions:Under maximal ER dose of 64 μg into the LCA, LCX-provoked spasm occurred significantly less than spasm in the other vessels and less than 70% patients had multiple spasms.
Background:Although Toll-like receptor 4 (TLR-4) is involved in monocyte activation in patients with accelerated forms of atherosclerosis, the relationship between the expression of TLR-4 on circulating monocytes and coronary plaque vulnerability has not previously been evaluated. We investigated this relationship using 64-slice multidetector computed tomography (MDCT) in patients with stable angina pectoris (SAP).
Methods and Results:We enrolled 65 patients with SAP who underwent MDCT. Three monocyte subsets (CD14++CD16−, CD14++CD16+, and CD14+CD16+) and expression of TLR-4 were measured by flow cytometry. Intracoronary plaques were assessed by 64-slice MDCT. We defined vulnerability of intracoronary plaques according to the presence of positive remodeling (remodeling index >1.05) and/or low CT attenuation (<35 HU). The circulating CD14++CD16+monocytes more frequently expressed TLR-4 than CD14++CD16−and CD14+CD16+monocytes (P<0.001). The relative proportion of the expression of TLR-4 on CD14++CD16+monocytes was significantly greater in patients with vulnerable plaque compared with those without (10.4 [4.1–14.5] % vs. 4.5 [2.8–7.8] %, P=0.012). In addition, the relative proportion of TLR-4 expression on CD14++CD16+monocytes positively correlated with the remodeling index (r=0.28, P=0.025) and negatively correlated with CT attenuation value (r=−0.31, P=0.013).
Conclusions:Upregulation of TLR-4 on CD14++CD16+monocytes might be associated with coronary plaque vulnerability in patients with SAP.
Pediatric Cardiology and Adult Congenital Heart Disease
Background:Left ventricular (LV) dysfunction in patients with repaired tetralogy of Fallot (rTOF) is an important risk factor for adverse outcomes. The aim of this study was to assess the details and time course of such LV dysfunction using layer-specific strain analysis by echocardiography.
Methods and Results:The 66 patients with rTOF (mean age, 16.3±9.3 years) were divided into 3 groups (T1: 4–10 years, T2: 11–20 years, T3: 21–43 years), and 113 controls of similar age (mean age, 17.2±9.3 years) were divided into 3 corresponding groups (C1, C2, and C3). Layer-specific longitudinal strain (LS) and circumferential strain (CS) of 3 myocardial layers (endocardial, midmyocardial, and epicardial) were determined by echocardiography. Basal and papillary endocardial CS values were decreased in T1 compared with C1. With the exception of papillary epicardial CS, basal/papillary CS and LS of all 3 layers decreased in T2 compared with C2. Excepting papillary epicardial CS, all other values were decreased in T3 compared with C3.
Conclusions:Potential myocardial damage was found in the endocardium at the basal and papillary levels of the LV in young patients with rTOF, extending from the endocardium to the epicardium and from the base to the apex. This is the possible time course of LV dysfunction in patients with rTOF.
Background:No studies have compared treatment efficacy between subcutaneous (SC) fondaparinux and oral edoxaban, which are categorized as factor Xa inhibitors, for venous thromboembolism (VTE) in the acute phase, and only a limited number of imaging-based quantitative studies have evaluated treatment.
Methods and Results:In this open-label, randomized study, 50 patients with acute non-massive pulmonary embolism (PE) and/or deep-vein thrombosis (DVT) were assigned to fondaparinux or edoxaban groups. Lower-limb venous ultrasonography (US), and chest computed tomography (CT) were compared before and 7 days after treatment. Thrombus volume in DVT was calculated using quantitative ultrasound thrombosis (QUT) score on US. For evaluation of PE thrombus volume, lung perfused blood volume (PBV) on CT was calculated. The measurements before and after treatment, respectively, were as follows: QUT score: fondaparinux, 8.1±7.3 to 4.1±4.5; edoxaban, 7.7±6.3 to 4.4±4.3, both significant decreases (P=0.001, P<0.001, respectively); lung PBV: fondaparinux, 32.0±7.8 to 32.1±8.2 HU; edoxaban, 34.2±8.6 to 38.5±11.8 HU (P=0.732, P=0.426, respectively). On subjective CT-based evaluation, all pulmonary artery-related filling defects decreased/disappeared after treatment in both groups (P=NS).
Conclusions:Both SC fondaparinux and oral edoxaban are effective in acute VTE. Effects on thrombus regression on imaging-based quantitative measurement did not differ between the 2 drugs.
Background:Osteoporosis and cardiovascular disease are major public health problems. A number of clinical studies have shown a link between osteoporosis and cardiovascular disease, but there is no information on the associations of risk of osteoporotic fracture with vascular function and vascular structure.
Methods and Results:The risk of major osteoporotic fracture was calculated using the World Health Organization fracture risk assessment tool (FRAX); vascular function was assessed using flow-mediated vasodilation (FMD) and nitroglycerine-induced vasodilation (NID), and vascular structure was assessed on brachial artery intima-media thickness (IMT) in 414 subjects (241 men and 173 women) who underwent health examinations. On univariate regression, FRAX was negatively correlated with FMD (total, r=–0.16, P<0.001; men, r=–0.19, P=0.003; women, r=–0.25, P<0.001) and NID (total, r=–0.22, P<0.001; men, r=–0.19, P=0.003; women, r=–0.30, P<0.001) and was positively correlated with brachial artery IMT (total, r=0.12, P=0.02; men, r=0.22, P<0.001; women, r=0.33, P<0.001). On multivariate analysis FRAX remained an independent predictor of FMD, NID, and brachial artery IMT in both men and women.
Conclusions:Increase in the risk of osteoporotic fracture evaluated on FRAX is associated with vascular dysfunction and abnormal vascular structure in both men and women. Osteoporosis should be monitored in order to reduce the risk of cardiovascular events.
Background:Hydrogen sulfide (H2S) exerts beneficial actions against the development of cardiovascular disease. Diallyl trisulfide (DATS) is an organic polysulfide found in garlic oil that liberates H2S under physiological conditions. This study investigated whether DATS modulates endothelial cell function, as well as revascularization processes in a mouse model of hind-limb ischemia.
Methods and Results:Wild-type (WT), endothelial nitric oxide synthase-deficient (eNOS-KO) and Akt1-heterogenic deficient (Akt-Het) mice were subjected to unilateral hindlimb ischemia (HLI). DATS or a vehicle control was injected into the abdomen of mice for up to 10 days following HLI induction. Treatment with DATS enhanced blood flow recovery and capillary density in the ischemic limbs of WT mice. This was accompanied by a reduction in apoptotic activity and oxidative stress in the ischemic muscles. DATS also increased the phosphorylation of Akt and eNOS in ischemic muscles. In contrast to WT mice, DATS did not improve blood flow of eNOS-KO and Akt-Het mice. In cultured human umbilical vein endothelium cells, DATS decreased apoptotic activity and oxidative stress under hypoxic conditions, and stimulated the phosphorylation of Akt and eNOS. Inhibition of Akt or NOS signaling reversed DATS-stimulated eNOS phosphorylation and blocked the effects of DATS on apoptosis and oxidative stress.
Conclusions:These observations suggest that DATS promotes revascularization in response to HLI through its ability to stimulate the Akt-eNOS signaling pathway.
Background:Maintaining cerebral oxygen delivery and metabolism during cardiac arrest (CA) through resuscitation is essential to improve the survival rate while avoiding brain injury. The effect of CA and cardiopulmonary resuscitation (CPR) on cerebral and muscle oxygen delivery and metabolism is not clearly quantified.
Methods and Results:A novel hyperspectral near-infrared spectroscopy (hNIRS) technique was developed and evaluated to measure cerebral oxygen delivery and aerobic metabolism during ventricular fibrillation (VF) CA and CPR in 14 pigs. The hNIRS parameters were measured simultaneously on the dura and skull to investigate the validity of non-invasive hNIRS measurements. In addition, we compared the hNIRS data collected simultaneously on the brain and muscle. Following VF induction, oxygenated hemoglobin (HbO2) declined with a 9.9 s delay and then cytochrome-c-oxidase (Cyt-ox) decreased on average 4.4 s later (P<0.05). CPR improved cerebral metabolism, which was reflected by an average 0.4 μmol/L increase in Cyt-ox, but had no significant effect on HbO2, deoxygenated hemoglobin (HHb) and tissue oxygen saturation (tSO2). Cyt-ox had greater correlation with HHb than HbO2. Muscle metabolism during VF and CPR was significantly different from that of the brain. The total hemoglobin concentration (in the brain only) increased after ~200 s of untreated CA, which is most likely driven by cerebral autoregulation through vasodilation.
Conclusions:Overall, hNIRS showed consistent measurements of hemodynamics and metabolism during CA and CPR.
Background:This study determined whether relaxin or matrix metalloproteinase (MMP)-9 influences angiotensin II (AngII)-induced abdominal aortic aneurysms (AAA).
Methods and Results:Male C57BL/6 or apolipoprotein E−/−mice were infused with AngII with or without relaxin. Relaxin did not influence AngII-induced AAA in either mouse strain. Infusion of AngII reduced, but relaxin increased, MMP-9 mRNA in macrophages. We then determined the effects of MMP-9 deficiency on AAA in apolipoprotein E−/−mice. MMP-9 deficiency led to AAA formation in the absence of AngII, and augmented AngII-induced aortic rupture and AAA incidence.
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