Mandibular Advancement vs CPAP for Blood Pressure Reduction in Patients With Obstructive Sleep Apnea.

BACKGROUND: Hypertension guidelines recommend diagnosis and treatment of obstructive sleep apnea (OSA) in patients with hypertension. The mandibular advancement device (MAD) is an oral appliance therapy for patients who decline or cannot tolerate continuous positive airway pressure (CPAP). OBJECTIVES: We compared the relative effectiveness of MAD vs CPAP in reducing 24-hour ambulatory blood pressure (BP). METHODS: In an investigator-initiated, randomized, noninferiority trial (prespecified margin 1.5 mm Hg), 321 participants aged ≥40 years with hypertension and increased cardiovascular risk were recruited at 3 public hospitals for polysomnography. Of these, 220 participants with moderate-to-severe OSA (apnea-hypopnea index ≥15 events per hour) were randomized to either MAD or CPAP (1:1). The primary outcome was the difference between the 24-hour mean arterial BP at baseline and 6 months. RESULTS: Compared with baseline, the 24-hour mean arterial BP decreased by 2.5 mm Hg (P = 0.003) at 6 months in the MAD group, whereas no change was observed in the CPAP group (P = 0.374). The between-group difference was -1.6 mm Hg (95% CI: -3.51 to 0.24, noninferiority P < 0.001). The MAD group demonstrated a larger between-group reduction in all secondary ambulatory BP parameters compared with the CPAP group, with the most pronounced effects observed in the asleep BP parameters. Both the MAD and CPAP improved daytime sleepiness, with the between-group difference similar (P = 0.384). There were no between-group differences in cardiovascular biomarkers. CONCLUSIONS: MAD is noninferior to CPAP for reducing 24-hour mean arterial BP in participants with hypertension and increased cardiovascular risk. (Cardiosleep Research Program on Obstructive Sleep Apnea, Blood Pressure Control and Maladaptive Myocardial Remodeling-Non-inferiority Trial [CRESCENT]; NCT04119999).

Multiparametric exercise stress cardiovascular magnetic resonance in the diagnosis of coronary artery disease: the EMPIRE trial.

BACKGROUND: Stress cardiovascular magnetic resonance (CMR) offers assessment of ventricular function, myocardial perfusion and viability in a single examination to detect coronary artery disease (CAD). We developed an in-scanner exercise stress CMR (ExCMR) protocol using supine cycle ergometer and aimed to examine the diagnostic value of a multiparametric approach in patients with suspected CAD, compared with invasive fractional flow reserve (FFR) as the reference gold standard. METHODS: In this single-centre prospective study, patients who had symptoms of angina and at least one cardiovascular disease risk factor underwent both ExCMR and invasive angiography with FFR. Rest-based left ventricular function (ejection fraction, regional wall motion abnormalities), tissue characteristics and exercise stress-derived (perfusion defects, inducible regional wall motion abnormalities and peak exercise cardiac index percentile-rank) CMR parameters were evaluated in the study. RESULTS: In the 60 recruited patients with intermediate CAD risk, 50% had haemodynamically significant CAD based on FFR. Of all the CMR parameters assessed, the late gadolinium enhancement, stress-inducible regional wall motion abnormalities, perfusion defects and peak exercise cardiac index percentile-rank were independently associated with FFR-positive CAD. Indeed, this multiparametric approach offered the highest incremental diagnostic value compared to a clinical risk model (χ2 for the diagnosis of FFR-positive increased from 7.6 to 55.9; P < 0.001) and excellent performance [c-statistic area under the curve 0.97 (95% CI: 0.94-1.00)] in discriminating between FFR-normal and FFR-positive patients. CONCLUSION: The study demonstrates the clinical potential of using in-scanner multiparametric ExCMR to accurately diagnose CAD. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03217227, Registered 11 July 2017-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT03217227?id=NCT03217227&draw=2&rank=1&load=cart.

T and Small Protrusion (TAP) vs Double-Kissing Crush Technique: Insights From In Vitro Models.

BACKGROUND: Percutaneous coronary interventions on complex bifurcation lesions may require implantation of two stents to appropriately treat diffuse side-branch (SB) disease. Comparisons among different bifurcation stenting techniques are continuously attempted by various study designs (bench tests, computer simulations, clinical studies). Among different techniques, double kissing crush (DKC) represents the last evolution for "crushing" while T and small Protrusion (TAP) represents the evolution of "T stenting". Both techniques are actually gaining popularity, but head-to-head comparisons are lacking. METHODS AND RESULTS: Two last generation drug-eluting stents (Synergy™, Boston Scientific, MA, USA and Ultimaster™,Terumo Corp., Japan) were implanted in left main bifurcation bench models using TAP (n = 6 sets) and DKC (n = 6 sets) techniques. A peristaltic pump with fresh porcine blood was used to perfuse the blood through the silicone model at a flow rate of 200 ml/min for 4 min. Optical coherence tomography (OCT) was used to assess stent struts geometry and thrombus formation. SB cross sectional area as well as SB obstruction did not significantly differ between the two techniques. Numerical (but not statistically significant) differences were found in terms of malapposed struts (fewer with TAP) and floating struts (fewer with DKC). Thrombus formation after blood perfusion was similar between TAP and DKC technique (1.53 ± 1.12 vs. 1.20 ± 1.01 mm2, p = 0.6). CONCLUSION: The result of the present in-vitro study shows the absence of significant difference between TAP and DKC in terms of stent struts apposition and acute thrombus formation potential. Despite the completely different technical steps required, both techniques have similar performance according to such articulated pre-clinical evaluation. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT?: Due to its limited complexity, T and Protrusion (TAP) technique is considered the to-go technique for bifurcation lesions with good long-term results. Recently, double kissing crush (DKC) technique has been gaining popularity and demonstrated promising results in randomized clinical trials. WHAT DOES THIS STUDY ADD?: This in-vitro bench test study provides a unique detailed OCT comparison and local hemodynamic environment analysis of the two techniques. HOW MIGHT THIS IMPACT ON CLINICAL PRACTICE?: New insights of acute thrombogenicity and computational flow model simulation may guide percutaneous therapeutic strategies of bifurcation lesions.

Impact of time of onset of symptom of ST-segment elevation myocardial infarction on 1-year rehospitalization for heart failure and mortality.

Circadian patterns in ST-segment elevation myocardial infarction (STEMI) patients have been previously reported, but little is known about the impact of time dependence of symptom onset on long-term prognosis. Our study population consisted of 11,731 STEMI patients treated by primary percutaneous coronary intervention (PPCI), enrolled in the Singapore Myocardial Infarction Registry (SMIR). Analysis of STEMI incidence trends over the 24-hour period showed the highest rate of symptom onset in the morning, with the peak incidence at 09:00 am. Patients with symptom onset in between 00:00 am-5:59 am showed the highest prevalence of diabetes (P = .010) and anterior STEMI (P < .001) and had the longest ischemic time (P < .001). After adjusting for confounders, we found an association between time of symptom onset of STEMI and rehospitalization for heart failure (HF) at 1 year, with symptom onset between 06:00 pm-11:59 pm and 00:00 am-05:59 am having an estimated 30% to 50% higher risk of rehospitalization for HF at 1 year. Moreover, symptom onset remained a predictor of worse prognosis only in the subgroup of patients with symptoms lasting longer than 120 minutes. The results of this study demonstrate for the first time that rehospitalization for HF in STEMI patients treated with PPCI has a dependence on the time of onset of symptoms, with prolonged ischemia time playing a pivotal role. This may be an additional risk factor to identify those who warrant closer monitoring and more rigorous optimization of their treatment at follow-up, to improve their outcomes.

Independent Predictors of Cardiac Mortality and Hospitalization for Heart Failure in a Multi-Ethnic Asian ST-segment Elevation Myocardial Infarction Population Treated by Primary Percutaneous Coronary Intervention.

We aimed to identify independent predictors of cardiac mortality and hospitalization for heart failure (HHF) from a real-world, multi-ethnic Asian registry [the Singapore Myocardial Infarction Registry] of ST-segment elevation myocardial infarction (STEMI) patients treated by primary percutaneous coronary intervention. 11,546 eligible STEMI patients between 2008 and 2015 were identified. In-hospital, 30-day and 1-year cardiac mortality and 1-year HHF rates were 6.4%, 6.8%, 8.3% and 5.2%, respectively. From the derivation cohort (70% of patients), age, Killip class and cardiac arrest, creatinine, hemoglobin and troponin on admission and left ventricular ejection fraction (LVEF) during hospitalization were predictors of in-hospital, 30-day and 1-year cardiac mortality. Previous ischemic heart disease (IHD) was a predictor of in-hospital and 30-day cardiac mortality only, whereas diabetes was a predictor of 1-year cardiac mortality only. Age, previous IHD and diabetes, Killip class, creatinine, hemoglobin and troponin on admission, symptom-to-balloon-time and LVEF were predictors of 1-year HHF. The c-statistics were 0.921, 0.901, 0.881, 0.869, respectively. Applying these models to the validation cohort (30% of patients) showed good fit and discrimination (c-statistic 0.922, 0.913, 0.903 and 0.855 respectively; misclassification rate 14.0%, 14.7%, 16.2% and 24.0% respectively). These predictors could be incorporated into specific risk scores to stratify reperfused STEMI patients by their risk level for targeted intervention.

Platelet inhibition to target reperfusion injury trial: Rationale and study design.

BACKGROUND: In ST-segment elevation myocardial infarction (STEMI) patients treated with primary percutaneous coronary intervention (PPCI), current oral P2Y12 platelet inhibitors do not provide maximal platelet inhibition at the time of reperfusion. Furthermore, administration of cangrelor prior to reperfusion has been shown in pre-clinical studies to reduce myocardial infarct (MI) size. Therefore, we hypothesize that cangrelor administered prior to reperfusion in STEMI patients will reduce the incidence of microvascular obstruction (MVO) and limit MI size in STEMI patients treated with PPCI. METHODS: The platelet inhibition to target reperfusion injury (PITRI) trial, is a phase 2A, multi-center, double-blinded, randomized controlled trial, in which 210 STEMI patients will be randomized to receive either an intravenous (IV) bolus of cangrelor (30 µg/kg) followed by a 120-minute infusion (4 µg/kg/min) or matching saline placebo, initiated prior to reperfusion (NCT03102723). RESULTS: The study started in October 2017 and the anticipated end date would be July 2020. The primary end-point will be MI size quantified by cardiovascular magnetic resonance (CMR) on day 3 post-PPCI. Secondary endpoints will include markers of reperfusion, incidence of MVO, MI size, and adverse left ventricular remodeling at 6 months, and major adverse cardiac and cerebrovascular events. SUMMARY: The aim of the PITRI trial is to assess whether cangrelor administered prior to reperfusion would reduce acute MI size and MVO, as assessed by CMR.

Stent malapposition and the risk of stent thrombosis: mechanistic insights from an in vitro model.

AIMS: The aim of this report was to examine the effect of underexpansion on stent thrombogenicity with an in vitro perfusion model. METHODS AND RESULTS: Drug-eluting stent (DES) samples were partially underdeployed in silicone tubes and perfused with porcine blood containing 10% anticoagulant citrate dextrose solution for four minutes at a flow rate of 200 ml/min. Thrombus formation was evaluated and compared between the well-apposed and malapposed sections. The malapposed sections showed significantly more thrombus formation compared to the well-apposed sections (13.9 vs. 0.41 mm2, p<0.001). CONCLUSIONS: Stent malapposition has a very direct impact on thrombus formation. Optimised stent implantation is required to minimise malapposition in DES and BVS to reduce thrombus formation.

Angiographic, optical coherence tomography and histology findings from combination of a drug-coated balloon with an everolimus-eluting stent in a porcine model.

BACKGROUND: We designed a porcine model to compare the angiographic, optical coherence tomography (OCT) and histological findings of implanting an everolimus-eluting stent (EES) in the same segment of the coronary artery pre-treated with a drug-coating balloon (DCB; paccocath as carrier) with EES alone and DCB plus a bare metal stent (BMS). METHODS: Seven female swine averaging 46.0±2.4kg were treated by random assignment as follows: DCB followed by EES; DCB followed by BMS; and EES alone. Quantitative coronary angiography (QCA) and OCT were carried out post-implantation and repeated after 28±1days. RESULTS: All arteries remained patent and demonstrated no sign of thrombus formation. There was no significant difference at 1month between the treatment groups in lumen loss (0.64±0.43, 0.44±0.43 and 0.33±0.28mm for EES, DCB/EES and DCB/BMS respectively, p=0.37) and binary restenosis (6.86 (2.91-9.12), 4.93 (-1.53-10.7) and 4.18 (3.27-10.2)% respectively, p=0.87). OCT found mean neointimal thickness of 0.15±0.09, 0.07±0.03 and 0.08±0.03mm (p=0.05) for EES, DCB/EES and DCB/BMS respectively. Endothelial strut coverage was 92.3±5.5, 85.4±8.6 and 89.1±8.9% (p=0.05) and mean neointimal area was 1.06±0.42, 0.95±0.24 and 1.20±0.28mm2 (p=0.09) respectively. Inflammation score was similar between the three groups: 0.20 (0.20-0.28), 0.30 (0.22-0.48), 0.30 (0.20-0.38) for EES, DCB/EES and DCB/BMS respectively (p=0.14) and there were no differences in fibrin deposition. CONCLUSIONS: The combination of DCB with EES appeared to be safe and effective. Using EES to bail out suboptimal DCB therapy appeared to be safe and effective in this porcine model.

Comparison of novel 6.5 Fr sheathless guiding catheters versus 5 Fr guiding catheters for transradial coronary intervention.

AIMS: To assess the safety and efficacy of a novel sheathless (SH) 6.5 Fr (French) hydrophilic-coated guiding catheter (GC) compared to the standard 5 Fr GCs in transradial coronary interventions (TRI). METHODS AND RESULTS: Patients undergoing TRI with 6.5 Fr SH or 5 Fr GCs were included. Baseline characteristics and in-hospital outcomes were recorded. Primary endpoints were procedural success and presence of radial pulse at discharge. Secondary endpoints were successful GC support, in-hospital adverse events, access-site complications, procedural duration and contrast load. There were 269 patients with 146 procedures in each group. The SH GC group had more non-ST elevation MI, in-stent restenosis, high-risk and bifurcation lesions. Procedural success in both arms was 95.2%. One patient in each group (0.7%) experienced radial artery occlusion (RAO) after TRI, without clinical sequelae. One access-site haematoma and one minor stroke occurred in the 5 Fr group (none in the SH group, both p=ns). Mean procedure time (52±21 vs. 45±21 minutes, p=0.004) and contrast load (160±45 ml vs. 140±45 ml, p=0.003) were greater in the SH group. CONCLUSIONS: Both 6.5 Fr SH GCs and 5 Fr GCs achieved high procedural TRI success with low RAO rates. The SH GC eliminated the disadvantages of the 5 Fr GC whilst maintaining the advantage of low RAO rates, and may become the GC of choice in TRI.

Different expression of large-conductance calcium-activated K+ channels in human internal mammary and radial arteries.

AIMS: In this study, we investigated and compared the electrophysiological and molecular properties of large-conductance Ca(2+)-activated K(+) (BK(Ca)) channels between human internal mammary arteries (IMA) and radial arteries (RA). METHODS AND RESULTS: IMA and RA sections were obtained from 79 patients (including 9 females) undergoing coronary artery bypass graft surgery. We examined the effects of K(+) channel blockers tetraethylammonium (TEA), iberiotoxin (IBTX), and 4-aminopyridine (4-AP) on isolated smooth muscle cells (SMCs) using patch clamping. Both TEA (1 mM) and IBTX (0.1 µM) significantly decreased K(+) currents in IMA SMCs and RA SMCs, while 4-AP (1 mM) only had a weak effect. IBTX had a greater K(+)-blocking effect on IMA SMCs than on RA SMCs. Consistently, TEA and IBTX evoked significant constriction of both intact vascular rings. IBTX had a greater constrictor effect on IMA rings (18.5 ± 6.7%, n= 8) than on RA rings (10.6 ± 3.1%, n= 8), P< 0.05. RT-PCR and western blot analysis demonstrated that gene and protein expression of the α-subunit of BK(Ca) channels from IMA was greater than that from RA. CONCLUSION: The density of BK(Ca) channels is greater in human IMA than in RA resulting in greater BK(Ca) currents in SMCs from IMA. This may partly explain the finding of less spasm in IMA grafts than in RA grafts. Our results may be of value in determining the best anti-spasm agent to use peri-operatively.

Angiopoietin: a TIE(d) balance in tumor angiogenesis.

Angiopoietins (ANG-1 and ANG-2) and their TIE-2 receptor tyrosine kinase have wide-ranging effects on tumor malignancy that includes angiogenesis, inflammation, and vascular extravasation. These multifaceted pathways present a valuable opportunity in developing novel inhibition strategies for cancer treatment. However, the regulatory role of ANG-1 and ANG-2 in tumor angiogenesis remains controversial. There is a complex interplay between complementary yet conflicting roles of both the ANGs in shaping the outcome of angiogenesis. Embryonic vascular development suggests that ANG-1 is crucial in engaging interaction between endothelial and perivascular cells. However, recruitment of perivascular cells by ANG-1 has recently been implicated in its antiangiogenic effect on tumor growth. It is becoming clear that TIE-2 signaling may function in a paracrine and autocrine manner directly on tumor cells because the receptor has been increasingly found in tumor cells. In addition, alpha(5)beta(1) and alpha(v)beta(5) integrins were recently recognized as functional receptors for ANG-1 and ANG-2. Therefore, both the ligands may have wide-ranging functions in cellular activities that affect overall tumor development. Collectively, these TIE-2-dependent and TIE-2-independent activities may account for the conflicting findings of ANG-1 and ANG-2 in tumor angiogenesis. These uncertainties have impeded development of a clear strategy to target this important angiogenic pathway. A better understanding of the molecular basis of ANG-1 and ANG-2 activity in the pathophysiologic regulation of angiogenesis may set the stage for novel therapy targeting this pathway.