Magnus Settergren

Percutaneous mitral valve edge-to-edge Repair: In-hospital results and 1-year follow-up of 628 patients of the 2011-2012 pilot European Sentinel Registry

BACKGROUNDnThe use of transcatheter mitral valve repair (TMVR) has gained widespread acceptance in Europe, but data on immediate success, safety, and long-term echocardiographic follow-up in real-world patients are still limited.nnnOBJECTIVESnThe aim of this multinational registry is to present a real-world overview of TMVR use in Europe.nnnMETHODSnThe Transcatheter Valve Treatment Sentinel Pilot Registry is a prospective, independent, consecutive collection of individual patient data.nnnRESULTSnA total of 628 patients (mean age 74.2 ± 9.7 years, 63.1% men) underwent TMVR between January 2011 and December 2012 in 25 centers in 8 European countries. The prevalent pathogenesis was functional mitral regurgitation (FMR) (n = 452 [72.0%]). The majority of patients (85.5%) were highly symptomatic (New York Heart Association functional class III or higher), with a high logistic EuroSCORE (European System for Cardiac Operative Risk Evaluation) (20.4 ± 16.7%). Acute procedural success was high (95.4%) and similar in FMR and degenerative mitral regurgitation (pxa0= 0.662). One clip was implanted in 61.4% of patients. In-hospital mortality was low (2.9%), without significant differences between groups. The estimated 1-year mortality was 15.3%, which was similar for FMR and degenerative mitral regurgitation. The estimated 1-year rate of rehospitalization because of heart failure was 22.8%, significantly higher in the FMR group (25.8% vs. 12.0%, p[log-rank]xa0= 0.009). Paired echocardiographic data from the 1-year follow-up, available for 368 consecutive patients in 15 centers, showed a persistent reduction in the degree of mitral regurgitation at 1 year (6.0% of patients with severe mitral regurgitation).nnnCONCLUSIONSnThis independent, contemporary registry shows that TMVR is associated with high immediate success,xa0low complication rates, and sustained 1-year reduction of the severity of mitral regurgitation and improvement of clinical symptoms.

Patent Foramen Ovale Closure or Antiplatelet Therapy for Cryptogenic Stroke

BACKGROUND The efficacy of closure of a patent foramen ovale (PFO) in the prevention of recurrent stroke after cryptogenic stroke is uncertain. We investigated the effect of PFO closure combined with antiplatelet therapy versus antiplatelet therapy alone on the risks of recurrent stroke and new brain infarctions. METHODS In this multinational trial involving patients with a PFO who had had a cryptogenic stroke, we randomly assigned patients, in a 2:1 ratio, to undergo PFO closure plus antiplatelet therapy (PFO closure group) or to receive antiplatelet therapy alone (antiplatelet‐only group). Imaging of the brain was performed at the baseline screening and at 24 months. The coprimary end points were freedom from clinical evidence of ischemic stroke (reported here as the percentage of patients who had a recurrence of stroke) through at least 24 months after randomization and the 24‐month incidence of new brain infarction, which was a composite of clinical ischemic stroke or silent brain infarction detected on imaging. RESULTS We enrolled 664 patients (mean age, 45.2 years), of whom 81% had moderate or large interatrial shunts. During a median follow‐up of 3.2 years, clinical ischemic stroke occurred in 6 of 441 patients (1.4%) in the PFO closure group and in 12 of 223 patients (5.4%) in the antiplatelet‐only group (hazard ratio, 0.23; 95% confidence interval [CI], 0.09 to 0.62; P=0.002). The incidence of new brain infarctions was significantly lower in the PFO closure group than in the antiplatelet‐only group (22 patients [5.7%] vs. 20 patients [11.3%]; relative risk, 0.51; 95% CI, 0.29 to 0.91; P=0.04), but the incidence of silent brain infarction did not differ significantly between the study groups (P=0.97). Serious adverse events occurred in 23.1% of the patients in the PFO closure group and in 27.8% of the patients in the antiplatelet‐only group (P=0.22). Serious device‐related adverse events occurred in 6 patients (1.4%) in the PFO closure group, and atrial fibrillation occurred in 29 patients (6.6%) after PFO closure. CONCLUSIONS Among patients with a PFO who had had a cryptogenic stroke, the risk of subsequent ischemic stroke was lower among those assigned to PFO closure combined with antiplatelet therapy than among those assigned to antiplatelet therapy alone; however, PFO closure was associated with higher rates of device complications and atrial fibrillation. (Funded by W.L. Gore and Associates; Gore REDUCE ClinicalTrials.gov number, NCT00738894.)

Effect of postconditioning on infarct size in patients with ST elevation myocardial infarction

Background Small studies suggest that postconditioning reperfusion interrupted by brief repetitive cycles of reocclusions, may protect the myocardium in the clinical setting. Objective To test the hypothesis that postconditioning limits infarct size in relation to the area at risk in patients with ST elevation myocardial infarction (STEMI). Methods 76 patients (aged 37–87u2005years) eligible for primary percutaneous coronary intervention due to STEMI were randomised to standard percutaneous coronary intervention (n=38) or postconditioning, consisting of four cycles of 60u2005s reperfusion and 60u2005s of reocclusion before permanent reperfusion (n=38). Results The area at risk was determined from angiographic abnormally contracting segments. Infarct size was quantified from delayed enhancement MRI on days 6–9. Infarct size, expressed in relation to the area at risk, did not differ between the control group (44%; 30, 56) (median and quartiles) and the post-conditioned group (47%; 23, 63). The slope of the regression lines relating infarct size to the area at risk differed between the two groups. Infarct size was significantly (p=0.001) reduced by postconditioning in patients with large areas at risk. The area under the curve and peak troponin T release and CKMB during 48u2005h did not differ between patients in the control and postconditioning groups. Conclusions This prospective, randomised trial suggests that postconditioning does not reduce infarct size in patients with STEMI in the overall study group. The data indicate that postconditioning may be of value in patients with large areas at risk. Clinical trial registration information Karolinska Clinical Trial Registration (http://www.kctr.se). Unique identifier: CT20080014.

Arginase Inhibition Improves Endothelial Function in Patients With Coronary Artery Disease and Type 2 Diabetes Mellitus

Background— Endothelial dysfunction plays an important role in the early development of atherosclerosis and vascular complications in type 2 diabetes mellitus. Increased expression and activity of arginase, metabolizing the nitric oxide substrate L-arginine, may result in reduced production of nitric oxide and thereby endothelial dysfunction. We hypothesized that inhibition of arginase activity improves endothelial function in patients with coronary artery disease (CAD) and type 2 diabetes mellitus. Methods and Results— Three groups of subjects were included: 16 patients with CAD, 16 patients with CAD and type 2 diabetes mellitus (CAD+Diabetes), and 16 age-matched healthy control subjects. Forearm endothelium-dependent and endothelium-independent vasodilatation were assessed with venous occlusion plethysmography before and during intra-arterial infusion of the arginase inhibitor N&ohgr;-hydroxy-nor-L-arginine (nor-NOHA; 0.1 mg/min). Nor-NOHA was also coinfused with the nitric oxide synthase inhibitor (NG-monomethyl L-arginine). The expression of arginase was determined in the internal mammary artery of patients undergoing bypass surgery. Nor-NOHA markedly increased endothelium-dependent vasodilatation (up to 2-fold) in patients with CAD+Diabetes and CAD (P<0.001) but not in the control group. NG-monomethyl L-arginine completely inhibited the increase in endothelium-dependent vasodilatation induced by nor-NOHA. Endothelium-independent vasodilatation was slightly improved by nor-NOHA in the CAD+Diabetes group. Arginase I was expressed in vascular smooth muscle cells and endothelial cells, and arginase II was expressed in endothelial cells of patients with and without diabetes mellitus. Conclusions— Arginase inhibition markedly improves endothelial function in patients with CAD and type 2 diabetes mellitus suggesting that increased arginase activity is a key factor in the development of endothelial dysfunction.

Cholesterol lowering is more important than pleiotropic effects of statins for endothelial function in patients with dysglycaemia and coronary artery disease.

AIMSnThe importance of pleiotropic effects of statins on endothelial function and inflammatory markers was investigated in patients with dysglycaemia and coronary artery disease (CAD).nnnMETHODS AND RESULTSnThirty-nine patients were randomized to simvastatin 80 mg daily (S80; n = 20) or ezetimibe 10 mg and simvastatin 10 mg daily (E10/S10; n = 19) for 6 weeks, aiming at similar cholesterol reduction. Endothelial function, evaluated by brachial artery flow-mediated vasodilatation (FMD) and the effect of endothelin receptor blockade, serum lipids, and inflammatory markers were evaluated at baseline and follow-up. At follow-up, low-density lipoprotein cholesterol decreased from 3.1 (2.8-3.4) (median and quartiles) to 1.5 mmol/L (1.4-1.7) and from 3.0 (2.5-3.4) to 1.3 mmol/L (1.1-1.8), in the S80 and E10/S10 groups, respectively. In the entire study group, FMD increased from 4.3% (3.4-6.1) at baseline to 5.5% (3.4-6.6) at follow-up, while C-reactive protein decreased from 3.1 (1.7-7.6) to 2.3 mg/L (0.9-6.5). The changes in FMD and C-reactive protein from baseline to follow-up were not significantly different between patients on S80 and E10/S10 groups. Endothelin blockade enhanced endothelium-dependent vasodilatation both at baseline and follow-up.nnnCONCLUSIONnLipid lowering is more important than pleiotropic effects of statins for improvement in endothelial function and inflammatory markers in patients with dysglycaemia and CAD.

l-Arginine and tetrahydrobiopterin protects against ischemia/reperfusion-induced endothelial dysfunction in patients with type 2 diabetes mellitus and coronary artery disease

Diminished levels of L-arginine and endothelial nitric oxide synthase (eNOS) uncoupling through deficiency of tetrahydrobiopterin (BH(4)) may contribute to endothelial dysfunction. We investigated the effect of L-arginine and BH(4) administration on ischemia-reperfusion (I/R)-induced endothelial dysfunction in patients with type 2 diabetes and coronary artery disease (CAD). Forearm blood flow was measured by venous occlusion plethysmography in 12 patients with type 2 diabetes or impaired glucose tolerance and CAD. Forearm ischemia was induced for 20 min, followed by 60 min of reperfusion. The patients received a 15 min intra-brachial infusion of L-arginine (20 mg/min) and BH(4) (500 microg/min) or 0.9% saline starting at 15 min of ischemia on two separate study occasions. Compared with pre-ischemia the endothelium-dependent vasodilatation (EDV) induced by acetylcholine was significantly reduced at 15 and 30 min of reperfusion when saline was infused (P<0.001), but not following L-arginine and BH(4) infusion. EDV was also significantly less reduced at 15 and 30 min of reperfusion following L-arginine and BH(4) infusion, compared to saline infusion (P<0.02). Endothelium-independent vasodilatation (EIDV) induced by nitroprusside was unaffected by I/R. Venous total biopterin levels in the infused arm increased from 37+/-7 at baseline to 6644+/-1240 nmol/l during infusion of L-arginine and BH(4) (P<0.0001), whereas there was no difference in biopterin levels during saline infusion. In conclusion L-arginine and BH(4) supplementation reduces I/R-induced endothelial dysfunction, a finding which may represent a novel treatment strategy to limit I/R injury in patients with type 2 diabetes and CAD.

The endothelin receptor antagonist bosentan improves peripheral endothelial function in patients with type 2 diabetes mellitus and microalbuminuria: a randomised trial

Aims/hypothesisEndothelial dysfunction is important in the development of vascular complications in diabetes. Patients with type 2 diabetes have increased production of the vasoconstrictor and pro-inflammatory peptide, endothelin-1. Short-term intra-arterial administration of endothelin antagonists improves endothelium-dependent vasodilatation in patients with type 2 diabetes. We tested the hypothesis that oral administration of the dual endothelin receptor antagonist, bosentan, improves peripheral endothelial function in patients with type 2 diabetes and microalbuminuria.MethodsThis placebo-controlled and double-blind study was performed on 46 patients with type 2 diabetes and microalbuminuria (urine albumin/creatinine ratio >3xa0mg/mmol) at a medical university department. Patients were randomised to bosentan, 125xa0mg two times per day (nu2009=u200928), or placebo (nu2009=u200928) for 4xa0weeks. The computer-generated randomisation code was kept in sealed envelopes. Patients and people doing examinations or assessing outcomes were blinded. The primary endpoint was change in microvascular endothelium-dependent vasodilatation, based on change in digital reactive hyperaemia index. The secondary endpoint was change in brachial artery flow-mediated vasodilatation.ResultsReactive hyperaemia index increased from 1.73u2009±u20090.43 (meanu2009±u2009SD) at baseline to 2.08u2009±u20090.59 at follow-up (pu2009<u20090.05) in the bosentan group (nu2009=u200922), but did not change in the placebo group (1.84u2009±u20090.49 to 1.87u2009±u20090.47; nu2009=u200924). The change in reactive hyperaemia index from baseline was greater in the bosentan group than in the placebo group (pu2009<u20090.05). Nitroglycerine-induced digital hyperaemia was not affected. Brachial artery flow-mediated vasodilatation and blood pressure did not change during treatment.Conclusions/interpretationOral treatment of 4xa0weeks duration with the dual endothelin receptor antagonist, bosentan, improves peripheral endothelial function in patients with type 2 diabetes and microalbuminuria.Trial Registration:ClinicalTrial.gov NCT01357109; Karolinska Clinical Trial Registration Identifier CT20090017 (see www.kctr.se)Funding:Research Council of Sweden, Swedish Heart and Lung Foundation, Novo Nordisk Foundation, Karolinska Institutet/Stockholm County Council Strategic Cardiovascular Programme, Gustav V and Queen Victoria Foundation, the Family Erling Persson Foundation, Actelion Pharmaceuticals and Actelion Research Award.

Endothelin-A receptor blockade increases nutritive skin capillary circulation in patients with type 2 diabetes and microangiopathy.

Aims: Endothelin-1 levels are elevated in patients with type 2 diabetes mellitus and may contribute to impaired microvascular function. We investigated the effect of selective endothelin-A (ETA) receptor blockade (BQ123) on skin microcirculation in patients with type 2 diabetes and albuminuria. Methods: Ten type 2 diabetes patients and 8 non-diabetic controls were investigated. Nutritive skin capillary circulation, investigated by videophotometric capillaroscopy, and total skin microcirculation, assessed by laser Doppler fluxmetry (LDF), were studied during intra-arterial infusion of saline for 15 min, followed by BQ123 infusion for 60 min. Results: Following BQ123 infusion there was a significant increase in resting capillary blood cell velocity (CBV) in patients with type 2 diabetes from 0.24 (0.20–0.34) mm/s at baseline to 0.61 (0.46–0.88) mm/s at 60 min, but no significant change in the control subjects [0.55 (0.10–0.68) vs. 0.38 (0.13–0.88) mm/s; p < 0.005 for difference between groups]. Peak CBV following arterial occlusion and skin temperature increased significantly in the type 2 diabetes group but not in the control group during BQ123 infusion. There were no significant changes in LDF parameters during infusion of BQ123 in either group. Conclusion: ETA receptor blockade improves nutritive skin capillary circulation in patients with type 2 diabetes and microangiopathy.

Echocardiographic and Clinical Outcomes of Central Versus Noncentral Percutaneous Edge-to-Edge Repair of Degenerative Mitral Regurgitation

OBJECTIVESnThis study aimed to assess the clinical and echocardiographic results of MitraClip implantation in noncentral degenerative mitral regurgitation (dMR) compared with central dMR.nnnBACKGROUNDnIt is unknown whether the use of MitraClip therapy in noncentral dMR is as safe and effective as in central dMR.nnnMETHODSnWe analyzed a multicenter registry of 173 patients treated with the MitraClip and compared results of central and noncentral dMR.nnnRESULTSnSeventy-nine patients (age 79.2 ± 8.0 years, 58.2% men) had dMR. Forty-nine patients (62%) had central dMR, with the remainder classified as noncentral dMR (nxa0= 30, 38%). Patients with noncentral dMR had a wider pre-procedural vena contracta (8.5 ± 2.0 mm vs. 6.9 ± 2.2 mm, pxa0= 0.039) and higher systolic pulmonary pressure (57.9 ± 18.0 vs. 47.3 ± 13.0 mm Hg, pxa0= 0.019). Procedural success was the same in both groups (95.5% central vs. 96.7% noncentral, pxa0= 0.866). Post-procedural MR and New York Heart Association (NYHA) functional class at 1 month (MRxa0≤2, 96.0% vs. 96.6%, pxa0= 0.866, and NYHA functional classxa0≤II, 81.6% vs. 90.0%, pxa0= 0.335) and 6 months (95.2% central vs. 91.7% noncentral, pxa0= 0.679; and NYHA functional class >II, 21.1% vs. 0%, pxa0= 0.128) did not differ between groups. There were also no differences in serious post-procedural adverse events: partial clip detachment (central nxa0= 1 [2.0%] vs. noncentral nxa0= 1 [3.3%], pxa0= 1.000), death (5.4% central vs. 13.0% noncentral, pxa0= 0.298), or heart failure admission (10.8% central vs. 8.7% noncentral, pxa0= 0.791).nnnCONCLUSIONSnIn experienced centers, MitraClip treatment can be performed safely and effectively in both central and noncentralxa0dMR.

Sepsis-induced myocardial depression and takotsubo syndrome

Abstract Background and objectives: Myocardial depression in the setting of sepsis and septic shock is common and has been recognized for a long time. The aim of this study is to find out an association and causal link between sepsis and takotsubo syndrome (TS). Methods: Fifteen cases of TS were studied. Critical review of the literature dealing with sepsis and myocardial depression was done Results: Fifteen cases of sepsis-induced TS are described. Fifty-three per cent of the patients were men. The ages ranged from 39 to 76 years (mean age 60 years). Two-thirds of the patients had ST-elevation myocardial infarction ECG changes. Complications occurred in 80% of the patients. No specific types of sepsis or micro-organisms were associated with the development of TS. Critical review of the sepsis-induced myocardial depression shows that the left ventricular dysfunction, which is reversible within one-to-two weeks, is characterized by segmental ventricular dysfunction, and involvement of the right ventricle in one fourth of cases. These features are also consistent with TS. Conclusions: Sepsis triggers TS, which may be the cause of the majority of cases of sepsis-induced myocardial depression. Acute cardiac sympathetic disruption with noradrenaline spill-over may be the cause of sepsis-induced TS.