Effects of atrial fibrillation and heart rate on percutaneous mitral valve repair with MitraClip: results from the TRAnscatheter Mitral valve Interventions (TRAMI) registry.

AIMS: In patients undergoing percutaneous edge-to-edge mitral valve repair for mitral valve regurgitation (MR), our aim was to evaluate acute and follow-up differences with pre-existing sinus rhythm (SR) or atrial fibrillation (AF), as well as comparisons stratified by baseline heart rate. METHODS AND RESULTS: Seven hundred and sixty patients who underwent a MitraClip procedure were prospectively enrolled in the TRAnscatheter Mitral valve Interventions (TRAMI) registry, and stratified according to baseline heart rhythm and heart rate with a cut-off value of 70 beats per minute. Technical success, procedural characteristics and MR reduction were similar throughout the subgroups. Overall, in-hospital adverse event rates were low in this high-risk patient collective. At 12 months, survival was higher in SR (83.5%) than AF patients (74.9%, p<0.05), while the cumulative major adverse cardio-cerebrovascular event rate did not differ, and a sustained improvement of NYHA functional class occurred in all subgroups. CONCLUSIONS: These registry data, comprising the largest number of unselected "real-world" MitraClip patients, suggest that the intervention can be performed safely and effectively, and reduces MR in the majority of patients irrespective of baseline rhythm or heart rate. While 12-month survival was higher for patients with SR, overall MACCE and clinical improvement did not differ between the subgroups.

Comparison of transcatheter aortic valve implantation with the newest-generation Sapien 3 vs. Direct Flow Medical valve in a single center cohort.

BACKGROUND: The latest generation transcatheter heart valves including Edwards Sapien 3 (ES3) and Direct Flow Medical (DFM) were designed to allow precise implantation at the intended position and to minimize prosthesis dysfunction as well as procedural complications. Our aim was to compare short-term functional and clinical outcomes of these 2 transcatheter aortic valve systems. METHODS: Of 174 patients undergoing transfemoral transcatheter aortic valve implantation (TAVI) at our institution between August 2013 and June 2015, 113 were treated with ES3 and 61 with DFM. Device success, residual aortic regurgitation and early safety endpoints were defined according to the updated VARC-2 criteria and prespecified as primary endpoints. RESULTS: Patients treated with ES3 had a significantly higher rate of procedural success (ES3 94% vs. DFM 79%, p=0.005), mainly driven by lower postprocedural gradients (ES3 8.6±0.5mmHg vs. DFM 14.6±1.4mmHg by invasive recordings; p=0.00012) and no incidence of more than mild aortic regurgitation. The occurrence of safety endpoints at 30days was low and comparable in the DFM vs. ES3 group (ES3 88% vs. DFM 95% of patients without endpoints, p=0.26). No significant differences were observed in 30day mortality, stroke or the incidence of new permanent pacemaker implantation. CONCLUSIONS: These single-center experience data show a higher rate of device success for ES3 treated patients, while 30day safety outcome was similar in both groups. Long-term follow-up and larger scale multicenter experience will have to assess possible effects of these observations on long-term clinical outcomes.

Transcatheter aortic valve implantation with the new-generation Evolut R™: Comparison with CoreValve® in a single center cohort.

BACKGROUND: The Medtronic Evolut R (EVR) is a novel transcatheter heart valve designed to allow precise implantation at the intended position and to minimize prosthesis dysfunction as well as procedural complications. Our aim was to compare short-term functional and clinical outcomes of the new EVR with the established Medtronic CoreValve (CV) system. METHODS AND RESULTS: Of 151 patients undergoing transfemoral transcatheter aortic valve implantation with a self-expanding valve at our institution between January 2013 and January 2016, 86 were treated with EVR and 65 with CV. Patients treated with EVR had a significantly lower rate of more-than-mild aortic regurgitation and a higher rate of device success. Recapture maneuvers to optimize valve deployment were performed in 22.1% of the EVR procedures. Transvalvular post-procedural gradients were slightly higher in the EVR group, while no differences were observed in the incidence of safety endpoints at 30 days, vascular complications, or need for permanent pacemaker implantation following asystole or complete atrioventricular block. CONCLUSIONS: These initial single-center experience data on the short-term outcomes after EVR valve implantation show a substantially reduced rate of more-than-mild paravalvular regurgitation and higher device success, while 30-day safety outcomes were similar to the CV system. Clinical outcome data from long-term follow-up and larger scale multicenter experience are now necessary.

Clinical, Angiographic, Functional, and Imaging Outcomes 12 Months After Implantation of Drug-Eluting Bioresorbable Vascular Scaffolds in Acute Coronary Syndromes.

OBJECTIVES: The purpose of this study was to describe the multimodal outcome 12 months after implantation of coronary bioresorbable scaffolds (BVS) for the treatment of patients with acute coronary syndromes (ACS). BACKGROUND: Functional and imaging data on the use of BVS are limited to simple, stable lesions; in the setting of ACS, only short-term clinical follow-up data are available, and no information from intracoronary imaging and vasomotion tests has been reported. METHODS: A total of 133 patients (age 62 ± 12 years, 74% males, 15% diabetic) underwent BVS (n = 166) implantation for the treatment of thrombotic lesions in the setting of ACS (43% non-ST-segment elevation myocardial infarction, 38% ST-segment elevation myocardial infarction, 20% unstable angina). Clinical, angiographic, intracoronary imaging, and vasomotor endpoints were evaluated at 12 months. RESULTS: During the 374 days (interquartile range: 359 to 411 days) of follow-up, there were 4 deaths; 3 definite and 1 probable in-BVS thromboses (all in the first 6 months). At 12-month angiography (75 patients, 83 BVS), in-segment late lumen loss was 0.19 ± 0.45 mm, and 3 (4%) patients showed binary restenosis. Optical coherence tomography (80 BVS, n = 70) showed a mean lumen area of 6.3 ± 2.3 mm(2). Malapposition was evidenced in 21 (26%) BVS. Endothelium-dependent and -independent vasodilation were observed in 48% and 49% of the BVS. CONCLUSIONS: Twelve months after BVS implantation, clinical, intracoronary imaging, and vasomotion data appear to provide a rationale for the use of BVS in the setting of ACS and the basis for a randomized study.

Feasibility and safety of left ventricular endomyocardial biopsy via transradial access: Technique and initial experience.

BACKGROUND: Endomyocardial biopsy constitutes an essential part of the diagnostic algorithm in patients with heart failure of unknown origin, but usually requires transfemoral access. METHODS AND RESULTS: Here, we describe a novel method that allows interventional cardiologists to obtain left ventricular biopsies via transradial access with a 7.5F sheathless multipurpose (MP1.0) guiding catheter. This approach was successfully conducted in 37 consecutive patients at our institution with only one intraprocedural minor complication (ventricular fibrillation during insertion of the guiding catheter). CONCLUSIONS: Transradial access to obtain left ventricular endomyocardial biopsies is a feasible and safe option for experienced radial operators.

Usefulness of 3D-PISA as compared to guideline endorsed parameters for mitral regurgitation quantification.

This study was intended to evaluate the diagnostic value of three dimensional proximal isovelocity surface area (3D PISA) derived effective regurgitant orifice area (EROA) and the accuracy of automatic 3D PISA detection in a population resembling clinical practice. Quantification of mitral regurgitation (MR) remains challenging and 3D PISA EROA is a novel diagnostic tool with promising results. However its' usefulness compared to guideline endorsed parameters has not been shown. In 93 consecutive patients examined in routine practice conventional parameters and 3D-datasets for offline 3D PISA evaluation were recorded. EROA was determined from the largest (peak) PISA and also averaged over systole for meanEROA. Results of 3D PISA calculation were compared with a combination of expert grading by two examiners and two scores for MR grading. In receiver operator characteristic-analysis the meanEROA as determined by 3D PISA had the best diagnostic value (AUC = 0.907 CI 0.832-0.983) as compared to peakEROA (AUC 0.840 CI 0.739-0.941), vena contracta width (AUC 0.831 CI 0.745-0.918) and 2D PISA (AUC 0.747 CI 0.644-0.850). A meanEROA of 0.15 cm(2) had a sensitivity of 88.2 % and a specificity of 81.4 % for distinguishing severe from non-severe MR. Semiautomatic 3D PISA detection correlated very well with manually corrected values (r = 0.955). Semiautomatic 3D PISA measurement is feasible in a clinical population and has better diagnostic value compared to 2D PISA. Calculation of mean EROA throughout systole further improves diagnostic value compared to conventional parameters.

Early outcome after implantation of Absorb bioresorbable drug-eluting scaffolds in patients with acute coronary syndromes.

AIMS: The safety of BVS implantation in patients with a high risk for early thrombotic complications has not been studied. We report on the outcomes of patients with acute coronary syndromes (ACS) treated with bioresorbable, everolimus-eluting, vascular scaffolds (BVS). METHODS AND RESULTS: 150 consecutive patients with ACS (194 lesions) treated with BVS between May 2012 and July 2013 were compared with a control group composed of 103 consecutive patients (129 lesions) who underwent everolimus drug-eluting stent (DES) implantation in the same time period. The incidence of major adverse cardiac events (MACE: death, non-fatal myocardial infarction, or reintervention) before discharge, at one month and six months was evaluated. Clinical characteristics and presentation were similar between groups. Procedural characteristics were also similar between groups, except for the use of glycoprotein IIb/IIIa inhibitors (p<0.01). Procedural success was obtained in all but two patients in the BVS group. In-hospital, 30-day and six-month MACE rates were similar between both groups (all p>0.5), with most complications occurring during the first ten days. Definite or probable in-stent/scaffold thrombosis occurred in two BVS patients and one DES patient during the index admission and it occurred in another patient in each group in the first month after BVS/DES implantation. In multivariate analysis, BVS utilisation did not influence the incidence of MACE (p>0.9). CONCLUSIONS: BVS implantation for patients with ACS is safe, with outcomes comparable with those of drug-eluting metal stents.

Transcatheter aortic valve implantation and four-year follow up in a 99-year-old patient.

Transcatheter aortic valve implantation (TAVI) has emerged as a life-saving therapy in patients with severe aortic valve stenosis who are considered to be high-risk surgical candidates. However, there is a paucity of data on the long-term survival and quality-of-life in very old patients undergoing TAVI. Here, the case is reported of a now 104-year-old patient who underwent percutaneous transfemoral TAVI with a CoreValve prosthesis at the age of 99 years; details of his four-year outcome data are also provided. To best of the authors' knowledge, this patient is the oldest reported to have undergone TAVI, and is currently living with good functional status more than four years after the intervention.

How should I treat a patient with typical angina, typical angiography, negative FFR?

BACKGROUND: A 63-year-old man was referred for cardiac catheterisation for typical angina. At angiography, high-grade stenosis of the first diagonal branch, of the proximal circumflex and of an intermediate branch was found. After treatment of the diagonal branch, fractional flow reserve of the circumflex and intermediate branch was negative, but symptoms persisted. INVESTIGATION: Physical examination, laboratory test, stress echocardiography, fractional flow reserve, coronary flow reserve. DIAGNOSIS: Complex interaction between epicardial stenosis and microvascular hyporeactivity. MANAGEMENT: Stenting.

Immediate effect of the MitraClip procedure on mitral ring geometry in primary and secondary mitral regurgitation.

AIMS: Percutaneous treatment of mitral regurgitation (MR) has been shown to reduce MR severity and improve functional outcomes. Surgical treatment of MR usually includes mitral annulus reduction. The influence of the MitraClip on annulus geometry is not clear. We wanted to investigate whether the procedure itself reduces annulus diameter and if there may be differences between secondary or functional (SMR) and primary (PMR) MR. METHODS AND RESULTS: We retrospectively assessed 3D echocardiography (3D-TEE) data of 55 patients acquired during the procedure shortly before and after clip placement for changes in annulus diameter and area. Measurements were done with QLAB software. Patients were categorized as having either SMR (n = 41) or PMR (n = 14). In SMR, we were able to demonstrate a significant reduction in annulus area (meanΔ 1.30 ± 1.44 cm2; P < 0.001), anterior-posterior (AP)-diameter (meanΔ 0.28 ± 0.32 cm; P < 0.001), tenting area (meanΔ 0.39 ± 0.49 cm2; P < 0.001). No significant change could be found for latero-medial (LM)-diameter. In contrast, we could not demonstrate significant changes in any of the parameters described above in patients with PMR. CONCLUSION: Percutaneous treatment with the MitraClip device can produce immediate reductions in mitral annulus size in SMR, probably supporting procedural success. It also reduces tenting, which may have prognostic implications. In contrast, these effects on mitral geometry cannot be demonstrated in PMR. Knowledge of this difference between SMR and PMR may be important to improve procedural strategies.

Parameters of blood viscosity do not correlate with the extent of coronary and carotid atherosclerosis and with endothelial function in patients undergoing coronary angiography.

While the role of physical forces on the control of atherogenesis and the modulation of endothelial function is well known, studies investigating the impact of shear stress on the extent of central atherosclerosis and flow-mediated dilation in humans produced controversial results. We investigated the relationship between viscosity, coronary atherosclerosis, carotid intima-media thickness and flow-mediated dilation in patients undergoing coronary angiography. 451 patients (306 males, mean age 66 ± 10) were enrolled. Viscosity, which was calculated using a validated formula, showed a positive association with platelet activation (P = 0.01), leukocyte counts (P = 0.006) and C-reactive protein (P = 0.03), a marker of inflammation; surprisingly, visocsity showed a negative association with FMD (FMD decreased 0.14 ± 0.05% per each cPoise increase in viscosity) but only in patients without coronary artery disease. Viscosity showed no association with the extent of coronary or carotid artery disease. We provide cross-sectional data on the relationship between whole blood viscosity and parameters of vascular structure and function. While viscosity correlated with parameters of vascular inflammation, it showed no relationship with the presence and severity of central atherosclerosis.

Impairment of the extrusion transporter for asymmetric dimethyl-L-arginine: a novel mechanism underlying vasospastic angina.

A 37-year old male patient presented with frequent angina attacks (up to 40/day) largely resistant to classical vasodilator therapy. The patient showed severe coronary and peripheral endothelial dysfunction, increased platelet aggregation and increased platelet-derived superoxide production. The endothelial nitric oxide synthase (eNOS)-inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) reduced superoxide formation in platelets identifying "uncoupled" eNOS as a superoxide source. Oral L-arginine normalized coronary and peripheral endothelial dysfunction and reduced platelet aggregation and eNOS-derived superoxide production. Plasma concentrations of the endogenous NOS inhibitor asymmetric dimethyl-L-arginine (ADMA), representing an independent risk factor for cardiovascular disease, were normal in the patient. However, immediately after oral administration of cationic amino acid (CAA), plasma ADMA levels rose markedly, demonstrating increased ADMA efflux from intracellular stores. ADMA efflux from mononuclear cells of the patient was accelerated by CAA, but not neutral amino acids (NAA) demonstrating impairment of y(+)LAT (whose expression was found reduced in these cells). These data suggest that impairment of y(+)LAT may cause intracellular (endothelial) ADMA accumulation leading to systemic endothelial dysfunction. This may represent a novel mechanism underlying vasospastic angina and vascular dysfunction in general. Moreover, these new findings contribute to the understanding of the l-arginine paradox, the improvement of eNOS activity by oral L-arginine despite sufficient cellular l-arginine levels to ensure proper function of this enzyme.

Endothelial function assessment: flow-mediated dilation and constriction provide different and complementary information on the presence of coronary artery disease.

AIMS: A number of risk factors for atherosclerosis have been identified, but it remains difficult, on an individual patient basis, to predict how these factors interact in determining the development of coronary artery disease (CAD). It also remains unclear whether the study of endothelial function provides information that is additive to that of traditional risk factors. METHODS AND RESULTS: Flow-mediated dilation (FMD) and low-flow-mediated constriction (L-FMC) were measured in 451 consecutive patients before coronary angiography. Low-flow-mediated constriction (P< 0.0001) and FMD (P=0.0005) progressively decreased with the number of diseased vessels, and L-FMC showed a significant linear correlation with the SYNTAX score (R=0.38; P< 0.0001). Logistic regression analysis confirmed the association between endothelial function parameters and CAD (P=0.001 for L-FMC, P=0.02 for FMD). Receiver operating characteristic analysis demonstrated that the addition of L-FMC alone and of the combination of FMD and L-FMC improved the predictive power of a model based on traditional risk factors for CAD (area under the curve of the risk factor model=0.716; risk factor model + FMD=0.734, P=0.1 compared with risk factor model; risk factor model + L-FMC=0.771, P=0.004; risk factor model + L-FMC + FMD=0.779, P=0.002). Reclassification statistics showed that the introduction of FMD to the model based on the traditional risk factors correctly reclassified an additional 5% of patients, and that the introduction of L-FMC net correctly reclassified 19% of the patients. There was no correlation between different parameters of endothelial function. CONCLUSION: Endothelial function assessment provides modest but statistically significant additional information in predicting the presence of CAD.

Peripheral hemorheological and vascular correlates of coronary blood flow.

The slow coronary flow phenomenon (SCF), a condition described by the presence of inappropriate delay in the progression of intracoronary contrast during angiography in the absence of stenoses, has been shown in some patients presenting with chest pain. While several conditions leading to "secondary" slow flow are known, there are no definitive conclusions regarding the exact pathogenesis of "primary" SCF. The present paper outlines the mechanisms that may lead to SCF, emphasizing the role of hemorheological and vascular factors in the pathogenesis of this phenomenon. Small vessel dysfunction has been proposed in the pathogenesis of SCF since the first description of this syndrome in 1972. Abnormalities in coronary microvascular function result from increased microvascular resistances and impaired endothelial release of vasoactive substances, especially in production and bioavailability of endothelium derived NO. Inflammatory conditions (increased levels of C-reactive protein, interleukin-6 and adhesion molecules) and metabolic abnormalities such as impaired glycemic control, hyperuricemia and elevated serum gamma-glutamyltransferase were also found to contribute to microvascular dysfunction in patients with SCF. New studies have also indicated that increased blood viscosity and one of its major determinants, erythrocyte aggregation, is associated with the SCF. Rheological variables play a role in the control of shear stress and contribute to blood flow velocity changes. Although platelets do not have a significant influence on blood viscosity, it has been demonstrated that they are involved in the development of SCF. Increased mean platelet volume (MPV), an indicator of platelet activation and platelet aggregability is also significantly higher in patients with SCF compared with patients with normal coronary flow.

Endothelial functions: Translating theory into clinical application.

The vascular endothelium plays a pivotal role in modulating endothelial homeostasis. A number of methods have been developed to assess the function of this important tissue in humans in vivo, in the hope that such data may contribute to the early diagnosis and risk stratification of patients at risk for, or with, cardiovascular disease. Despite these efforts, a number of issues, both practical and theoretical, arise from the attempt of quantifying the elusive "endothelial function", and from the attempt of defining what is "endothelial dysfunction". The present paper, based on a lecture held at the conference of the European Society of Hemorheology and Microcirculation, will try to deal with these issues.

Ischemic and non-ischemic preconditioning: Endothelium-focused translation into clinical practice.

Pathophysiological studies have clearly demonstrated that the relationship between endothelial [dys]function and tissue ischemia is bidirectional: while it is well accepted that endothelial dysfunction has a key role in the progression and destabilization of coronary atherosclerosis, it is also well known that the endothelium is particularly sensitive to ischemia and reperfusion injury, and that this damage critically determines the extent of tissue damage, e.g. myocardial infarct size. Therefore, protecting the endothelium from ischemia could potentially have important clinical implications. In this scenario, reactive oxygen species [ROS] play a particularly important role: these elusive mediators are involved in determining the endothelial toxic effect of risk factors and are involved in reperfusion injury; however, most importantly, ROS are also key mediators of endothelial preconditioning, a protective process that is characterized by a reduced sensitivity to ischemia and reperfusion injury. We report considerations regarding these phenomena and their potential pharmacologic manipulation as discussed in a lecture at the recent Conference of the European Society of Clinical Hemorheology and Microcirculation held in Pontresina, Switzerland.

Sirolimus-induced vascular dysfunction. Increased mitochondrial and nicotinamide adenosine dinucleotide phosphate oxidase-dependent superoxide production and decreased vascular nitric oxide formation.

OBJECTIVES: This study sought to analyze mechanisms that mediate vascular dysfunction induced by sirolimus. BACKGROUND: Despite excellent antirestenotic capacity, sirolimus-eluting stents have been found to trigger coronary endothelial dysfunction and impaired re-endothelialization. METHODS: To mimic the continuous sirolimus exposure of a stented vessel, Wistar rats underwent drug infusion with an osmotic pump for 7 days. RESULTS: Sirolimus treatment caused a marked degree of endothelial dysfunction as well as a desensitization of the vasculature to the endothelium-independent vasodilator nitroglycerin. Also, sirolimus stimulated intense transmural superoxide formation as detected by dihydroethidine fluorescence in aortae. Increased superoxide production was mediated in part by the vascular nicotinamide adenosine dinucleotide phosphate (NADPH) oxidase as indicated by a marked stimulation of p67(phox)/rac1 NADPH oxidase subunit expression and by increased rac1 membrane association. In addition, superoxide production in rat heart mitochondria was up-regulated by sirolimus, as measured by L012-enhanced chemiluminescence. As a consequence, electron spin resonance measurements showed a 40% reduction in vascular nitric oxide bioavailability, which was further supported by decreased serum nitrite levels. CONCLUSIONS: Sirolimus causes marked vascular dysfunction and nitrate resistance after continuous treatment for 7 days. This impaired vasorelaxation may, in part, be induced by up-regulated mitochondrial superoxide release as well as by an up-regulation of NADPH oxidase-driven superoxide production. Both processes could contribute to endothelial dysfunction observed after coronary vascular interventions with sirolimus-coated stents.

Neointimal expression of rapamycin receptor FK506-binding protein FKBP12: postinjury animal and human in-stent restenosis tissue characteristics.

Despite excellent clinical results for sirolimus (rapamycin)-eluting stents, the exact mechanisms of antirestenotic activity and affected cellular targets are incompletely understood. Therefore, we determined the presence and tem- porospatial expression pattern of FKBP12, the primary intracellular receptor of rapamycin, in rat carotid arteries after balloon injury, as well as in human in-stent restenosis and primary stable coronary atheroma. FKBP12 expression was assessed by immunohistochemistry. Rat carotid arteries revealed maximal expression in 57.7 +/- 4.0% of neointimal cells at day 7. A large proportion of these FKBP12+ cells showed luminally confined co-expression with dendritic cell markers. Despite a considerably thicker neointima at day 28, presence of FKBP12 decreased (8.5 +/- 1.9%, p = 0.02) with a scattered pattern in luminal and deep neointima. Likewise, human in-stent restenosis atherectomy specimens (time after stent implantation 2-12 months) revealed a comparable extent of cellular rapamycin receptor expression (9.3 +/- 1.0%) that significantly differed from that found in primary stable atheroma (1.3 +/- 0.4%, p < 0.001). In conclusion, the rapamycin receptor is predominantly present during early neointima formation, while mature neointimal atheromas show a relatively low expression without confinement to luminal areas. Co-expression of FKBP12 and dendritic cell markers suggests that dendritic cells may be another important target for early and long-term rapamycin effects.