Florian Krackhardt

Use of the Instantaneous Wave-free Ratio or Fractional Flow Reserve in PCI

Background Coronary revascularization guided by fractional flow reserve (FFR) is associated with better patient outcomes after the procedure than revascularization guided by angiography alone. It is unknown whether the instantaneous wave‐free ratio (iFR), an alternative measure that does not require the administration of adenosine, will offer benefits similar to those of FFR. Methods We randomly assigned 2492 patients with coronary artery disease, in a 1:1 ratio, to undergo either iFR‐guided or FFR‐guided coronary revascularization. The primary end point was the 1‐year risk of major adverse cardiac events, which were a composite of death from any cause, nonfatal myocardial infarction, or unplanned revascularization. The trial was designed to show the noninferiority of iFR to FFR, with a margin of 3.4 percentage points for the difference in risk. Results At 1 year, the primary end point had occurred in 78 of 1148 patients (6.8%) in the iFR group and in 83 of 1182 patients (7.0%) in the FFR group (difference in risk, ‐0.2 percentage points; 95% confidence interval [CI], ‐2.3 to 1.8; P<0.001 for noninferiority; hazard ratio, 0.95; 95% CI, 0.68 to 1.33; P=0.78). The risk of each component of the primary end point and of death from cardiovascular or noncardiovascular causes did not differ significantly between the groups. The number of patients who had adverse procedural symptoms and clinical signs was significantly lower in the iFR group than in the FFR group (39 patients [3.1%] vs. 385 patients [30.8%], P<0.001), and the median procedural time was significantly shorter (40.5 minutes vs. 45.0 minutes, P=0.001). Conclusions Coronary revascularization guided by iFR was noninferior to revascularization guided by FFR with respect to the risk of major adverse cardiac events at 1 year. The rate of adverse procedural signs and symptoms was lower and the procedural time was shorter with iFR than with FFR. (Funded by Philips Volcano; DEFINE‐FLAIR ClinicalTrials.gov number, NCT02053038.)

Beyond the sarcomere: CSRP3 mutations cause hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is a frequent genetic cardiac disease and the most common cause of sudden cardiac death in young individuals. Most of the currently known HCM disease genes encode sarcomeric proteins. Previous studies have shown an association between CSRP3 missense mutations and either dilated cardiomyopathy (DCM) or HCM, but all these studies were unable to provide comprehensive genetic evidence for a causative role of CSRP3 mutations. We used linkage analysis and identified a CSRP3 missense mutation in a large German family affected by HCM. We confirmed CSRP3 as an HCM disease gene. Furthermore, CSRP3 missense mutations segregating with HCM were identified in four other families. We used a newly designed monoclonal antibody to show that muscle LIM protein (MLP), the protein encoded by CSRP3, is mainly a cytosolic component of cardiomyocytes and not tightly anchored to sarcomeric structures. Our functional data from both in vitro and in vivo analyses suggest that at least one of MLPs mutated forms seems to be destabilized in the heart of HCM patients harbouring a CSRP3 missense mutation. We also present evidence for mild skeletal muscle disease in affected persons. Our results support the view that HCM is not exclusively a sarcomeric disease and also suggest that impaired mechano-sensory stress signalling might be involved in the pathogenesis of HCM.

Heart rate following short‐term beta‐blocker titration predicts all‐cause mortality in elderly chronic heart failure patients: insights from the CIBIS‐ELD trial

Beta‐blockers (BBs) improve outcomes in heart failure. Results from the Cardiac Insufficiency Bisoprolol Study in Elderly (CIBIS‐ELD) trial previously demonstrated the feasibility of heart rate, not maximum dose, as a treatment goal. In this pre‐specified analysis, we investigated the prognostic value of achieved heart rate after BB optimization on long‐term mortality.

Modulation of contractions to ergonovine and methylergonovine by nitric oxide and thromboxane A2 in the human coronary artery.

This study explored the modulatory effects of nitric oxide and thromboxane A2 on contractions to ergonovine and methylergonovine in human coronary arteries. To elucidate the different role of nitric oxide synthase in the response to the ergot alkaloids, the serotonin (5-HT) receptors involved in nitric oxide synthase in the response to the ergot alkaloids, the 5-HT receptors involved in nitric oxide release and the contraction of the vascular smooth muscle were characterized with more selective 5-HT-receptor agonists and antagonists. Rings of human coronary arteries from explanted hearts were suspended in organ chambers for isometric tension recording. After testing for contractile (potassium chloride, 60 mM) and endothelial function (substance P, 10(-8) M), respectively, they were exposed to ergot alkaloids or other agonists in the absence or presence of U 46619 (10(-9) M), or nitro-L-arginine (10(-4) M), or both. Ergonovine and methylergonovine were comparable, weak vasoconstrictors in untreated preparations. Contractions to ergonovine were augmented by U 46619, but not by nitro-L-arginine. Contractions to methylergonovine were augmented only by combining U 46619 and nitro-L-arginine. Serotonin and methylergonovine, but not ergonovine, elicited endothelium-dependent, nitric oxide-mediated relaxations. Nonselective 5-HT(1B/1D)-receptor stimulation caused both contractions and relaxations; selective 5-HT1B stimulation caused relaxations only. In the human coronary artery, contractions to ergonovine are not dependent on NO release but are synergistically augmented by thromboxane. Methylergonovine causes similar effects on the vascular smooth muscle, but contractions are inhibited by the release of NO from the endothelium. The 5-HT receptor on the endothelium appears to be different from the receptor on the vascular smooth muscle, which mediates the contractile response to the ergot alkaloids.

Polymer-free sirolimus-eluting stents in a large-scale all-comers population

Objective The objective of this study was to assess the safety and efficacy of a polymer-free sirolimus coated, ultrathin strut drug-eluting stent (PF-SES) in an unselected patient population with a focus on acute coronary syndrome (ACS). Furthermore, stable coronary artery disease (CAD) with short (≤6 months) versus long (>6 months) dual antiplatelet therapy (DAPT) were also studied. Methods Patients who received PF-SES were investigated in an unselected large-scale international, single-armed, multicenter, ‘all comers’ observational study. The primary endpoint was the 9-month target lesion revascularisation (TLR) rate, whereas secondary endpoints included the 9-month major adverse cardiac events (MACE) and procedural success rates. A priori defined subgroups such as patients with ACS, diabetes, lesion subsets and procedural characteristics relative to DAPT were investigated. Results A total of 2877 patients of whom 1084 had ACS were treated with PF-SES (1.31±0.75 stents per patient). At 9 months, the accumulated overall TLR rate was 2.3% (58/2513). There was no significant difference between ACS and stable CAD (2.6% vs 2.1%, p=0.389). However, the overall MACE rate was 4.3% (108/2513) with a higher rate in patients with ACS when compared with the stable CAD subgroup (6.1%, 58/947 vs 3.2%, 50/1566, p<0.001). Conclusions PF-SES angioplasty is safe and effective in the daily clinical routine with low rates of TLR and MACE in an unselected patient population. Our data are in agreement with prior clinical findings that extended DAPT duration beyond 6 months do not improve clinical outcomes in patients with stable CAD (ClinicalTrials.gov Identifier NCT02629575). Trial registration number NCT02629575.

Low permanent pacemaker rates following Lotus device implantation for transcatheter aortic valve replacement due to modified implantation protocol

BACKGROUND Conduction disturbances requiring permanent pacemaker implantation following transcatheter aortic valve replacement (TAVR) are a common problem. Pacemaker implantation rates after TAVR appear to be higher compared to conventional aortic valve replacement. The aim of this study was to analyze whether a high annulus implantation conveys the benefit of a decreased rate of permanent pacemaker implantation while being safe and successful according to Valve Academic Research Consortium 2 (VARC2)-criteria. METHODS A total of 23 patients with symptomatic severe aortic valve stenosis, an aortic annulus of 19-27 mm and at high risk for surgery were treated with the Lotus valve. In all patients the valve was implanted in a high annulus position via femoral access. The primary device performance endpoint was VARC2-defined device success after 30 days and the primary safety endpoint was the need for permanent pacemaker implantation. RESULTS The mean age was 73.23 ± 7.65 years, 46% were female, 38% were New York Heart Association class III/IV at baseline. Thirty-day follow-up data were available for all patients. The VARC2-defined device success rate after 30 days was 22/23 (96%). 2/21 (10%) patients required a newly implanted pacemaker due to 3rd degree atrioventricular block. 25% of the patients developed a new left bundle branch block after valvuloplasty or device implantation. 21 of the 23 patients (96%) had no other signs of conduction disturbances after 30 days. CONCLUSIONS The approach of the modified implantation technique of Lotus TAVR device was safe and effective. The incidence of need for a permanent pacemaker following TAVR could be significantly reduced due to adopted implantation protocol.

[Cardiovascular risk of androgen deprivation therapy for treatment of hormone-dependent prostate cancer : Differences between GnRH antagonists and GnRH agonists].

ZusammenfassungAus mehreren Studien geht hervor, dass das Absenken der Testosteronspiegel bei Patienten mit Prostatakarzinom im Rahmen einer Androgendeprivationstherapie (ADT) mit einem erhöhten Risiko für das Auftreten kardiovaskulärer Ereignisse einhergehen kann, was besonders beim Einsatz von GnRH („gonadotropin-releasing hormone“)-Agonisten aufgefallen ist. Eine ADT mit GnRH-Antagonisten muss jedoch in diesem Zusammenhang aufgrund ihres anderen Wirkmechanismus separat betrachtet werden. In dieser Übersichtsarbeit werden Ursachen für das Auftreten kardiovaskulärer Ereignisse unter ADT diskutiert, die Unterschiede zwischen GnRH-Agonisten und GnRH-Antagonisten im Hinblick auf ihren Wirkmechanismus erläutert, relevante Studien präsentiert und praktische Empfehlungen für den Arzt abgeleitet. Dazu wurde eine Literaturrecherche zu Veröffentlichungen im Zeitraum von 2005 bis September 2015 durchgeführt. Diese ergab, dass Patienten mit Prostatakarzinom unter GnRH-Antagonisten ein geringeres kardiovaskuläres Risiko aufwiesen als Patienten, die mit GnRH-Agonisten behandelt wurden. Dies galt insbesondere für Patienten, die kardiovaskulär erkrankt waren. Die unterschiedlichen Wirkmechanismen beider Substanzklassen liefern erste Erklärungen für das geringere kardiovaskuläre Risiko unter GnRH-Antagonisten. Patienten mit kardiovaskulärer Vorerkrankung oder dem Risiko für ein kardiovaskuläres Ereignis sollten vorzugsweise mit einem GnRH-Antagonisten behandelt werden.AbstractBackgroundSeveral studies have indicated that reduction of testosterone levels in patients with prostate cancer undergoing androgen deprivation therapy (ADT) with gonadotropin-releasing hormone (GnRH) agonists can be associated with an increased risk of cardiovascular events. The GnRH antagonists have a different mode of action compared with GnRH agonists and may be preferred in ADT for patients with cardiovascular disease.ObjectiveThis review article discusses potential mechanisms underlying the development of cardiovascular events associated with ADT when using GnRH agonists and explains the differences in mode of action between GnRH agonists and GnRH antagonists. Additionally, relevant studies are presented and practical recommendations for the clinical practice are provided.Material and methodsA literature search was performed. Full publications and abstracts published in the last 10 years up to September 2015 were considered to be eligible.ResultsThe GnRH antagonists were associated with a decreased risk of cardiovascular events compared with GnRH agonists in prostate cancer patients undergoing ADT and particularly in patients with cardiovascular risk factors or a history of cardiovascular disease. This decrease may be due to the different mode of action of GnRH antagonists compared with GnRH agonists.ConclusionProstate cancer patients with either cardiovascular disease or an increased risk of experiencing a cardiovascular event undergoing ADT should be preferentially treated with GnRH antagonists.

DCB meets DES

The drug-coated balloon (DCB) technique hasmainly been tested in the clinical scenario of in-stent restenosis, where it demonstrated a similar clinical efficacy to additional drug-eluting stent (DES) implantation [1]. Recently, several studies have shown that the usage of DCB in de novo lesions might be beneficial, including in small-vessel disease [2] and bifurcation lesions [3]. DCB offers numerous advantages including rapid and uniform antiproliferative drug transfer to the arterial wall, without the need for permanent metal struts in the vessel wall, thereby avoiding the effect of stents on long-term vascular healing and reducing the duration of double antiplatelet therapy. However, DCB usage requires careful vessel preparation, which implies a change in strategies. When using DCBs, vessel preparation is mandatory and, according to the recommendations of the German Consensus Group on DCB interventions [4], it involves pre-dilatation of the stenotic artery with an angioplasty balloon. If the lesion shows a flow-limiting dissection (thrombolysis in myocardial infarction [TIMI] score ≤ 2), i. e., a dissection of type C–F according to the National Heart, Lung, and Blood Institute classification [5], or a residual stenosis of >30% after initial balloon inflation, a strategy change is recommendedwith the implantation of a DES according to the usual recommendations [6]. Thus, a DCB should be selected only after successful pre-dilatation. It is important to note that the DCB is only used to deliver the drug locally, and should not succeed the pre-dilatation balloon in diameter. If, nevertheless, a significant dissection and/or a residual stenosis of >30% after DCB occurs, bare metal stent (BMS) spot stenting is recommended, again avoiding geographical mismatch. This is to avoid combination of paclitaxel (DCB) with a limus agent (DES), the effects of which on coronary vasculature are largely unknown. However, this might yield inferior results, given the well-demonstrated superior efficacy ofDES-containing limus analogues compared with paclitaxel-coated DES. Ong et al. recently showed that the combinationofDCBwithDESappears to be safe and effective, at least in a porcine model at 28 days of follow-up [7]. Previously, a small study analyzed 69 patients with de novo lesions treated either with a DCB alone or a combination of a DEB andDES and showed that the 7.4% of patients (n =5) treated with DCB and DES as bail-out had outcome rates comparable to those who were treated with DES alone at the 2-year follow-up (major adverse cardiac events = 20.8% vs. 22.7%, p = 0.74; target vessel revascularization (repeat PCI or CABG of the target vessel) = 14.8% vs. 11.5%, p = 0.44; target lesion revascularization = 9.6% vs. 9.3%, p = 0.84) [8]. Intheirpaper,Moketal. provideadditional insights into this matter [9]. They analyzed 76 patients who were treated with either BMS or a DES after DCB employment (10% for recoil, 52% for a dissection, and 38% for other reasons). Of these patients, 52 were treated with a BMS and 24 with a DES, and at the 1-year follow-up there were nomajor differences in terms of clinical endpoints (major adverse cardiac events, CV death, myocardial infarction, or target lesion revascularization). Angiographically, only 15 patients in the PCB + BMS group and eight patients in the PCB + DES group had follow-up angiograms, of whom five (33.3%) and one (12.5%) patients, respectively, showed significant in-stent restenosis. The authors therefore concluded that that use of DES following PCB appeared to be clinically safe and effective in their cohort. In conclusion, DCB offers possible advantages in a subset of coronary anatomies. When using DCB, careful vessel preparation is mandatory. The turning point in a DCB–percutaneous coronary intervention concept is the angiographic result after vessel preparation. If angioplasty has yielded a vessel dissection or suboptimal vessel reparation, subsequent stent implantation is recommended. Once vessel preparation has yielded an optimal result, the DCB can be used as planned solely for local delivery of the drug. If, nevertheless, the drug delivery has resulted in flow-limiting dissection of the vessel, the current study and the results in animal models indicate that bailout stenting with a DES is safe and efficient.

N-terminal pro-B-type natriuretic peptide and long-term mortality in non-ischaemic cardiomyopathy

ZusammenfassungZIEL: N-Terminales Pro-B-Typ Natriuretisches Peptid (NT-proBNP) ist ein starker Prädiktor für Sterblichkeit bei Patienten mit akuter und chronischer Herzinsuffizienz bedingt durch eine ischämische Herzerkrankung. Hingegen ist die prognostische Aussagekraft bei Patienten mit nicht-ischämischer Herzerkrankung weit weniger etabliert. Wir haben daher den Zusammenhang von NT-proBNP Serumspiegeln und Langzeit-Sterblichkeit von Patienten mit nicht-ischämischer Kardiomyopathie untersucht. METHODEN: Bei 156 Patienten, die sich mit einer invasiv gesicherten nicht-ischämischen Herzinsuffizienz in unserer Klinik vorstellten, wurden die NT-proBNP Serumspiegel bestimmt. Die Gesamtsterblichkeitsrate wurde im Rahmen eines mittleren Beobachtungszeitraums von 8.9 Jahren erhoben. ERGEBNISSE: Unter Verwendung eines proportionalen Cox Risiko Models konnte in multivariaten Analysen NT-proBNP und der linksventrikuläre diastolische Durchmesser als Prädiktoren für kardial bedingte Sterblichkeit mit einer geschätzten Hazard Ratio von 2.76 (95 % KI: 1.53, 4.98) und 1.06 (95 % KI: 1.02, 1.10) beobachtet werden. SCHLUSSFOLGERUNG: In dieser bisher längsten Nachbeobachtung eignete sich NT-proBNP auch bei Patienten mit nicht-ischämischer Kardiomyopathie als Risikoprädiktor für Sterblichkeit und war einer Beurteilung nach der New York Heart Association Klasse und der linksventrikulären Ejektionsfraktion überlegen.SummaryAIM: The inactive N-terminal fragment of B-type natriuretic peptide is a strong predictor of mortality among patients with acute and chronic heart failure secondary to ischaemic heart disease. Its prognostic utility in patients with non-ischaemic heart disease is not well established. We therefore assessed the relationship of N-terminal proBNP levels and long-term mortality in patients with non-ischaemic cardiomyopathy. METHODS: N-terminal proBNP was measured in serum samples of 156 patients who presented to a single academic centre with worsening heart failure secondary to non-ischaemic cardiomyopathy. The rate of death from all causes was determined after a mean follow-up of 8.9 years. RESULTS: Multivariate analyses, using Cox proportional hazards models, established NT-proBNP and left ventricular diastolic diameter as predictors for cardiac mortality with estimated hazard ratios of 2.76 (95% confidence interval: 1.53, 4.98) and 1.06 (95% confidence interval: 1.02, 1.10), respectively. CONCLUSION: This to date longest-term analysis of N-terminal proBNP and mortality in patients with proven non-ischaemic cardiomyopathy confirms this cardiac-specific biomarker as powerful, independent risk predictor. It is a superior prognostic determinant to New York Heart Association functional class and left ventricular ejection fraction.

Drug-coated balloons for de novo lesions in small coronary arteries: rationale and design of BASKET-SMALL 2

The treatment of coronary small vessel disease (SVD) remains an unresolved issue. Drug‐eluting stents (DES) have limited efficacy due to increased rates of instent‐restenosis, mainly caused by late lumen loss. Drug‐coated balloons (DCB) are a promising technique because native vessels remain structurally unchanged. Basel Stent Kosten‐Effektivitäts Trial: Drug‐Coated Balloons vs. Drug‐Eluting Stents in Small Vessel Interventions (BASKET‐SMALL 2) is a multicenter, randomized, controlled, noninferiority trial of DCB vs DES in native SVD for clinical endpoints. Seven hundred fifty‐eight patients with de novo lesions in vessels <3 mm in diameter and an indication for percutaneous coronary intervention such as stable angina pectoris, silent ischemia, or acute coronary syndromes are randomized 1:1 to angioplasty with DCB vs implantation of a DES after successful initial balloon angioplasty. The primary endpoint is the combination of cardiac death, nonfatal myocardial infarction, and target‐vessel revascularization up to 1 year. Secondary endpoints include stent thrombosis, Bleeding Academic Research Consortium (BARC) type 3 to 5 bleeding, and long‐term outcome up to 3 years. Based on clinical endpoints after 1 year, we plan to assess the noninferiority of DCB compared to DES in patients undergoing primary percutaneous coronary intervention for SVD. Results will be available in the second half of 2018. This study will compare DCB and DES regarding long‐term safety and efficacy for the treatment of SVD in a large all‐comer population.