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Aims: Circular irrigated radiofrequency ablation using the nMARQ catheter has recently been introduced for the treatment of atrial fibrillation (AF). The aim of this study is to report the safety and efficacy of catheter ablation using this technology in patients with paroxysmal and persistent AF., Methods and Results: The data of a prospective registry describing the experience of a single operator using this technology on 327 consecutive patients were analysed. The mean procedure time was 69 ± 22 min for paroxysmal AF (n = 228) and 75 ± 23 min for persistent AF (n = 97). Follow-up was available for 206 (63%) patients for 6 ± 5 months (range 1-23, median 3.3). Single procedure success off antiarrhythmic drugs was 75% in paroxysmal AF and 52% in persistent AF. Including the 5% redo cases and those on antiarrhythmic medication, freedom from AF was documented in 90 and 83% of paroxysmal and persistent AF patients, respectively. There were no serious complications in the first 325 patients, but the last two consecutive patients (0.6%) developed atrio-oesophageal fistulas and had a fatal outcome. The catheter has been recalled from market., Conclusion: The nMARQ catheter is a highly effective tool for treatment of paroxysmal and persistent AF. Nevertheless, the occurrence of life-threatening oesophageal fistulas is of major concern and requires further investigation., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.)

Background: For successful cardiac resynchronisation therapy (CRT) a spatial and electrical separation of right and left ventricular electrodes is essential. The spatial distribution of electrical delays within the coronary sinus (CS) tributaries has not yet been identified., Objective: Electrical delays within the CS are described during sinus rhythm (SR) and right ventricular pacing (RVP). A coordinate system grading the mitral ring from 0° to 360° and three vertical segments is proposed to define the lead positions irrespective of individual CS branch orientation., Methods: In 13 patients undergoing implantation of a CRT device 6±2.5, (median 5) lead positions within the CS were mapped during SR and RVP. The delay to the onset and the peak of the local signal was measured from the earliest QRS activation or the pacing spike. Fluoroscopic positions were compared to localizations on a nonfluoroscopic electrode imaging system., Results: During SR, electrical delays in the CS were inhomogenous in patients with or without left bundle branch block (LBBB). During RVP, the delays increased by 44±32 ms (signal onset from 36±33 ms to 95±30 ms; p<0.001, signal peak from 105±44 ms to 156±30 ms; p<0.001). The activation pattern during RVP was homogeneous and predictable by taking the grading on the CS ring into account: (% QRS) = 78-0.002 (grade-162)(2), p<0.0001. This indicates that 78% of the QRS duration can be expected as a maximum peak delay at 162° on the CS ring., Conclusion: Electrical delays within the CS vary during SR, but prolong and become predictable during RVP. A coordinate system helps predicting the local delays and facilitates interindividual comparison of lead positions irrespective of CS branch anatomy.

Aims: We investigated whether myeloid-related protein 8/14 complex (MRP8/14) expressed by infiltrating monocytes and granulocytes may represent a mediator and early biomarker of acute coronary syndromes (ACS)., Methods and Results: Immunohistochemistry of coronary thrombi was done in 41 ACS patients. Subsequently, levels of MRP8/14 were assessed systemically in 75 patients with ACS and culprit lesions, with stable coronary artery disease (CAD), or with normal coronary arteries. In a subset of patients, MRP8/14 was measured systemically and at the site of coronary occlusion. Macrophages and granulocytes, but not platelets stained positive for MRP8/14 in 76% of 41 thrombi patients. In ACS, local MRP8/14 levels [22.0 (16.2-41.5) mg/L] were increased when compared with systemic levels [13.4 (8.1-14.7) mg/L, P = 0.03]. Systemic levels of MRP8/14 were markedly elevated [15.1 (12.1-21.8) mg/L, P = 0.001] in ACS when compared with stable CAD [4.6 (3.5-7.1) mg/L] or normals [4.8 (4.0-6.3) mg/L]. Using a cut-off level of 8 mg/L, MRP8/14 but not myoglobin or troponin, identified ACS presenting within 3 h from symptom onset., Conclusion: In ACS, MRP8/14 is markedly expressed at the site of coronary occlusion by invading phagocytes. The occurrence of elevated MRP8/14 in the systemic circulation prior to markers of myocardial necrosis makes it a prime candidate for the detection of unstable plaques and management of ACS.

Background: Crossing chronic total occlusions (CTO) of coronary arteries continues to challenge interventional cardiologists. A clinical study was undertaken in four European centers to examine the feasibility of using the new CROSSER system that utilizes high-frequency mechanical vibration to penetrate atherosclerotic plaque material to cross CTOs in patients where conventional guidewire techniques had failed. The objective of the study was to determine whether the CROSSER system could safely cross such CTOs., Patients and Methods: A total of 55 CTO lesions in 53 patients were treated in two clinical phases: (1) Phase 1 feasibility study (30 CTOs), with a primary focus on device safety; and (2) Phase 2 pivotal study (25 CTOs) using an improved version of the device, with a primary focus on effectiveness., Results: The primary endpoint of device efficacy and the secondary endpoint of clinical success were both 76% (19 of 25) in the pivotal study phase. No major adverse cardiac events of death, Q-wave myocardial infarction or target lesion revascularization (by either coronary artery bypass graft surgery or percutaneous coronary intervention) were observed through 30-day follow up. No coronary perforation or pericardial tamponade occurred., Conclusions: The CROSSER system is a safe device that can cross many occlusions after a conventional guidewire failure. With additional refinement and improvements to the device, this success rate could be further increased.

Natriuretic peptides play an important role in water and salt homeostasis and in the regulation of the cardiovascular system. In recent years, exogenous administration of natriuretic peptides has primarily been used to improve our understanding of the role of natriuretic peptides. Also, it became evident that natriuretic peptides may be used therapeutically. Because of their peptide character, they cannot be administered orally and, therefore, may be used for short-term intravenous therapy only. In recent years, inhibitors of neutral endopeptidase, which degrades natriuretic peptides to inactive metabolites, have been investigated. This review focuses on the potential benefits of increasing natriuretic peptide levels, either through exogenous administration or inhibiting the degradation of endogenous natriuretic peptides.

Endothelin-1 (ET-1) regulates vascular tone in congestive heart failure and modulates renal function. Its role in patients with normal left ventricular (LV) function and its renal effects are unclear. Cardiac and renal hemodynamics were studied in 24 patients with normal LV function and coronary arteries after single-dose, double-blind, randomized administration of TAK-044 (25, 50, or 100 mg, i.v.), an ET(A/B)-receptor antagonist, or placebo. Hemodynamics were monitored using Swan-Ganz and arterial catheters, and ET levels were measured. Renal function was assessed by clearance techniques. In the absence of a dose-response relation, TAK-044 patients were analyzed as a single group. Most hemodynamic effects occurred during the first 4 h. TAK-044 reduced mean arterial (-9.3 mm Hg, p < 0.001), pulmonary (-1.8 mm Hg, p = 0.01), and pulmonary capillary wedge pressure (-1.6 mm Hg, p < 0.001) between 30 min and 4 h. Mean reduction in systemic vascular resistance was 279 dyne/s/cm2 (p < 0.001), whereas heart rate increased 6.1 beats/min (p < 0.001) and cardiac index by 0.37 L/m2 (p = 0.01). Stroke volume index, right atrial pressure, and pulmonary vascular resistance did not change. TAK-044 increased renal plasma flow in proportion to the increase in cardiac output (+119 ml/min, 4 h after TAK-044; p < 0.05) and ET-1 levels (2.5-fold; p < 0.05). No serious side effects were noted. In patients with normal cardiac function, ET-receptor blockade causes vasodilation and reduces systemic but not pulmonary vascular resistance and increases cardiac index and renal plasma flow.

Endothelin (ET)-1 is a potent vasoconstrictor with growth promoting and mitogenic properties associated with various cardiovascular diseases (CVD) and has been found to be an important protagonist in congestive heart failure (CHF). The introduction of ET-1 receptor antagonists into the arena of clinical research has amplified our understanding of the ET system: the first human trials with acute and chronic inhibition of the ET system have shown promising results and confirm the findings from experimental models. The availability of oral compounds such as bosentan has raised the hope that these novel drugs might become a new therapeutic class of agents for the treatment of CVD and, in particular, of CHF. The question, however, remains whether the beneficial effects observed so far in patients with CHF go beyond simple hemodynamic improvements and whether these compounds improve long-term survival in these patients.

Background: The vasoconstrictor peptide endothelin-1 (ET-1) is important for increased vascular tone in patients with chronic heart failure, but the effects of endothelin-receptor blockade in addition to conventional triple therapy are unknown., Methods and Results: Thirty-six men (mean age+/-SD, 55+/-8 years) with symptomatic heart failure (NYHA class III; left ventricular ejection fraction, 22.4+/-4.5%) despite treatment with diuretics, digoxin, and ACE inhibitors received, in a double-blind and randomized fashion, either additional oral bosentan (1.0 g BID; n=24) or placebo (n=12) over 2 weeks. Hemodynamic and hormonal (plasma ET-1, norepinephrine, renin activity, and angiotensin II) measurements were obtained before and repeatedly for 24 hours after administration of bosentan on days 1 and 14. Bosentan was discontinued in 1 patient with symptomatic hypotension, and 2 patients (bosentan group) declined hemodynamic investigations on day 14. Compared with placebo, bosentan on day 1 significantly decreased mean arterial pressure (difference from baseline over 12 hours [95% CIs], -13.9% [-16.0% to -11.7%]), pulmonary artery mean (-12.9% [-17. 4% to -8.3%]) and capillary wedge (-14.5% [-20.5% to -8.5%]) pressures, and right atrial pressure (-20.2% [-29.4% to -11.0%]). Cardiac output increased (15.1% [10.7% to 19.7%]), but heart rate was unchanged. Both systemic (-24.2% [-28.1% to -20.3%]) and pulmonary (-19.9% [-28.4% to -11.4%]) vascular resistance were reduced. After 2 weeks, cardiac output had further increased (by 15. 2% [10.8% to 19.6%]) and systemic (-9.3% [-12.3% to -6.4%]) and pulmonary (-9.7% [-16.3% to -3.1%]) vascular resistances further decreased compared with day 1. Heart rate remained unchanged. Plasma ET-1 levels increased after bosentan, but baseline levels of the other hormones were unchanged., Conclusions: Additional short-term oral endothelin-receptor antagonist therapy improved systemic and pulmonary hemodynamics in heart failure patients who were symptomatic with standard triple-drug therapy. Further investigations are warranted to characterize the effects of long-term endothelin-receptor antagonist therapy on symptoms, morbidity, and mortality in such patients.

Patients with chronic heart failure (CHF) are hemodynamically characterized by increased vasoconstriction and a reduced vasodilator response to exercise. In addition to various compensatory neurohumoral mechanisms, there is evidence that the endothelium plays an important role in the abnormal vasodilator response. This evidence comes from studies investigating the microvascular response to regional, intra-arterial administration of the endothelium-dependent vasodilator acetylcholine, which found that the vasodilator response and therefore the bioavailability of nitric oxide (NO) was impaired in the microcirculation of the leg, forearm, and myocardium of patients with CHF. The mechanisms underlying this abnormal response are not entirely clear but may reflect a muscarinic receptor abnormality. Because conduit artery vasodilatation during hyperemic blood flow is also impaired and because this response is not dependent on muscarinic receptor activation, this possibility appears to be unlikely. However, impaired smooth muscle responsiveness to NO stimulation, impaired L-arginine availability or utilization, endothelial release of vasoconstricting prostanoids, increased NO degradation and reduced NO synthase activity have all been implicated in this impaired response. In addition, the vasoconstrictor activity of endothelin (ET)-1 appears to play an important role in the regulation of tone in CHF, although the importance of different ET receptors is not yet clear.

Objective: To describe the entity of isolated ventricular noncompaction (IVNC) and present a series of cases of this rare disorder in an adult population., Material and Methods: We review a 10-year experience with the diagnosis of IVNC and discuss the clinical, echocardiographic, and pathologic features of this condition. Echocardiographic diagnostic criteria included the absence of coexisting cardiac abnormalities, the presence of prominent and excessive trabeculations of one or more ventricular wall segments, and intertrabecular spaces perfused from the ventricular cavity. Pathologic examination focused on regions with exaggerated trabeculations and deep intertrabecular spaces., Results: IVNC is an unexplained arrest of myocardial morphogenesis previously encountered mainly in pediatric patients. Among 37,555 transthoracic echocardiographic studies performed at our hospital between January 1984 and October 1993, 17 cases of IVNC were identified in adult subjects (14 men and 3 women, 18 to 71 years of age). The mean time from onset of symptoms to correct diagnosis was 3.5 +/- 5.7 years, and the mean duration of follow-up was 30 +/- 28 months. Common clinical symptoms were heart failure, ventricular arrhythmias, and a history of embolic events. Two-dimensional echocardiography revealed 10 patients with left ventricular and 7 (41%) with biventricular IVNC. During a 6-year follow-up period, eight patients died and two underwent heart transplantation., Conclusion: Although the diagnosis of IVNC in an adult population is often delayed because of similarities with more frequently diagnosed conditions, two-dimensional echocardiography will facilitate the diagnosis of IVNC in this subset of patients. Because of the high incidence of heart failure, ventricular arrhythmias, and embolization in adults with IVNC, early diagnosis is important.

Background: The significance of International Society for Heart Transplantation (ISHT) grade 2 cardiac allograft rejection has been questioned, and the medical community is not in complete agreement as to its clinical management. We therefore retrospectively analyzed the follow-up of all available endomyocardial biopsy samples obtained from 161 transplant patients since introduction of the ISHT nomenclature at our institution., Methods and Results: Of 2868 biopsies performed 3 days to 8.9 years after transplantation, 420 biopsies had no follow-up or were preceded by intensified immunosuppression and were excluded from analysis. Of the remaining 2448 biopsies, 374 (15.3%) were repeat biopsies performed 7 to 10 days after prior ISHT 2 rejection without change of treatment. Of these, 70 (18.7%) had progressed to > or = ISHT 3A, whereas 82 (21.9%) remained unchanged and 222 (59.4%) resolved. In contrast, follow-up of 2074 biopsies with lower-grade rejection showed graft rejection classified as > or = ISHT 3A in 153 (7.4%), ISHT 2 in 240 (11.6%), and < or = ISHT 1B in 1681 (81.1%) biopsy samples (P < .0001). In univariate analysis, the odds ratio (OR) of graft rejection > or = ISHT 3A after ISHT 2 rejection was 2.89. Other univariate predictors of rejection > or = ISHT 3A were time after transplantation (OR = 0.96 per month, P < .0001), blood group type B (OR = 1.62, P < .005), "Quilty" lesion on previous biopsy (OR = 1.70, P < .005), number of HLA mismatches (OR = 1.27 per mismatch, P < .005), female sex (OR = 1.55, P < .05), and serum creatinine level (OR = 0.93 per 10 mumol/L, P < .005). Young age of recipients was a risk factor during long-term (> or = 2 years) follow-up (P < .002), and lower cyclosporine level was a risk factor during the first month after transplantation (P < .01). In multivariate logistic regression analysis, ISHT 2 rejection on previous biopsy remained the strongest predictor of rejection > or = ISHT 3A (OR = 2.40, P < .0001)., Conclusions: Several factors independently increase the risk of rejection classified as > or = ISHT 3A. The strongest predictor of a grade of > or = ISHT 3A was ISHT 2 rejection on the previous biopsy obtained 7 to 10 days earlier. Therefore, ISHT 2 graft rejection is of clinical significance, and short-term follow-up appears to be warranted even late after transplantation.

The ideal therapy for patients with chronic heart failure should reduce symptoms related to pulmonary congestion or low perfusion, prevent the progression of left ventricular dysfunction and, ultimately, should reduce mortality. Extensive studies in humans have investigated the effects of angiotensin-converting enzyme (ACE) inhibitors on these goals of therapy. As an example, the ACE inhibitor cilazapril significantly improved exercise tolerance, as borne out by a meta-analysis of six placebo-controlled, randomized 3-month trials. Comparison of the effects of cilazapril and captopril vs. placebo in one of the trials documented similar improvement in exercise tolerance (14 vs. 17%). Results from other randomized comparative trials suggest that the improvement in symptoms represents a class effect of ACE inhibitors. A beneficial effect of ACE inhibition on the progression of left ventricular dysfunction has also been demonstrated in the SOLVD trial, and a reduction of mortality has been amply documented in several mortality trials (CONSENSUS I, SOLVD, V-HeFT-II, SAVE, AIRE, SMILE) in patients with or without preceding myocardial infarction. Reports that ACE inhibitors also reduce the incidence of reinfarction after myocardial infarction have not been confirmed in all studies but raise the interesting concept that ACE inhibition may interact, in a beneficial but thus far not well-understood way, with key processes in the development of atherosclerosis, thereby preventing plaque rupture, thrombus formation, and myocardial infarction. Taken together, a large database convincingly demonstrates that ACE inhibitors are effective not only in improving symptoms but also in the prevention of progression of left ventricular dysfunction, in the reduction of mortality, and possibly in stabilizing the atherosclerotic disease process.

Objectives: The present study was designed to evaluate the effects of surgical procedure on left ventricular systolic and diastolic function in patients with mitral regurgitation., Background: Left ventricular systolic function has been shown to decline after operation in patients with chronic mitral regurgitation., Methods: Using simultaneous cineangiography and left ventricular micromanometry, we evaluated left ventricular systolic and diastolic function in 14 patients with chronic mitral regurgitation both preoperatively and at an average of 22 months after operation. Eight patients underwent mitral valve reconstruction, and six had a valve replacement with interruption of the chordae tendineae. We compared these patients with 10 control subjects., Results: Preoperatively, patients with mitral regurgitation demonstrated normal global and regional left ventricular systolic function. Peak rate of diastolic filling was increased (p < 0.01), and passive chamber stiffness was decreased, compared with that in control subjects (p < 0.01), and there was normal myocardial stiffness. Postoperatively, systolic and diastolic function returned to normal in patients undergoing mitral valve reconstruction. In contrast, global systolic function was depressed in patients after valve replacement (p < 0.05), with regional dysfunction in the area of papillary muscle attachment (p < 0.01). Diastolic function was depressed in this group, with a prolonged time constant of pressure decay (p < 0.01) and a depressed rate of early diastolic filling and strain rate (p < 0.05). Passive elastic stiffness was within the normal range in all postoperative patients., Conclusions: The type of operation performed to correct chronic mitral regurgitation has an important effect on postoperative left ventricular function. Systolic and diastolic function are preserved after mitral valve reconstruction. Mitral valve replacement with chordal interruption is associated with global and regional systolic dysfunction and early diastolic filling and relaxation abnormalities.

Microvascular angina is characterized by exercise-induced angina in patients with normal coronary arteries and reduced coronary flow reserve. Recently, a generalized disorder of abnormal vascular reactivity in microvascular angina has been postulated. Therefore, coronary flow reserve was determined by the coronary sinus thermodilution technique and compared with the cutaneous flux ratio in 6 control subjects (group 1) and 12 patients with microvascular angina (group 2). Coronary flow reserve was calculated from maximal coronary flow after 0.5 mg/kg of dipyridamole divided by flow at rest. Cutaneous flow ratio was estimated by laser Doppler fluxmetry (right forearm) before and after 4 min of suprasystolic blood pressure occlusion. Coronary flow at rest was identical in the two groups, but after maximal vasodilation with dipyridamole, coronary flow was higher in group 1 than in group 2 (p less than 0.05). Coronary flow reserve differed significantly between the two groups (2.9 in group 1 and 1.3 in group 2; p less than 0.001). Cutaneous Doppler flux at rest was higher in group 1 than in group 2 (p less than 0.05). However, the hyperemic response was identical in both groups. It is concluded that the cutaneous flux ratio in patients with microvascular angina is not impaired. Local peripheral vasomotor tone appears to be increased in patients with microvascular angina because cutaneous flow at rest is reduced. Thus, a generalized disorder of abnormal vascular reactivity cannot be confirmed in patients with microvascular angina.