Rationale and design of the ELEANOR trial early aortic valve surgery versus watchful waiting strategy in severe asymptomatic aortic regurgitation, ACRONYM: ELEANOR.

Background: The optimal treatment of patients with severe symptomatic aortic regurgitation (AR) is state-of-the-art surgery. Asymptomatic patients with advanced left ventricular (LV) dilatation and/or impaired ejection fraction should undergo surgical treatment, but there is no guidelines consensus on cut-off values for this recommendation. Multimodality imaging has brought new tools for the accurate selection of asymptomatic patients at risk of early clinical deterioration, however, prospective and randomized data are pending. Cardiac magnetic resonance (CMR)-derived AR quantification along with LV remodeling assessment appears to be the most accurate tool for a selection of such patients at risk. Trial design: The objective of our prospective and multicenter study is to determine whether patients at risk of early clinical deterioration as per CMR assessment will benefit from early surgical treatment. The study is designed as a superiority trial to demonstrate that early surgical treatment is safe and more effective than the standard treatment. A total of 217 asymptomatic patients with severe AR, but without current guidelines-based surgical indication, will be enrolled across all centers. We expect 24 % of patients identified as high clinical risk and therefore eligible for 1:1 randomization to early surgical treatment within 3 months or a watchful waiting strategy. Follow-up will be annual. We expect a complete restoration of LV size and function along with improved quality of life and physical performance in a short-term follow-up of 12 months. The primary endpoint will be a composite safety and efficacy with all criteria mandatory: 15 % or larger reduction of baseline CMR-derived LV end-diastolic volume index, LV ejection fraction >50 %, and no major adverse cardiovascular events. The annual follow-up will continue for a minimum of 4 years until the required number of endpoints is achieved to show a statistically significant difference in cardiovascular morbidity and mortality in early surgically treated patients. Conclusion: The ELEANOR trial is the first multicenter randomized controlled study to compare early surgical treatment with a watchful waiting strategy in asymptomatic patients with chronic severe AR at high risk of early clinical deterioration as per CMR assessment but without guidelines-based indications for surgical treatment.

Fibrosis and expression of extracellular matrix proteins in human interventricular septum in aortic valve stenosis and regurgitation.

Valvular heart disease leads to ventricular pressure and/or volume overload. Pressure overload leads to fibrosis, which might regress with its resolution, but the limits and details of this reverse remodeling are not known. To gain more insight into the extent and nature of cardiac fibrosis in valve disease, we analyzed needle biopsies taken from the interventricular septum of patients undergoing surgery for valve replacement focusing on the expression and distribution of major extracellular matrix protein involved in this process. Proteomic analysis performed using mass spectrometry revealed an excellent correlation between the expression of collagen type I and III, but there was little correlation with the immunohistochemical staining performed on sister sections, which included antibodies against collagen I, III, fibronectin, sarcomeric actin, and histochemistry for wheat germ agglutinin. Surprisingly, the immunofluorescence intensity did not correlate significantly with the gold standard for fibrosis quantification, which was performed using Picrosirius Red (PSR) staining, unless multiplexed on the same tissue section. There was also little correlation between the immunohistochemical markers and pressure gradient severity. It appears that at least in humans, the immunohistochemical pattern of fibrosis is not clearly correlated with standard Picrosirius Red staining on sister sections or quantitative proteomic data, possibly due to tissue heterogeneity at microscale, comorbidities, or other patient-specific factors. For precise correlation of different types of staining, multiplexing on the same section is the best approach.

Targeted left ventricular lead positioning to the site of latest activation in cardiac resynchronization therapy: a systematic review and meta-analysis.

AIMS: Several studies have evaluated the use of electrically- or imaging-guided left ventricular (LV) lead placement in cardiac resynchronization therapy (CRT) recipients. We aimed to assess evidence for a guided strategy that targets LV lead position to the site of latest LV activation. METHODS AND RESULTS: A systematic review and meta-analysis was performed for randomized controlled trials (RCTs) until March 2023 that evaluated electrically- or imaging-guided LV lead positioning on clinical and echocardiographic outcomes. The primary endpoint was a composite of all-cause mortality and heart failure hospitalization, and secondary endpoints were quality of life, 6-min walk test (6MWT), QRS duration, LV end-systolic volume, and LV ejection fraction. We included eight RCTs that comprised 1323 patients. Six RCTs compared guided strategy (n = 638) to routine (n = 468), and two RCTs compared different guiding strategies head-to-head: electrically- (n = 111) vs. imaging-guided (n = 106). Compared to routine, a guided strategy did not significantly reduce the risk of the primary endpoint after 12-24 (RR 0.83, 95% CI 0.52-1.33) months. A guided strategy was associated with slight improvement in 6MWT distance after 6 months of follow-up of absolute 18 (95% CI 6-30) m between groups, but not in remaining secondary endpoints. None of the secondary endpoints differed between the guided strategies. CONCLUSION: In this study, a CRT implantation strategy that targets the latest LV activation did not improve survival or reduce heart failure hospitalizations.

Multiparametric Strategy to Predict Early Disease Decompensation in Asymptomatic Severe Aortic Regurgitation.

BACKGROUND: Use of the current echocardiography-based indications for aortic regurgitation (AR) surgery might result in late valve replacement at the stage of irreversible myocardial damage. Therefore, we aimed to identify simple models combining multiple echocardiography or magnetic resonance imaging (MRI)-derived indices and natriuretic peptides (BNP [brain natriuretic peptide] or NT-proBNP [N-terminnal pro-B type natriuretic peptide]) to predict early disease decompensation in asymptomatic severe AR. METHODS: This prospective and multicenter study included asymptomatic patients with severe AR, preserved left ventricular ejection fraction (>50%), and sinus rhythm. The echocardiography and MRI images were analyzed centrally in the CoreLab. The study end point was the onset of indication for aortic valve surgery as per current guidelines. RESULTS: The derivative cohort consisted of 127 asymptomatic patients (age 45±14 years, 84% males) with 41 (32%) end points during a median follow-up of 1375 (interquartile range, 1041-1783) days. In multivariable Cox regression analysis, age, BNP, 3-dimensional vena contracta area, MRI left ventricular end-diastolic volume index, regurgitant volume, and a fraction were identified as independent predictors of end point (all P<0.05). However, a combined model including one parameter of AR assessment (MRI regurgitant volume or regurgitant fraction or 3-dimensional vena contracta area), 1 parameter of left ventricular remodeling (MRI left ventricular end-diastolic volume index or echocardiography 2-dimensional global longitudinal strain or E wave), and BNP showed significantly higher predictive accuracy (area under the curve, 0.74-0.81) than any parameter alone (area under the curve, 0.61-0.72). These findings were confirmed in the validation cohort (n=100 patients, 38 end points). CONCLUSIONS: In asymptomatic severe AR, multimodality and multiparametric model combining 2 imaging indices with natriuretic peptides, showed high accuracy to identify early disease decompensation. Further prospective studies are warranted to explore the clinical benefit of implementing these models to guide patient management. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02910349.

Aortic Valve Replacement Versus Conservative Treatment in Asymptomatic Severe Aortic Stenosis: The AVATAR Trial.

BACKGROUND: Surgical aortic valve replacement (SAVR) represents a class I indication in symptomatic patients with severe aortic stenosis (AS). However, indications for early SAVR in asymptomatic patients with severe AS and normal left ventricular function remain debated. METHODS: The AVATAR trial (Aortic Valve Replacement Versus Conservative Treatment in Asymptomatic Severe Aortic Stenosis) is an investigator-initiated international prospective randomized controlled trial that evaluated the safety and efficacy of early SAVR in the treatment of asymptomatic patients with severe AS, according to common criteria (valve area ≤1 cm2 with aortic jet velocity >4 m/s or a mean transaortic gradient ≥40 mm Hg), and with normal left ventricular function. Negative exercise testing was mandatory for inclusion. The primary hypothesis was that early SAVR would reduce the primary composite end point of all-cause death, acute myocardial infarction, stroke, or unplanned hospitalization for heart failure compared with a conservative strategy according to guidelines. The trial was designed as event-driven to reach a minimum of 35 prespecified events. The study was performed in 9 centers in 7 European countries. RESULTS: Between June 2015 and September 2020, 157 patients (mean age, 67 years; 57% men) were randomly allocated to early surgery (n=78) or conservative treatment (n=79). Follow-up was completed in May 2021. Overall median follow-up was 32 months: 28 months in the early surgery group and 35 months in the conservative treatment group. There was a total of 39 events, 13 in early surgery and 26 in the conservative treatment group. In the early surgery group, 72 patients (92.3%) underwent SAVR with operative mortality of 1.4%. In an intention-to-treat analysis, patients randomized to early surgery had a significantly lower incidence of primary composite end point than those in the conservative arm (hazard ratio, 0.46 [95% CI, 0.23-0.90]; P=0.02). There was no statistical difference in secondary end points, including all-cause mortality, first heart failure hospitalizations, major bleeding, or thromboembolic complications, but trends were consistent with the primary outcome. CONCLUSIONS: In asymptomatic patients with severe AS, early surgery reduced a primary composite of all-cause death, acute myocardial infarction, stroke, or unplanned hospitalization for heart failure compared with conservative treatment. This randomized trial provides preliminary support for early SAVR once AS becomes severe, regardless of symptoms. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02436655.

Assessment of Asymptomatic Severe Aortic Regurgitation by Doppler-Derived Echo Indices: Comparison with Magnetic Resonance Quantification.

Reliable quantification of aortic regurgitation (AR) severity is essential for clinical management. We aimed to compare quantitative and indirect echo-Doppler indices to quantitative cardiac magnetic resonance (CMR) parameters in asymptomatic chronic severe AR. Methods and Results: We evaluated 104 consecutive patients using echocardiography and CMR. A comprehensive 2D, 3D, and Doppler echocardiography was performed. The CMR was used to quantify regurgitation fraction (RF) and volume (RV) using the phase-contrast velocity mapping technique. Concordant grading of AR severity with both techniques was observed in 77 (74%) patients. Correlation between RV and RF as assessed by echocardiography and CMR was relatively good (rs = 0.50 for RV, rs = 0.40 for RF, p < 0.0001). The best correlation between indirect echo-Doppler and CMR parameters was found for diastolic flow reversal (DFR) velocity in descending aorta (rs = 0.62 for RV, rs = 0.50 for RF, p < 0.0001) and 3D vena contracta area (VCA) (rs = 0.48 for RV, rs = 0.38 for RF, p < 0.0001). Using receiver operating characteristic analysis, the largest area under curve (AUC) to predict severe AR by CMR RV was observed for DFR velocity (AUC = 0.79). DFR velocity of 19.5 cm/s provided 78% sensitivity and 80% specificity. The AUC for 3D VCA to predict severe AR by CMR RV was 0.73, with optimal cut-off of 26 mm2 (sensitivity 80% and specificity 66%). Conclusions: Out of the indirect echo-Doppler indices of AR severity, DFR velocity in descending aorta and 3D vena contracta area showed the best correlation with CMR-derived RV and RF in patients with chronic severe AR.

Silent coronary artery disease in asymptomatic patients with severe aortic stenosis and normal exercise testing.

OBJECTIVE: There are no data about the prevalence of silent coronary artery disease in asymptomatic severe aortic stenosis patients with normal exercise testing. Importantly, unmasking significant coronary artery disease in patients with aortic stenosis could influence the choice/timing of treatment in these patients. METHOD: Exercise testing was performed on semi-supine ergobicycle. Cardiopulmonary analysis during exercise testing, echocardiography, and laboratory analysis at rest was done. Standard clinical/electrocardiography criteria were assessed for symptoms/signs of ischemia during/after exercise testing. In patients with normal exercise testing coronary angiography was performed using standard femoral/radial percutaneous approach. Coronary stenosis was considered significant if >70% of vessel diameter or 50%-70% with fractional flow reserve ≤0.8. RESULTS: Total of 96 patients with normal exercise testing were included (67.6 years, 50.6% males). No patient had any complication or adverse event. The Pmean was 52.7 mmHg, mean indexed aortic valve area was 0.36 cm/m and left ventricular ejection fraction, 69.5%. 19/96 patients (19.8%) had significant coronary artery disease on coronary angiography. Multivariate logistic regression analysis revealed brain natriuretic peptide and blood glucose as independent predictors of silent coronary artery disease. Brain natriuretic peptide value of 118 pg/ml had sensitivity/specificity of 63%/73% for predicting coronary artery disease (area under the curve 0.727, P = 0.006). CONCLUSION: Our results are the first to show that in patients with severe aortic stenosis, normal left ventricular ejection fraction,, and normal exercise testing, significant coronary artery disease is present in as many as 1/5 patients. In such patients, further prospective studies are warranted to address the diagnostic value of brain natriuretic peptide in detecting silent coronary artery disease.

New Imaging Markers of Clinical Outcome in Asymptomatic Patients with Severe Aortic Regurgitation.

Background: Determining the value of new imaging markers to predict aortic valve (AV) surgery in asymptomatic patients with severe aortic regurgitation (AR) in a prospective, observational, multicenter study. Methods: Consecutive patients with chronic severe AR were enrolled between 2015-2018. Baseline examination included echocardiography (ECHO) with 2- and 3-dimensional (2D and 3D) vena contracta area (VCA), and magnetic resonance imaging (MRI) with regurgitant volume (RV) and fraction (RF) analyzed in CoreLab. Results: The mean follow-up was 587 days (interquartile range (IQR) 296-901) in a total of 104 patients. Twenty patients underwent AV surgery. Baseline clinical and laboratory data did not differ between surgically and medically treated patients. Surgically treated patients had larger left ventricular (LV) dimension, end-diastolic volume (all p < 0.05), and the LV ejection fraction was similar. The surgical group showed higher prevalence of severe AR (70% vs. 40%, p = 0.02). Out of all imaging markers 3D VCA, MRI-derived RV and RF were identified as the strongest independent predictors of AV surgery (all p < 0.001). Conclusions: Parameters related to LV morphology and function showed moderate accuracy to identify patients in need of early AV surgery at the early stage of the disease. 3D ECHO-derived VCA and MRI-derived RV and RF showed high accuracy and excellent sensitivity to identify patients in need of early surgery.

Cardiac resynchronization therapy guided by cardiac magnetic resonance imaging: A prospective, single-centre randomized study (CMR-CRT).

BACKGROUND: Cardiac resynchronization therapy (CRT) improves symptoms of heart failure (HF), morbidity and mortality in selected population. The aim of the study was to investigate the impact of cardiac magnetic resonance (CMR)-guided left ventricular (LV) lead placement on clinical outcomes and LV reverse remodelling in CRT recipients. METHODS: Patients with CRT indication were randomized for CMR-guided (CMR group) or electrophysiologically guided (EP group) LV lead placement between 2011 and 2014. The target site in the CMR group was defined as the most delayed, scar-free, in the EP group as the site with the longest interval between the QRS onset and local electrogram. The primary endpoint was a combination of cardiovascular death or HF hospitalization. Secondary endpoints were New York Heart Association (NYHA) Class improvement ≥1, LV endsystolic diameter reduction >10%, B-type natriuretic peptide reduction by ≥30%. RESULTS: A total of 99 patients (47 in the CMR and 52 in the EP group) were enrolled. During a median follow-up of 47 months, primary composite endpoint occurred in 5 patients in the CMR group and 14 patients in the EP group (HR = 0.46; 95% CI: 0.16-1.32). Patients with left bundle branch block and NYHA Class >2 had better clinical outcome in the CMR group (HR = 0.09; 95% CI: 0.01-0.75). CONCLUSIONS: The use of CMR did not result in significant reduction of combined endpoint of cardiovascular death or HF hospitalization in the total study population. Significant clinical benefit from CMR-guided procedure was observed in a subgroup of optimum CRT candidates with advanced HF.

Endocardial Fibroelastosis is Secondary to Hemodynamic Alterations in the Chick Embryonic Model of Hypoplastic Left Heart Syndrome.

BACKGROUND: Endocardial fibroelastosis (EFE) is a diffuse thickening of the ventricular endocardium, causing myocardial dysfunction and presenting as unexplained heart failure in infants and children. One of the postulated causes is persistent and increased wall tension in the ventricles. RESULTS: To examine whether reduced ventricular pressure in a chick model of hypoplastic left heart syndrome (HLHS) induced by left atrial ligation (LAL) at embryonic day (ED) 4 is associated with EFE at later stages, myocardial fibrosis was evaluated by histology and immunoconfocal microscopy and mass spectrometry (MS) at ED12. Immunohistochemistry with collagen I antibody clearly showed a significant thickening of the layer of subendocardial fibrous tissue in LAL hearts, and MS proved this significant increase of collagen I. To provide further insight into pathogenesis of this increased fibroproduction, hypoxyprobe staining revealed an increased extent of hypoxic regions, normally limited to the interventricular septum, in the ventricular myocardium of LAL hearts at ED8. CONCLUSIONS: Abnormal hemodynamic loading during heart development leads to myocardial hypoxia, stimulating collagen production in the subendocardium. Therefore, EFE in this chick embryonic model of HLHS appears to be a secondary effect of abnormal hemodynamics. Developmental Dynamics 247:509-520, 2018. © 2017 Wiley Periodicals, Inc.

Prognostic Implications of Magnetic Resonance-Derived Quantification in Asymptomatic Patients With Organic Mitral Regurgitation: Comparison With Doppler Echocardiography-Derived Integrative Approach.

BACKGROUND: Magnetic resonance imaging (MRI) is an accurate method for the quantitative assessment of organic mitral regurgitation (OMR). The aim of the present study was to compare the discriminative power of MRI quantification and the recommended Doppler echocardiography (ECHO)-derived integrative approach to identify asymptomatic patients with OMR and adverse outcome. METHODS: The study population consisted of 258 asymptomatic patients (63±14 years, 60% men) with preserved left ventricular ejection fraction (>60%) and chronic moderate and severe OMR (flail 25%, prolapse 75%) defined by using the ECHO-derived integrative approach. All patients underwent MRI to quantify regurgitant volume (RV) of OMR by subtracting the aortic forward flow volume from the total left ventricular stroke volume. Severe OMR was defined as RV≥60 mL. RESULTS: Mean ECHO-derived RV was on average 17.1 mL larger than the MRI-derived RV (P<0.05). Concordant grading of OMR severity with both techniques was observed in 197 (76%) individuals with 62 (31%) patients having severe OMR (MRI SEV-ECHO SEV) and 135 (69%) patients having moderate OMR (MRI MOD-ECHO MOD). The remaining 61 (24%) individuals had discordant findings (MRI SEV-ECHO MOD or MRI MOD-ECHO SEV) between the 2 techniques. The majority of these differences in OMR classification were observed in patients with late systolic or multiple jets (both κ<0.2). Patients with eccentric jets showed moderate agreement (κ=0.53; 95% confidence interval, 0.41-0.64). In contrast, a very good agreement (κ=0.90; 95% confidence interval, 0.82-0.98) was observed in a combination of holosystolic, central, and single jet. During a median follow-up of 5.0 years (interquartile range, 3.5-6.0 years), 38 (15%) patients died and 106 (41%) either died or developed indication for mitral valve surgery. In separate Cox regression analyses, the MRI-derived left ventricular end-systolic volume index, RV, and OMR category (severe versus moderate), and the ECHO-derived OMR category were independent predictors of all-cause mortality (all P<0.05). The MRI-derived RV showed the largest area under the curve to predict mortality (0.72) or its combination with the development of indication for mitral valve surgery (0.83). CONCLUSIONS: The findings of the present study suggest that the MRI-derived assessment of OMR can better identify patients with severe OMR and adverse outcome than ECHO-derived integrative approach warranting close follow-up and perhaps, early mitral valve surgery.

B-type natriuretic peptide: powerful predictor of end-stage chronic heart failure in individuals with systolic dysfunction of the systemic right ventricle.

AIM: To assess whether B-type natriuretic peptide (BNP) can serve as a predictor of end-stage chronic heart failure (CHF) in patients with severe systolic dysfunction of the systemic right ventricle (SRV). METHODS: We performed a retrospective analysis in 28 patients with severe systolic dysfunction of the SRV (ejection fraction 23 ± 6%) who were evaluated as heart transplant (HTx) candidates between May 2007 and October 2014. The primary endpoints of the study (end-stage CHF) were progressive CHF, urgent HTx, and ventricular assist device (VAD) implantation. Plasma BNP levels were measured using a chemiluminescent immunoassay. RESULTS: During median follow-up of 29 months (interquartile range, 9-50), 3 patients died of progressive CHF, 5 patients required an urgent HTx, and 6 patients underwent VAD implantation. BNP was a strong predictor of end-stage CHF (hazard ratio per 100 ng/L: 1.079, 95% confidence interval, 1.042-1.117, P<0.001). The following variables with corresponding areas under the curve (AUC) were identified as the most significant predictors of end-stage CHF: BNP (AUC 1.00), New York Heart Association functional class class III or IV (AUC 0.98), decompensated CHF in the last year (AUC 0.96), and systolic dysfunction of the subpulmonal ventricle (AUC 0.96). CONCLUSION: BNP is a powerful predictor of end-stage CHF in individuals with systolic dysfunction of the SRV.

Native T1 Relaxation Time and Extracellular Volume Fraction as Accurate Markers of Diffuse Myocardial Fibrosis in Heart Valve Disease　- Comparison With Targeted Left Ventricular Myocardial Biopsy.

BACKGROUND: The aim of our study was to investigate the relationship between the cardiac magnetic resonance (CMR)-derived native T1 relaxation time and myocardial extracellular volume (ECV) fraction and the extent of diffuse myocardial fibrosis (DMF) on targeted myocardial left ventricular (LV) biopsy. METHODS AND RESULTS: The study population consisted of 40 patients (age 63±8 years, 65% male) undergoing valve and/or ascending aorta surgery for severe aortic stenosis (77.5%), root dilatation (7.5%) or valve regurgitation (15%). The T1 relaxation time was assessed in the basal interventricular septum pre- and 10-min post-contrast administration using the modified Look-Locker Inversion recovery sequence prior to surgery. LV myocardial biopsy specimen was obtained during surgery from the basal interventricular septal segment matched with the T1 mapping assessment. The percentage of myocardial collagen was quantified using picrosirius red staining. The average percentage of myocardial collagen was 22.0±14.8%. Both native T1 relaxation time with cutoff value ≥1,010 ms (sensitivity=90%, specificity=73%, area under the curve=0.82) and ECV with cutoff value ≥0.32 (sensitivity=80%, specificity=90%, area under the curve=0.85) showed high accuracy to identify severe (>30%) DMF. The native T1 relaxation time showed significant correlation with LV mass (P<0.01). CONCLUSIONS: Native T1 relaxation time and ECV at 10 min after contrast administration are accurate markers of DMF. (Circ J 2016; 80: 1202-1209).

Clinical value of assessment of left atrial late gadolinium enhancement in patients undergoing ablation of atrial fibrillation.

BACKGROUND: Left atrial (LA) fibrosis begets atrial fibrillation (AF). Cardiovascular magnetic resonance (CMR) using the late gadolinium enhancement (LGE) technique might visualize the LA fibrosis and thus help to choose an appropriate strategy for treatment of AF. In this regard, we investigated whether the extent of preablation LA LGE would predict AF recurrence after ablation in a non-selected patient population. METHODS: CMR was performed in 95 patients before radiofrequency ablation of AF. An interpretable scan was available in 73 patients (age, 59 ± 8 years; men, 71%; persistent/paroxysmal AF, 55/45%). The extent of LA LGE was quantified by three established thresholding techniques. In addition, CMR was used to quantify LA volume and reservoir function. The patients were followed for AF recurrence for 1.3 ± 0.8 years. RESULTS: The arrhythmia recurred in 29 (40%) of the patients. The extent of LA LGE did not differ between paroxysmal and persistent AF and it did not predict the AF recurrence. Moreover, the extent of LA LGE did not correlate with LA volume, reservoir function and bipolar voltage. CONCLUSIONS: Our data indicate a limited value of a routine assessment of LA LGE before ablation of AF. Further experimental and clinical researches should be done before applying the method to a wide clinical practice.

Three-dimensional echocardiography-derived vena contracta area at rest and its increase during exercise predicts clinical outcome in mild-moderate functional mitral regurgitation.

BACKGROUND: This study assessed the independent significance of color Doppler 3-D vena contracta area (VCA) at rest and during exercise as a predictor of clinical outcome in mild-moderate functional mitral regurgitation (FMR). METHODS AND RESULTS: The subjects consisted of 62 patients (age, 68±11 years; 76% male) with chronic systolic heart failure and mild-moderate FMR (<2+/4) at rest. All patients underwent VCA assessment at rest and during semi-supine bicycle exercise. During median follow-up of 17 months (IQR, 13-20 months), 15 patients (24%) had composite endpoint of all-cause death (n=3), heart failure admission (n=11), and heart transplantation (n=1). At baseline, patients with vs. without endpoint had significantly larger VCA at rest (17±6 mm(2)vs. 13±7 mm(2), P=0.002) and at peak exercise (35±16 mm(2)vs. 21±12 mm(2), P<0.001). On Cox regression analysis, large (≥15-mm(2)) resting VCA (HR, 7.6; 95% CI: 1.93-13.02; P=0.004) and large (≥20-mm(2)) exercise-induced increase of VCA (HR, 5.1; 95% CI: 1.39-15.21; P=0.014) were independently associated with composite endpoint. Concomitant presence of large VCA at rest and its large increase during exercise occurred in 53% of patients with, vs. in only 8% without, endpoint (negative predictive value, 86%). CONCLUSIONS: The presence of relatively large VCA at rest and its significant increase during exercise is independently associated with adverse clinical outcome in patients with mild-moderate FMR at rest.

Adenylyl cyclase signaling in the developing chick heart: the deranging effect of antiarrhythmic drugs.

The adenylyl cyclase (AC) signaling system plays a crucial role in the regulation of cardiac contractility. Here we analyzed the key components of myocardial AC signaling in the developing chick embryo and assessed the impact of selected ß-blocking agents on this system. Application of metoprolol and carvedilol, two commonly used ß-blockers, at embryonic day (ED) 8 significantly downregulated (by about 40%) expression levels of AC5, the dominant cardiac AC isoform, and the amount of Gsα protein at ED9. Activity of AC stimulated by forskolin was also significantly reduced under these conditions. Interestingly, when administered at ED4, these drugs did not produce such profound changes in the myocardial AC signaling system, except for markedly increased expression of Giα protein. These data indicate that ß-blocking agents can strongly derange AC signaling during the first half of embryonic heart development.

[Percutaneous approach for treating mitral regurgitation with mitral clip (MitraClip)]. / Katetrizacní metoda lécby chronické mitrální regurgitace pomocí mitrální svorky (MitraClip).

Mitral regurgitation (MR) is the second most commonly encountered valvular lesion and it has been positively correlated with the subsequent development of heart failure and death. MitraClip therapy is a new percutaneous approach for treating mitral regurgitation which involves mechanical edge-to-edge coaptation of the mitral leaflets that is analogous to the surgical Alfieri technique. Indication for MitraClip in patients with severe degenerative or functional mitral regurgitation is based on clinical symptoms (NYHA II-IV) and specific anatomic criteria including a primary central regurgitant jet associated with the A2/P2 segments, in functional MR a coaptation length 2 mm, a coaptation depth 11 mm, in degenerative MR a flail gap <10 mm, and a flail width < 15 mm. Key exclusion criteria included LVEF 25%, LV end-systolic dimension > 55 mm, mitral valve orifice area < 4 cm2, recent myocardial infarction or endocarditis. The safety profile of the procedure appears to be excellent. Acute outcomes are favourable, and mid-term durability (up to 2 years) is reasonable. Patients who are older, at higher risk for surgical therapy, or with functional mitral regurgitation (FMR) and depressed ejection fractions will constitute the initial target population for MitraClip therapy. Since FMR is primarily a ventricular problem, it remains to be seen whether a leaflet intervention will have durable efficacy.

Heart rate changes mediate the embryotoxic effect of antiarrhythmic drugs in the chick embryo.

A significant increase in cardiovascular medication use during pregnancy occurred in recent years. Only limited evidence on safety profiles is available, and little is known about the mechanisms of adverse effect on the fetus. We hypothesized that drug-induced bradycardia is the leading mechanism of developmental toxicity. Embryotoxicity was tested in ovo after administration of various doses of metoprolol, carvedilol, or ivabradine. Embryonic day (ED) 4 and 8 chick embryos were studied by video microscopy and ultrasound biomicroscopy ex ovo after intraamniotic injection of the drug for a period of 30 min. Stroke volume was calculated by the Simpson method and prolate ellipsoid formula. Significant dose-dependent mortality was achieved in embryos injected with carvedilol and ivabradine. In ED4 embryos, metoprolol, carvedilol, and ivabradine reduced the heart rate by 33%, 27%, and 55%, respectively, compared with controls (6%). In ED8 embryos this effect was more pronounced with a heart rate reduction by 71%, 54%, and 53%, respectively (controls, 36%). Cardiac output decreased in all tested groups but only proved significant in the metoprolol group in ED8 embryos. The number of ß-adrenergic receptors showed a downward tendency during embryonic development. A negative chronotropic effect of metoprolol, carvedilol, and ivabradine was increasingly pronounced with embryonic maturity despite a downward trend in the number of ß-adrenergic receptors. This effect was associated with reduced cardiac output in chick embryos, probably leading to premature death. Although standard doses of these drugs appear relatively safe, high doses have a potentially adverse effect on the fetus through reduced heart rate.

Chronic radial artery occlusion after transradial catheterization. Re-canalization via an ipsilateral ulnar artery.

Transradial approach to coronary angiography is a progressive and increasingly more often used technique. Apart from its advantages, radial artery occlusion (RAO) represents the most serious drawback. Re-canalization of an iatrogenic RAO, although asymptomatic in the majority of cases, remains a discussed and challenging topic. Besides its clear indications in symptomatic patients, it still remains questionable whether to perform this procedure in order to enable future repeated cannulations using the same access site and preserving the other remaining sites. For this particular reason we performed an antegrade re-canalization of an unrecognized RAO, likely a result of a previous transradial approach intervention. After a failed radial approach, the intervention was successfully performed via an ipsilateral ulnar artery. Following an uncomplicated coronary re-catheterization, RAO was angiographically diagnosed and re-canalized via the same (ulnar) access site using standard coronary equipment. Radial and ulnar artery patency were examined and checked on the following day and one month later using duplex ultrasonography.