Bleeding and thrombotic risk of different antiplatelet regimens posttranscatheter edge-to-edge mitral valve repair in patients with an indication for oral anticoagulation: Results from an all-comers national registry.

BACKGROUND: Evidence-based recommendations for antithrombotic treatment in patients who have an indication for oral anticoagulation (OAC) after transcatheter edge-to-edge mitral valve repair (TEER) are lacking. AIMS: To compare bleeding and thrombotic risk for different antithrombotic regimens post-TEER with MitraClip in an unselected population with the need for OACs. METHODS: Bleeding and thrombotic complications (stroke and myocardial infarction) up to 3 months after TEER with mitraclip were evaluated in 322 consecutive pts with an indication for OACs. These endpoints were defined by the Mitral Valve Academic Research Consortium criteria and were compared between two antithrombotic regimens: single antithrombotic therapy with OAC (single ATT) and double/triple ATT with a combination of OAC and aspirin and/or clopidogrel (combined ATT). RESULTS: Collectively, 108 (34%) patients received single ATT, 203 (63%) received double ATT and 11 (3%) received triple ATT. Bleeding events occurred in 67 patients (20.9%), with access site related events being the most frequent cause (37%). Bleeding complications were observed more frequently in the combined ATT group than in the single ATT group: 24% versus 14% [p = 0.03, adjusted RR: 0.55 (0.3-0.98)]. Within the combined group, the bleeding risk was 23% in the double ATT and 45% in the triple ATT group. Thrombotic complications occurred in only three patients (0.9%), and all belonged to the combined ATT group. CONCLUSIONS: In patients with an indication for OACs, withholding of antiplatelet therapy post-TEER with Mitraclip was associated with a 45% reduction in bleeding and without a signal of increased thrombotic risk.

Targeting high glucose-induced epigenetic modifications at cardiac level: the role of SGLT2 and SGLT2 inhibitors.

BACKGROUND: Sodium-glucose co-transporters (SGLT) inhibitors (SGLT2i) showed many beneficial effects at the cardiovascular level. Several mechanisms of action have been identified. However, no data on their capability to act via epigenetic mechanisms were reported. Therefore, this study aimed to investigate the ability of SGLT2 inhibitors (SGLT2i) to induce protective effects at the cardiovascular level by acting on DNA methylation. METHODS: To better clarify this issue, the effects of empagliflozin (EMPA) on hyperglycemia-induced epigenetic modifications were evaluated in human ventricular cardiac myoblasts AC16 exposed to hyperglycemia for 7 days. Therefore, the effects of EMPA on DNA methylation of NF-κB, SOD2, and IL-6 genes in AC16 exposed to high glucose were analyzed by pyrosequencing-based methylation analysis. Modifications of gene expression and DNA methylation of NF-κB and SOD2 were confirmed in response to a transient SGLT2 gene silencing in the same cellular model. Moreover, chromatin immunoprecipitation followed by quantitative PCR was performed to evaluate the occupancy of TET2 across the investigated regions of NF-κB and SOD2 promoters. RESULTS: Seven days of high glucose treatment induced significant demethylation in the promoter regions of NF-kB and SOD2 with a consequent high level in mRNA expression of both genes. The observed DNA demethylation was mediated by increased TET2 expression and binding to the CpGs island in the promoter regions of analyzed genes. Indeed, EMPA prevented the HG-induced demethylation changes by reducing TET2 binding to the investigated promoter region and counteracted the altered gene expression. The transient SGLT2 gene silencing prevented the DNA demethylation observed in promoter regions, thus suggesting a role of SGLT2 as a potential target of the anti-inflammatory and antioxidant effect of EMPA in cardiomyocytes. CONCLUSIONS: In conclusion, our results demonstrated that EMPA, mainly acting on SGLT2, prevented DNA methylation changes induced by high glucose and provided evidence of a new mechanism by which SGLT2i can exert cardio-beneficial effects.

Glycated ACE2 reduces anti-remodeling effects of renin-angiotensin system inhibition in human diabetic hearts.

BACKGROUND: High glycated-hemoglobin (HbA1c) levels correlated with an elevated risk of adverse cardiovascular outcomes despite renin-angiotensin system (RAS) inhibition in type-2 diabetic (T2DM) patients with reduced ejection fraction. Using the routine biopsies of non-T2DM heart transplanted (HTX) in T2DM recipients, we evaluated whether the diabetic milieu modulates glycosylated ACE2 (GlycACE2) levels in cardiomyocytes, known to be affected by non-enzymatic glycosylation, and the relationship with glycemic control. OBJECTIVES: We investigated the possible effects of GlycACE2 on the anti-remodeling pathways of the RAS inhibitors by evaluating the levels of Angiotensin (Ang) 1-9, Ang 1-7, and Mas receptor (MasR), Nuclear-factor of activated T-cells (NFAT), and fibrosis in human hearts. METHODS: We evaluated 197 first HTX recipients (107 non-T2DM, 90 T2DM). All patients were treated with angiotensin-converting enzyme inhibitor (ACE-I) or angiotensin receptor blocker (ARB) at hospital discharge. Patients underwent clinical evaluation (metabolic status, echocardiography, coronary CT-angiography, and endomyocardial biopsies). Biopsies were used to evaluate ACE2, GlycACE2, Ang 1-9, Ang 1-7, MasR, NAFT, and fibrosis. RESULTS: GlycACE2 was higher in T2DM compared tonon-T2DM cardiomyocytes. Moreover, reduced expressions of Ang 1-9, Ang 1-7, and MasR were observed, suggesting impaired effects of RAS-inhibition in diabetic hearts. Accordingly, biopsies from T2DM recipients showed higher fibrosis than those from non-T2DM recipients. Notably, the expression of GlycACE2 in heart biopsies was strongly dependent on glycemic control, as reflected by the correlation between mean plasma HbA1c, evaluated quarterly during the 12-month follow-up, and GlycACE2 expression. CONCLUSION: Poor glycemic control, favoring GlycACE2, may attenuate the cardioprotective effects of RAS-inhibition. However, the achievement of tight glycemic control normalizes the anti-remodeling effects of RAS-inhibition. TRIAL REGISTRATION: https://clinicaltrials.gov/ NCT03546062.

Simplified Assessment of the Index of Microvascular Resistance.

BACKGROUND: To validate a simplified invasive method for the calculation of the index of microvascular resistance (IMR). METHODS: This is a prospective, single-center study of patients with chronic coronary syndromes presenting with nonobstructive coronary artery disease. IMR was obtained using both intravenous (IV) adenosine and intracoronary (IC) papaverine. Each IMR measurement was obtained in duplicate. The primary objective was the agreement between IMR acquired using adenosine and papaverine. Secondary objectives include reproducibility of IMR and time required for the IMR measurement. RESULTS: One hundred and sixteen IMR measurements were performed in 29 patients. The mean age was 68.8 ± 7.24 years, and 27.6% was diabetics. IMR values were similar between papaverine and adenosine (17.7 ± 7.26 and 20.1 ± 8.6, p=0.25; Passing-Bablok coefficient A 0.58, 95% CI -2.42 to 3.53; coefficient B 0.90, 95% CI -0.74 to 1.07). The reproducibility of IMR was excellent with both adenosine and papaverine (ICC 0.78, 95% CI 0.63 to 0.88 and ICC 0.93, 95% CI 0.87 to 0.97). The time needed for microvascular assessment was significantly shortened by the use of IC papaverine (3.23 (2.84, 3.78) mins vs. 5.48 (4.94, 7.09) mins, p < 0.0001). CONCLUSION: IMR can be reliably measured using IC papaverine with similar results compared to intravenous infusion of adenosine with increased reproducibility and reduced procedural time. This approach simplifies the invasive assessment of the coronary microcirculation in the catheterization laboratory.

Fractional flow reserve in patients with reduced ejection fraction.

AIMS: Fractional flow reserve (FFR) has never been investigated in patients with reduced ejection fraction and associated coronary artery disease (CAD). We evaluated the impact of FFR on the management strategies of these patients and related outcomes. METHODS AND RESULTS: From 2002 to 2010, all consecutive patients with left ventricular ejection fraction (LVEF) ≤50% undergoing coronary angiography with ≥1 intermediate coronary stenosis [diameter stenosis (DS)% 50-70%] treated based on angiography (Angiography-guided group) or according to FFR (FFR-guided group) were screened for inclusion. In the FFR-guided group, 433 patients were matched with 866 contemporary patients of the Angiography-guided group. For outcome comparison, 617 control patients with LVEF >50% were included. After FFR, stenotic vessels per patient were significantly downgraded compared with the Angiography-guided group (1.43 ± 0.98 vs. 1.97 ± 0.84; P < 0.001). This was associated with lower revascularization rate (52% vs. 62%; P < 0.001) in the FFR-guided vs. the Angiography-guided group. All-cause death at 5 years of follow-up was significantly lower in the FFR-guided as compared with Angiography-guided group [22% vs. 31%. HR (95% CI) 0.64 (0.51-0.81); P < 0.001]. Similarly, rate of major adverse cardiovascular and cerebrovascular events (MACCE: composite of all-cause death, myocardial infarction, revascularization, and stroke) was significantly lower in the FFR-guided group [40% vs. 46% in the Angiography-guided group. HR (95% CI) 0.81 (0.67-0.97); P = 0.019]. Higher rates of death and MACCE were observed in patients with reduced LVEF compared with the control cohort. CONCLUSIONS: In patients with reduced LVEF and CAD, FFR-guided revascularization was associated with lower rates of death and MACCE at 5 years as compared with the Angiography-guided strategy. This beneficial impact was observed in parallel with less coronary artery bypass grafting and more patients deferred to percutaneous coronary intervention or medical therapy.

Vessel Fractional Flow Reserve and Graft Vasculopathy in Heart Transplant Recipients.

BACKGROUND: Cardiac allograft vasculopathy (CAV) remains the Achilles' heel of long-term survival after heart transplantation (HTx). The severity and extent of CAV is graded with conventional coronary angiography (COR) which has several limitations. Recently, vessel fractional flow reserve (vFFR) derived from COR has emerged as a diagnostic computational tool to quantify the functional severity of coronary artery disease. PURPOSE: The present study assessed the usefulness of vFFR to detect CAV in HTx recipients. METHODS: In HTx patients referred for annual check-up, undergoing surveillance COR, the extent of CAV was graded according to the criteria proposed by the international society of heart and lung transplantation (ISHLT). In addition, three-dimensional coronary geometries were constructed from COR to calculate pressure losses using vFFR. RESULTS: In 65 HTx patients with a mean age of 53.7 ± 10.1 years, 8.5 years (IQR 1.90, 15.2) years after HTx, a total number of 173 vessels (59 LAD, 61 LCX, and 53 RCA) were analyzed. The mean vFFR was 0.84 ± 0.15 and median was 0.88 (IQR 0.79, 0.94). A vFFR ≤ 0.80 was present in 24 patients (48 vessels). HTx patients with a history of ischemic cardiomyopathy (ICMP) had numerically lower vFFR as compared to those with non-ICMP (0.70 ± 0.22 vs. 0.79 ± 0.13, p = 0.06). The use of vFFR reclassified 31.9% of patients compared to the anatomical ISHLT criteria. Despite a CAV score of 0, a pathological vFFR ≤ 0.80 was detected in 8 patients (34.8%). CONCLUSION: The impairment in epicardial conductance assessed by vFFR in a subgroup of patients without CAV according to standard ISHLT criteria suggests the presence of a diffuse vasculopathy undetectable by conventional angiography. Therefore, we speculate that vFFR may be useful in risk stratification after HTx.

Angiography Versus Hemodynamics to Predict the Natural History of Coronary Stenoses: Fractional Flow Reserve Versus Angiography in Multivessel Evaluation 2 Substudy.

BACKGROUND: Among patients with documented stable coronary artery disease and in whom no revascularization was performed, we compared the respective values of angiographic diameter stenosis (DS) and fractional flow reserve (FFR) in predicting natural history. METHODS: The present analysis included the 607 patients from the FAME 2 trial (Fractional Flow Reserve Versus Angiography in Multivessel Evaluation 2) in whom no revascularization was performed. FFR varied from 0.20 to 1.00 (average 0.74±0.16), and DS (by quantitative coronary analysis) varied from 8% to 98% (average 53±15). The primary end point, defined as vessel-oriented clinical end point (VOCE) at 2 years, was a composite of prospectively adjudicated cardiac death, vessel-related myocardial infarction, vessel-related urgent, and not urgent revascularization. The stenoses were divided into 4 groups according to FFR and %DS values: positive concordance (FFR≤0.80; DS≥50%), negative concordance (FFR>0.80; DS<50%), positive mismatch (FFR≤0.80; DS<50%), and negative mismatch (FFR>0.80; DS≥50%). RESULTS: The rate of VOCE was highest in the positive concordance group (log rank: X2=80.96; P=0.001) and lowest in the negative concordance group. The rate of VOCE was higher in the positive mismatch group than in the negative mismatch group (hazard ratio, 0.38; 95% confidence interval, 0.21-0.67; P=0.001). There was no significant difference in VOCE between the positive concordance and positive mismatch groups (FFR≤0.80; hazard ratio, 0.77; 95% confidence interval, 0.57-1.09; P=0.149) and no significant difference in rate of VOCE between the negative mismatch and negative concordance groups (FFR>0.80; hazard ratio, 1.89; 95% confidence interval, 0.96-3.74; P=0.067). CONCLUSIONS: In patients with stable coronary disease, physiology (FFR) is a more important determinant of the natural history of coronary stenoses than anatomy (DS). CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov. Unique identifier: NCT01132495.

Treatment of Diuretic Resistance with a Novel Percutaneous Blood Flow Regulator: Concept and Initial Experience.

Diuretic resistance in acute heart failure is a common clinical problem, and it is associated with adverse outcomes. Effective therapies are still lacking. The Doraya catheter, a temporary intravenous flow regulator placed in the inferior vena cava below the level of the renal veins, is a novel device designed to target renal and cardiac congestion, thereby improving diuretic response. A first-in-man clinical study is currently ongoing.

Biomarkers to predict the response to cardiac resynchronization therapy.

Cardiac resynchronization therapy (CRT) is an established non-pharmacological treatment for selected heart failure patients with wide QRS duration. However, there is a persistent number of non-responders throughout. The prediction of the CRT response is paramount to adequately select the correct patients for CRT. One of the expanding fields of research is the development of biomarkers that predict the response to CRT. A review of the available literature on biomarkers in CRT patients has been performed to formulate a critical appraisal of the available data. The main conclusion of our review is that biomarker research in this patient population is very fragmented and broad. This results in the use of non-uniform endpoints to define the CRT response, which precludes an in-depth comparison of the available data. To improve research development in this field, a uniform definition of the CRT response and relevant endpoints is necessary to better predict the CRT response.

Cardiac Resynchronization Therapy Optimization: A Comprehensive Approach.

Since the first report on biventricular pacing in 1994, cardiac resynchronization therapy (CRT) has become standard for patients with advanced heart failure (HF) and ventricular conduction delay. CRT improves myocardial function by resynchronizing myocardial contraction, which results in reverse left ventricular remodeling and improves symptoms and clinical outcomes. Despite the accelerated development of CRT device technology and its increased application in treating HF patients, almost one-third of these patients do not respond to the therapy or gain any clinical benefit from device implantation. Over the last decade, multiple cardiac imaging modalities have provided a deeper understanding of myocardial pathophysiology, thereby improving HF treatment management. However, the optimal strategy for improving the CRT response remains debatable. This article provides an updated overview of the electropathophysiology of myocardial dysfunction in ventricular conduction delay and the diagnostic approaches involving the use of multiple modalities.

Natriuretic Peptide Processing in Patients with and Without Left Ventricular Dysfunction.

This study aimed to examine the relationship between corin expression and circulating brain natriuretic peptide in patients with left ventricular (LV) dysfunction.Circulating levels of B-type natriuretic peptide (BNP) can be an indicator of LV dysfunction. The 32-amino-acid BNP is cleaved by corin, a cardiac serine protease, from its108-amino-acid pro-brain natriuretic peptide (proBNP) precursor.This study included 25 patients with idiopathic dilated cardiomyopathy (DCMP) and LV dysfunction and 44 heart transplant recipients with normal LV function who underwent diagnostic left and right heart catheterization. Blood samples were used to determine the ratio of plasma proBNP/BNP levels, and LV endomyocardial biopsies were used to determine the expression of NPPB, which encode BNP and corin, respectively, by quantitative reverse transcription-polymerase chain reaction.Patients with DCMP revealed worse hemodynamic profiles and higher plasma proBNP and BNP levels than those of the transplant recipients. Myocardial NPPB expression was higher and CORIN expression was lower in the DCMP patients than in the transplant recipients. CORIN expression significantly correlated with NPPB expression (r = -0.585; P < 0.001), ejection fraction (EF; r = 0.694; P < 0.01), LV end-diastolic pressure (r = -0.373; P < 0.05), and indexed end-diastolic LV volume (r = -0.452; P < 0.001). In addition, the plasma proBNP/BNP levels inversely correlated with the CORIN expression (r = -0.362; P < 0.005).Decreased myocardial CORIN expression and the corresponding higher levels of circulating unprocessed proBNP in DCMP may partly account for the relative BNP resistance observed in patients with LV dysfunction.

Imaging of Myocardial Fibrosis and Its Functional Correlates in Aortic Stenosis: A Review and Clinical Potential.

Patients with severe aortic stenosis (AS) show progressive fibrotic changes in the myocardium, which may impair cardiac function and patient outcomes even after successful aortic valve replacement. Detection of patients who need an early operation remains a diagnostic challenge as myocardial functional changes may be subtle. In recent years, speckle tracking echocardiography (STE) and cardiac magnetic resonance mapping have been shown to provide complementary information for the assessment of left ventricular mechanics and identification of subtle damage by focal or diffuse myocardial fibrosis, respectively. Little is known, however, about how focal and diffuse myocardial fibrosis occurring in severe AS are related to measurable functional changes by echocardiography and to which extent both parameters have prognostic and diagnostic value. The aims of this review are to discuss the occurrence of focal and diffuse myocardial fibrosis in patients with severe AS and to explore their relation with myocardial function, determined by STE, as well as the prognostic and diagnostic potential of both parameters.

Cardiopoietic cell therapy for advanced ischaemic heart failure: results at 39 weeks of the prospective, randomized, double blind, sham-controlled CHART-1 clinical trial.

AIMS: Cardiopoietic cells, produced through cardiogenic conditioning of patients' mesenchymal stem cells, have shown preliminary efficacy. The Congestive Heart Failure Cardiopoietic Regenerative Therapy (CHART-1) trial aimed to validate cardiopoiesis-based biotherapy in a larger heart failure cohort. METHODS AND RESULTS: This multinational, randomized, double-blind, sham-controlled study was conducted in 39 hospitals. Patients with symptomatic ischaemic heart failure on guideline-directed therapy (n = 484) were screened; n = 348 underwent bone marrow harvest and mesenchymal stem cell expansion. Those achieving > 24 million mesenchymal stem cells (n = 315) were randomized to cardiopoietic cells delivered endomyocardially with a retention-enhanced catheter (n = 157) or sham procedure (n = 158). Procedures were performed as randomized in 271 patients (n = 120 cardiopoietic cells, n = 151 sham). The primary efficacy endpoint was a Finkelstein-Schoenfeld hierarchical composite (all-cause mortality, worsening heart failure, Minnesota Living with Heart Failure Questionnaire score, 6-min walk distance, left ventricular end-systolic volume, and ejection fraction) at 39 weeks. The primary outcome was neutral (Mann-Whitney estimator 0.54, 95% confidence interval [CI] 0.47-0.61 [value > 0.5 favours cell treatment], P = 0.27). Exploratory analyses suggested a benefit of cell treatment on the primary composite in patients with baseline left ventricular end-diastolic volume 200-370 mL (60% of patients) (Mann-Whitney estimator 0.61, 95% CI 0.52-0.70, P = 0.015). No difference was observed in serious adverse events. One (0.9%) cardiopoietic cell patient and 9 (5.4%) sham patients experienced aborted or sudden cardiac death. CONCLUSION: The primary endpoint was neutral, with safety demonstrated across the cohort. Further evaluation of cardiopoietic cell therapy in patients with elevated end-diastolic volume is warranted.

Significance of Intermediate Values of Fractional Flow Reserve in Patients With Coronary Artery Disease.

BACKGROUND: The fractional flow reserve (FFR) value of 0.75 has been validated against ischemic testing, whereas the FFR value of 0.80 has been widely accepted to guide clinical decision making. However, revascularization when FFR is 0.76 to 0.80, within the so-called gray zone, is still debatable. METHODS AND RESULTS: From February 1997 to June 2013, all patients with single-segment disease and an FFR value within the gray zone or within the 2 neighboring FFR strata (0.70-0.75 and 0.81-0.85) were included. Study end points consisted of major adverse cardiovascular events (death, myocardial infarction, and any revascularization) up to 5 years. Of 17 380 FFR measurements, 1459 patients were included. Of them, 449 patients were treated with revascularization and 1010 patients were treated with medical therapy. In the gray zone, the major adverse cardiovascular events rate was similar (37 [13.9%] versus 21 [11.2%], respectively; P=0.3) between medical therapy and revascularization, whereas a strong trend toward a higher rate of death or myocardial infarction (25 [9.4] versus 9 [4.8], P=0.06) and overall death (20 [7.5] versus 6 [3.2], P=0.059) was observed in the medical therapy group. Among medical therapy patients, a significant step-up increase in major adverse cardiovascular events rate was observed across the 3 FFR strata, especially with proximal lesion location. In revascularization patients, the major adverse cardiovascular events rate was not different across the 3 FFR strata. CONCLUSIONS: FFR in and around the gray zone bears a major prognostic value, especially in proximal lesions. These data confirm that FFR≤0.80 is valid to guide clinical decision making.

Rationale and design of the Aortic Valve replAcemenT versus conservative treatment in Asymptomatic seveRe aortic stenosis (AVATAR trial): A randomized multicenter controlled event-driven trial.

Aortic valve replacement (AVR) therapy is an obvious choice for symptomatic severe aortic stenosis (AS) patients as it improves symptoms, left ventricular function, and survival. The treatment decisions and indication for AVR in asymptomatic patients with severe AS and normal left ventricular ejection fraction are less well established and the subject of ongoing debate. Many efforts have been made to define the best treatment option in asymptomatic AS patients with normal left ventricular ejection fraction. Retrospective and observational data imply that elective AVR for asymptomatic severe AS may lead to improvement in outcomes in comparison to surgery performed after onset of symptoms. The AVATAR trial will aim to assess outcomes among asymptomatic AS patients randomized to either elective early AVR or medical management with vigilant follow-up. In the latter group, AVR would be delayed until either the onset of symptoms or changes in predefined echocardiographic parameters. To the best of the authors' knowledge, it will be the first large prospective, randomized, controlled, multicenter clinical trial that will evaluate the safety and efficacy of elective AVR in this specific group of patients.

Should MRAs be at the front row in heart failure? A plea for the early use of mineralocorticoid receptor antagonists in medical therapy for heart failure based on clinical experience.

The brand new 2016 ESC guidelines for the treatment of acute and chronic heart failure continue to give a prominent place to mineralocorticoid receptor antagonists in the treatment of chronic heart failure with reduced ejection fraction (HFrEF). In the prevention of HF hospitalization and death, a class I, level of recommendation A, is given to MRAs for patients with HFrEF, who remain symptomatic despite treatment with an ACE-inhibitor and a beta-blocker and have an LVEF below 35 %. This recommendation is primarily based on two landmark trials, the RALES trial (for spironolactone) and the EMPHASIS-HF trial (for eplerenone). A crucial question is, however, why MRAs are advised only in "third place," i.e., after optimal up-titration of ACE-inhibitors and beta-blockers. We wonder whether MRAs could not or should not be given earlier in the treatment of HFrEF, namely before or together with the up-titration of ACE-inhibitors and beta-blockers. Several arguments to support this plea are described in this short paper.

Evolving concepts of angiogram: fractional flow reserve discordances in 4000 coronary stenoses.

AIMS: The present analysis addresses the potential clinical and physiologic significance of discordance in severity of coronary artery disease between the angiogram and fractional flow reserve (FFR) in a large and unselected patient population. METHODS AND RESULTS: Between September 1999 and December 2011, FFR and percent diameter stenosis (DS) as assessed by quantitative coronary angiography were obtained in 2986 patients (n = 4086 coronary stenoses), in whom at least one stenosis was of intermediate angiographic severity. Fractional flow reserve correlated slightly but significantly with DS [-0.38 (95% CI: -0.41; -0.36); P < 0.001]. The sensitivity, specificity, and diagnostic accuracy of a ≥ 50% DS for predicting FFR ≤ 0.80 were 61% (95% CI: 59; 63), 67% (95% CI: 65; 69), and 0.64 (95% CI: 0.56; 0.72), respectively. In different anatomical settings, sensitivity and specificity showed marked variations between 35 to 74% and 58 to 76%, respectively, resulting in a discordance in 35% of all cases for these thresholds. For an angiographic threshold of 70% DS, the diagnostic performance by the Youden's index decreased from 0.28 to 0.11 for the overall population. CONCLUSION: The data confirm that one-third of a large patient population shows discordance between angiogram ≥ 50%DS and FFR ≤ 0.8 thresholds of stenosis severity. Left main stenoses are often underestimated by the classical 50% DS cut-off compared with FFR. This discordance offers physiologic insights for future trials. It is hypothesized that the discordance between angiography and FFR is related to technical limitations, such as imprecise luminal border detection by angiography, as well as to physiologic factors, such as variable minimal microvascular resistance.

Activation of the ergoreceptors in cardiac patients with and without heart failure.

BACKGROUND: The presence of ergoreflex activity and its current relationship to hyperventilation and prognosis in cardiac patients is unclear. Therefore, we evaluated ergoreflex activity in cardiac patients with and without heart failure (CHF) as well as in healthy subjects, and we examined how ergoreceptor activity was related to a mortality risk score in CHF (MAGGIC). METHODS AND RESULTS: Twenty-five healthy subjects and 76 patients were included, among whom were 25 with ischemic heart disease (IHD), 24 with stable CHF, and 27 with unstable CHF. Ergoreflex activity was measured with a dynamic handgrip exercise, followed by post-handgrip regional circulatory occlusion (PH-RCO). Ergoreflex activity contributed significantly to ventilation (median [interquartile range] %V) in unstable CHF (81 [73-91] %V without PH-RCO, 92 [82-107] %V with PH-RCO, and 11 [6-20] difference in %V; P < .001) and was positively correlated with the MAGGIC risk score (Spearman ρ = 0.431; P = .002). No ergoreflex activity was observed in healthy subjects (-4 [-10 to 5] difference in %V), IHD (0 [-8 to 3] Diff in %V) and stable CHF (-3 [-11 to 6] difference in %V). CONCLUSIONS: Ergoreflex activity contributes to hyperventilation, but only in CHF patients with persistent symptoms, and is closely related to the MAGGIC risk score. Ergoreflex activity was not present in patients with IHD or stable CHF, suggesting other reasons for the increased ventilatory drive in those patients.

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.

Self-limiting left ventricular wall rupture following myocardial infarction: a case report and literature review.

We report the case of a 62-year-old woman presenting with symptoms and findings of myocardial infarction and a left ventricular free wall rupture. Coronary angiography revealed a critical stenosis in the middle right coronary artery. A contrast left ventriculogram revealed extravasation of contrast through the inferolateral wall of the left ventricle. Left ventricular free wall rupture is a rare complication of acute myocardial infarction, occurring in approximately 2% of cases. It is often fatal because of the development of haemopericardium and tamponade. Some patients, like the one described in this case, may present with small leaks that might close spontaneously by epicardial fibrin deposits, thus self-limiting, without requiring surgical intervention. This patient received only intense medical treatment. Indeed, blood clots at the endocardial and the epicardial site of the rupture have often been identified, suggesting protection for further rupture.