Comparison of quantitative flow ratio with instantaneous wave-free ratio and resting full-cycle ratio during daily routine in the catheterization laboratory.

BACKGROUND: Quantitative flow ratio (QFR) is a novel, software-based method to evaluate the physiology of coronary lesions. The aim of this study was to compare QFR with the established invasive measurements of coronary blood flow using instantaneous wave-free ratio (iFR) or resting full-cycle ratio (RFR) in daily cathlab routine. METHODS: 102 patients with stable coronary artery disease and a coronary stenosis of 40%-90% were simultaneously assessed with QFR and iFR or RFR. QFR-computation was performed by two certified experts using the appropriate software (QAngio XA 3D 3.2). RESULTS: QFR showed a significant correlation (r = 0.75, p < 0.001) to iFR and RFR. The area under the receiver curve for all measurements was 0.93 (95% confidence interval, 0.87-0.98) for QFR compared to iFR or RFR. QFR based assessment required less time with a median of 501 s (IQR 421-659 s) compared to iFR or RFR which required a median of 734 s to obtain the result (IQR 512-967 s; p < 0.001). The median use of contrast medium was similar with 21 mL (IQR 16-30 mL) for the QFR-based and 22 mL (IQR 15-35 mL) for the iFR- or RFR-based diagnostic. QFR diagnostic required less radiation. The median dose area product for QFR was 307cGycm2 (IQR 151-429 cGycm2 ) compared to 599 cGycm2 (IQR 345-1082 cGycm2 ) for iFR or RFR, p < 0.001. CONCLUSION: QFR measurements of coronary artery blood flow correlate with iFR or RFR measurements and are associated with shorter procedure times and reduced radiation dose.

Rac1 GTPase regulates 11ß hydroxysteroid dehydrogenase type 2 and fibrotic remodeling.

The aim of the study was to characterize the role of Rac1 GTPase for the mineralocorticoid receptor (MR)-mediated pro-fibrotic remodeling. Transgenic mice with cardiac overexpression of constitutively active Rac1 (RacET) develop an age-dependent phenotype with atrial dilatation, fibrosis, and atrial fibrillation. Expression of MR was similar in RacET and WT mice. The expression of 11ß hydroxysteroid dehydrogenase type 2 (11ß-HSD2) was age-dependently up-regulated in the atria and the left ventricles of RacET mice on mRNA and protein levels. Statin treatment inhibiting Rac1 geranylgeranylation reduced 11ß-HSD2 up-regulation. Samples of human left atrial myocardium showed a positive correlation between Rac1 activity and 11ß-HSD2 expression (r = 0.7169). Immunoprecipitation showed enhanced Rac1-bound 11ß-HSD2 relative to Rac1 expression in RacET mice that was diminished with statin treatment. Both basal and phorbol 12-myristate 13-acetate (PMA)-induced NADPH oxidase activity were increased in RacET and correlated positively with 11ß-HSD2 expression (r = 0.788 and r = 0.843, respectively). In cultured H9c2 cardiomyocytes, Rac1 activation with l-buthionine sulfoximine increased; Rac1 inhibition with NSC23766 decreased 11ß-HSD2 mRNA and protein expression. Connective tissue growth factor (CTGF) up-regulation induced by aldosterone was prevented with NSC23766. Cardiomyocyte transfection with 11ß-HSD2 siRNA abolished the aldosterone-induced CTGF up-regulation. Aldosterone-stimulated MR nuclear translocation was blocked by the 11ß-HSD2 inhibitor carbenoxolone. In cardiac fibroblasts, nuclear MR translocation induced by aldosterone was inhibited with NSC23766 and spironolactone. NSC23766 prevented the aldosterone-induced proliferation and migration of cardiac fibroblasts and the up-regulation of CTGF and fibronectin. In conclusion, Rac1 GTPase regulates 11ß-HSD2 expression, MR activation, and MR-mediated pro-fibrotic signaling.

True rate of mineralocorticoid receptor antagonists-related hyperkalemia in placebo-controlled trials: A meta-analysis.

BACKGROUND: Mineralocorticoid receptor antagonists (MRA) improve survival in heart failure with reduced ejection fraction but are often underused, mostly due to concerns of hyperkalemia. Because hyperkalemia occurs also on placebo, we aimed to determine the truly MRA-related rate of hyperkalemia. METHODS: We performed a meta-analysis including randomized, placebo-controlled trials reporting hyperkalemia on MRAs in patients after myocardial infarction or with chronic heart failure. We evaluated the truly MRA-related rate of hyperkalemia that represents hyperkalemia on MRA, corrected for hyperkalemia on placebo (Pla), according to the equation: True MRA (%)=(MRA (%) - Pla (%))/MRA (%). RESULTS: A total number of 16,065 patients from 7 trials were analyzed. Hyperkalemia was more frequently observed on MRA (9.3%) vs placebo (4.3%) (risk ratio 2.17, 95% CI 1.92-2.45, P<.0001). Truly MRA-related hyperkalemia was 54%, whereas 46% were non-MRA related. In trials using eplerenone, hyperkalemia was documented in 5.0% on eplerenone and in 2.6% on placebo (P<.0001). In spironolactone trials, hyperkalemia was documented in 17.5% and in 7.5% of patients on placebo (P=.0001). Hypokalemia occurred less frequently in patients on MRA (9.3%) compared with placebo (14.8%) (risk ratio 0.58, CI 0.47-0.72, P<.0001). CONCLUSION: This meta-analysis shows that in clinical trials, 54% of hyperkalemia cases were specifically related to the MRA treatment and 46% to other reasons. Therefore, non-MRA-related rises in potassium levels might be underestimated and should be rigorously explored before cessation of the evidence-based therapy with MRAs.

The mineralocorticoid receptor promotes fibrotic remodeling in atrial fibrillation.

We studied the role of the mineralocorticoid receptor (MR) in the signaling that promotes atrial fibrosis. Left atrial myocardium of patients with atrial fibrillation (AF) exhibited 4-fold increased hydroxyproline content compared with patients in sinus rhythm. Expression of MR was similar, as was 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD2), which also increased. 11ß-HSD2 converts cortisol to receptor-inactive metabolites allowing aldosterone occupancy of MR. 11ß-HSD2 was up-regulated by arrhythmic pacing in cultured cardiomyocytes and in a mouse model of spontaneous AF (RacET). In cardiomyocytes, aldosterone induced connective tissue growth factor (CTGF) in the absence but not in the presence of cortisol. Hydroxyproline expression was increased in cardiac fibroblasts exposed to conditioned medium from aldosterone-treated cardiomyocytes but not from cardiomyocytes treated with both cortisol and aldosterone. Aldosterone increased connective tissue growth factor and hydroxyproline expression in cardiac fibroblasts, which were prevented by BR-4628, a dihydropyridine-derived selective MR antagonist, and by spironolactone. Aldosterone activated RhoA GTPase. Rho kinase inhibition by Y-27632 prevented CTGF and hydroxyproline, whereas the RhoA activator CN03 increased CTGF expression. Aldosterone and CTGF increased lysyl oxidase, and aldosterone enhanced miR-21 expression. MR antagonists reduced the aldosterone but not the CTGF effect. In conclusion, MR signaling promoted fibrotic remodeling. Increased expression of 11ß-HSD2 during AF leads to up-regulation of collagen and pro-fibrotic mediators by aldosterone, specifically RhoA activity as well as CTGF, lysyl oxidase, and microRNA-21 expression. The MR antagonists BR-4628 and spironolactone prevent these alterations. MR inhibition may, therefore, represent a potential pharmacologic target for the prevention of fibrotic remodeling of the atrial myocardium.

Time to Recovery from Systolic Dysfunction Correlates with Left Ventricular Fibrosis in Arrhythmia-Induced Cardiomyopathy.

BACKGROUND: Arrhythmia-induced cardiomyopathy (AIC) is characterized by the reversibility of left ventricular (LV) systolic dysfunction (LVSD) after rhythm restoration. This study is a cardiac magnetic resonance tomography substudy of our AIC trial with the purpose to investigate whether left ventricular fibrosis affects the time to recovery (TTR) in patients with AIC. METHOD: Patients with newly diagnosed and otherwise unexplainable LVSD and tachyarrhythmia were prospectively recruited. LV ejection fraction (LVEF) was measured by echocardiography at baseline and 2, 4, and 6 months after rhythm control, and stress markers were assessed. After initial rhythm control, LV fibrosis was assessed through late gadolinium enhancement (LGE). Patients were diagnosed with AIC if their LVEF improved by ≥15% (or ≥10% when LVEF reached ≥50%). Non-responders served as controls (non-AIC). RESULTS: The LGE analysis included 39 patients, 31 of whom recovered (AIC). LV end-systolic diameters decreased and LVEF increased during follow-up. LV LGE content correlated positively with TTR (r = 0.63, p = 0.003), with less LGE favoring faster recovery, and negatively with ΔLVEF (i.e., LVEF at month 2 compared to baseline) as a marker of fast recovery (r = -0.55, p = 0.012), suggesting that LV fibrosis affects the speed of recovery. CONCLUSION: LV fibrosis correlated positively with the time to recovery in patients with AIC. This correlation may help in the estimation of the recovery period and in the optimization of diagnostic and therapeutic strategies for patients with AIC.

Clinical Characterization of Arrhythmia-Induced Cardiomyopathy in Patients With Tachyarrhythmia and Idiopathic Heart Failure.

BACKGROUND: Arrhythmia-induced cardiomyopathy (AIC) is a known entity, but prospective evidence for its characterization is limited. OBJECTIVES: This study aimed to: 1) determine the relative frequency of the pure form of AIC in the clinically relevant cohort of patients with newly diagnosed, otherwise unexplained left ventricular systolic dysfunction (LVSD) and tachyarrhythmia; 2) assess the time to recovery from LVSD; and 3) identify parameters for an early diagnosis of AIC. METHODS: Patients were prospectively included, underwent effective rhythm restoration, and were followed-up at 2, 4, and 6 months to evaluate clinical characteristics, biomarkers, and cardiac imaging including cardiac magnetic resonance imaging. Patients with recurred arrhythmia were excluded from analysis. RESULTS: 41 of 50 patients were diagnosed with AIC 6 months after rhythm restoration. Left ventricular (LV) ejection fraction increased 2 months after rhythm restoration from 35.4% ± 8.2% to 52.7% ± 8.0% in AIC patients vs 37.0% ± 9.5% to 43.3% ± 7.0% in non-AIC patients. From month 2 to 6, LV ejection fraction continued to increase in AIC patients (57.2% ± 6.1%; P < 0.001) but remained stable in non-AIC patients (44.0% ± 7.8%; P = 0.628). Multivariable logistic regression analysis revealed that lower LV end-diastolic diameter at baseline could be used for early diagnosis of AIC, whereas biomarkers and other morphological or functional parameters, including late LV gadolinium enhancement, did not show suitability for early diagnosis. CONCLUSIONS: We observed a high prevalence of AIC in patients with otherwise unexplained LVSD and concomitant tachyarrhythmia, suggesting that this condition may be underdiagnosed in clinical practice. Most patients recovered fast, within months, from LVSD. A low initial LV end-diastolic diameter may constitute an early marker for diagnosis of AIC.

Native T1 mapping for the diagnosis of cardiac amyloidosis in patients with left ventricular hypertrophy.

BACKGROUND: Cardiac magnetic resonance (CMR) with parametric mapping can improve the characterization of myocardial tissue. We studied the diagnostic value of native T1 mapping to detect cardiac amyloidosis in patients with left ventricular (LV) hypertrophy. METHODS: One hundred twenty-five patients with increased LV wall thickness (≥ 12 mm end-diastole) who received clinical CMR in a 3 T scanner between 2017 and 2020 were included. 31 subjects without structural heart disease served as controls. Native T1 was measured as global mean value from 3 LV short axis slices. The study was registered at German clinical trial registry (DRKS00022048). RESULTS: Mean age of the patients was 66 ± 14 years, 83% were males. CA was present in 24 patients, 21 patients had hypertrophic cardiomyopathy (HCM), 80 patients suffered from hypertensive heart disease (HHD). Native T1 times were higher in patients with CA (1409 ± 59 ms, p < 0.0001) compared to healthy controls (1225 ± 21 ms), HCM (1266 ± 44 ms) and HHD (1257 ± 41 ms). HCM and HHD patients did not differ in their native T1 times but were increased compared to control (p < 0.01). ROC analysis of native T1 demonstrated an area under the curve for the detection of CA vs. HCM and HHD of 0.9938 (p < 0.0001), which was higher than that of extracellular volume (0.9876) or quantitative late gadolinium enhancement (0.9406; both p < 0.0001). The optimal cut-off value of native T1 to diagnose CA was 1341 ms (sensitivity 100%, specificity 97%). CONCLUSION: Non-contrast CMR imaging with native T1 mapping provides high diagnostic accuracy to diagnose cardiac amyloidosis in patients with left ventricular hypertrophy.

Increased lysyl oxidase expression and collagen cross-linking during atrial fibrillation.

The aim of the study is to characterize the signal transduction leading to interstitial fibrosis in the pathogenesis of atrial fibrillation (AF) and atrial remodeling. Samples of the left atrial appendage (LA) from patients with AF showed higher collagen content (73 ± 5 vs. 38 ± 2 µg/mg protein) and 2.5-fold increased collagen crosslinking compared to patients with sinus rhythm (SR). Affymetrix-assays, RT-PCR and western Blot analysis revealed that LA of AF patients are characterized by increased lysyl oxidase (LOX) mRNA (218 ± 42%) and protein (253 ± 11%) expression. This was associated with increased expression of connective tissue growth factor (CTGF), fibronectin and Rac1 activity compared to SR. In neonatal cardiac fibroblasts, the Rac1 specific small molecule inhibitor NSC23766 prevented angiotensin II (AngII) induced upregulation of LOX (214 ± 16%) expression. Inhibition of CTGF by siRNA transfections completely inhibited AngII induced LOX expression. The LOX specific small molecule inhibitor BAPN prevented AngII and CTGF induced fibronectin expression. Left atria of transgenic mice with cardiac overexpression of Rac1 (RacET) that develop AF at high age exhibited upregulation of CTGF as well as LOX (187 ± 7%) and fibronectin (627 ± 146%) expression. Atria of RacET showed increased collagen content (28 ± 2 µg/mg protein) and crosslinking (10 ± 0.7) compared to wildtypes (20 ± 0.4 µg/mg protein; 5 ± 0.9). Left atrial myocardium of patients with atrial fibrillation is characterized by increased lysyl oxidase and fibronectin expression as well as collagen cross-linking. In cardiac fibroblasts, Rac1 GTPase mediates upregulation of fibronectin via LOX and CTGF. Inhibition of this signaling pathway may therefore represent a target for the prevention of fibrotic atrial remodeling.

Long-term clinical and haemodynamic results after transcatheter annuloplasty for secondary mitral regurgitation.

AIMS: The study sought to investigate the long-term outcome after transcatheter mitral valve annuloplasty for secondary mitral regurgitation (MR). METHODS AND RESULTS: Consecutive patients with symptomatic secondary MR undergoing transcatheter mitral valve annuloplasty with the Carillon device at Leipzig University Hospital between 2012 and 2018 were studied prospectively. Left ventricular (LV) function and MR severity were quantified by standardized echocardiography. 33 patients were included. Mean age was 75 ± 10 years, and 20 patients were women. A Society of Thoracic Surgeons score of 8.1 ± 7.2% indicated high-risk status. In 24 patients, MR resulted from LV remodelling and dysfunction, eight suffered from left atrial dilatation, and one patient had MR due to combined primary and secondary aetiology. LV ejection fraction at baseline was (median) 38% [inter-quartile range (IQR) 30-49%]. During the mean follow-up time of 45 ± 20 months, 17 patients died, two patients withdraw consent, and four patients were lost. Of the remaining patients, four were hospitalized for decompensated heart failure. Two of these patients underwent additional transcatheter edge-to-edge mitral valve repair. At follow-up, New York Heart Association (NYHA) functional class improved from 95% in Class III/IV at baseline to 70% in Class I/II with no patients in NYHA Class IV (P < 0.0001). Mitral regurgitant volume was reduced from 27 mL (IQR 25-42 mL) to 8 mL (IQR 3-17 mL) (P = 0.018) and regurgitant fraction from 42% (IQR 34-54%) to 11% (IQR 8-24%) (P = 0.014). LV end-diastolic volume index [92 mL/m2 (IQR 74-107 mL/m2 ) vs. 67 mL/m2 (IQR 46-101 mL/m2 ), P = 0.065] and end-systolic volume index [50 mL/m2 (IQR 44-69 mL/m2 ) vs. 32 mL/m2 (IQR 20-53 mL/m2 ), P = 0.037] decreased. Total stroke volume remained unchanged [38 mL/m2 (IQR 33-43 mL/m2 ) vs. 33 mL/m2 (IQR 26-44 mL/m2 ), P = 0.695], while LV ejection fraction increased [43% (IQR 35-49%) vs. 54% (IQR 46-57%), P = 0.014]. Forward stroke volume, heart rate, and forward cardiac output were not significantly altered. CONCLUSIONS: Among high-risk patients undergoing transcatheter mitral valve annuloplasty for symptomatic secondary MR, mortality was ~50% at 4 years. In the surviving patients, reduced MR severity was associated with reduced NYHA functional class, reverse LV remodelling, and improved LV function.

Echocardiographic assessment of mitral regurgitation: discussion of practical and methodologic aspects of severity quantification to improve diagnostic conclusiveness.

The echocardiographic assessment of mitral valve regurgitation (MR) by characterizing specific morphological features and grading its severity is still challenging. Analysis of MR etiology is necessary to clarify the underlying pathological mechanism of the valvular defect. Severity of mitral regurgitation is often quantified based on semi-quantitative parameters. However, incongruent findings and/or interpretations of regurgitation severity are frequently observed. This proposal seeks to offer practical support to overcome these obstacles by offering a standardized workflow, an easy means to identify non-severe mitral regurgitation, and by focusing on the quantitative approach with calculation of the individual regurgitant fraction. This work also indicates main methodological problems of semi-quantitative parameters when evaluating MR severity and offers appropriateness criteria for their use. It addresses the diagnostic importance of left-ventricular wall thickness, left-ventricular and left atrial volumes in relation to disease progression, and disease-related complaints to improve interpretation of echocardiographic findings. Finally, it highlights the conditions influencing the MR dynamics during echocardiographic examination. These considerations allow a reproducible, verifiable, and transparent in-depth echocardiographic evaluation of MR patients ensuring consistent haemodynamic plausibility of echocardiographic results.

Reduced left ventricular contractility, increased diastolic operant stiffness and high energetic expenditure in patients with severe aortic regurgitation without indication for surgery.

OBJECTIVES: Recent mortality studies showed worse prognosis in patients (ARNS) with severe aortic regurgitation and preserved ejection fraction (EF) not fulfilling the criteria of current guidelines for surgery. The aim of our study was to analyse left ventricular (LV) systolic and diastolic function and mechanical energetics to find haemodynamic explanations for the reduced prognosis of these patients and to seek a new concept for surgery. METHODS: Global longitudinal strain (GLS) and echo-based single-beat pressure-volume analyses were performed in patients with ARNS (LV end-diastolic diameter <70 mm, EF >50%, GLS > -19% n = 41), with indication for surgery (ARS; n = 19) and in mild hypertensive controls (C; n = 20). Additionally, end-systolic elastance (LV contractility), stroke work and total energy (pressure-volume area) were calculated. RESULTS: ARNS demonstrated significantly depressed LV contractility versus C: end-systolic elastance (1.58 ± 0.7 vs 2.54 ± 0.8 mmHg/ml; P < 0.001), despite identical EF (EF: 59 ± 6% vs 59 ± 7%). Accordingly, GLS was decreased [-15.7 ± 2.7% (n = 31) vs -21.2 ± 2.4%; P < 0.001], end-diastolic volume (236 ± 90 vs 136 ± 30 ml; P < 0.001) and diastolic operant stiffness were markedly enlarged, as were pressure-volume area and stroke work, indicating waste of energy. The correlation of GLS versus end-systolic elastance was good (r = -0.66; P < 0.001). ARNS and ARS patients demonstrated similar haemodynamic disorders, whereas only GLS was worse in ARS. CONCLUSIONS: ARNS patients almost matched the ARS patients in their haemodynamic and energetic deterioration, thereby explaining poor prognosis reported in literature. GLS has been shown to be a reliable surrogate for LV contractility, possibly overestimating contractility due to exhausted preload reserve in aortic regurgitation patients. GLS may outperform conventional echo parameters to predict more precisely the timing of surgery.

Left ventricular mechanical dispersion in flow-gradient patterns of severe aortic stenosis with narrow QRS complex.

Patients with severe aortic stenosis are classified according to flow-gradient patterns. We investigated whether left ventricular (LV) mechanical dispersion, a marker of dyssynchrony and predictor of mortality, is associated with low-flow status in aortic stenosis. 316 consecutive patients with aortic stenosis and QRS duration < 120 ms were included in the retrospective analysis. Patients with severe aortic stenosis (aortic valve area ≤ 1.0 cm2) were classified as normal-flow (NF; stroke volume index > 35 ml/m2) high-gradient (HG; mean transvalvular gradient ≥ 40 mmHg) (n = 79), NF low-gradient (LG) (n = 62), low-flow (LF) LG ejection fraction (EF) ≥ 50% (n = 57), and LF LG EF < 50% (n = 23). Patients with moderate aortic stenosis (aortic valve area 1.5-1.0 cm2; n = 95) served as comparison group. Mechanical dispersion (calculated as standard deviation of time from Q/S onset on electrocardiogram to peak longitudinal strain in 17 left ventricular segments) was similar in patients with NF HG (49.4 ± 14.7 ms), NF LG (43.5 ± 12.9 ms), LF LG EF ≥ 50% (47.2 ± 16.3 ms) and moderate aortic stenosis (44.2 ± 15.7 ms). In patients with LF LG EF < 50%, mechanical dispersion was increased (60.8 ± 20.7 ms, p < 0.05 vs. NF HG, NF LG, LF LG EF ≥ 50% and moderate AS). Mechanical dispersion correlated with global longitudinal strain (r = 0.1354, p = 0.0160) and heart rate (r = 0.1587, p = 0.0047), but not with parameters of aortic stenosis. Mechanical dispersion was similar among flow-gradient subgroups of severe aortic stenosis with preserved LVEF, but increased in patients with low-flow low-gradient and reduced LVEF. These findings indicate that mechanical dispersion is rather a marker of systolic myocardial dysfunction than of aortic stenosis.

Angiography-based quantitative coronary contrast-flow ratio measurements correlate with myocardial ischemia assessed by stress MRI.

Contrast-flow quantitative flow ratio (cQFR) is a new technology for quantitative evaluation of coronary stenosis using computational fluid dynamics based on angiograms. The aim of this study was to assess the sensitivity and specificity of cQFR to detect myocardial ischemia using stress magnetic resonance imaging (MRI) as a reference standard. Patients who received stress MRI and coronary angiography were selected from the hospital database. Relevant ischemia on stress MRI was defined as a perfusion deficit in ≥ 2 of 16 segments. cQFR was quantitated based on 3-dimensional quantitative coronary angiography using QAngio XA3D1.1 software by two blinded and independent investigators. A cQFR of ≤ 0.80 was considered abnormal. Among 87 patients 230 vessels met the criteria for full analysis by cQFR (88%). In vascular territories with a significant perfusion deficit, cQFR was significantly lower compared to areas with normal perfusion (0.72 (0.62-0.78) vs. 0.96 (0.89-0.99); p < 0.001). The sensitivity of cQFR in detecting significant epicardial stenoses of coronary vessels with documented ischemia in stress MRI was 81% (68-90%), the specificity was 88% (82-92%). Diameter stenoses (DS) and area stenoses (AS) in vessels with positive stress MRI were significantly higher than in vessels without ischemia (DS 59.1% (49.4-68.4%) vs. 34.8% (27.1-46.1%) p < 0.001; AS 75.6% (63.0-85.2%) vs. 45.0% (30.8-63.6%), p < 0.001). The analysis reveals a high correlation between coronary stenosis measured by cQFR and ischemic areas detected by stress MRI. The data set the stage to plan randomized studies assessing cQFR measurements with regard to clinical outcomes.

Echocardiographic analysis of acute effects of percutaneous mitral annuloplasty on severity of secondary mitral regurgitation.

AIMS: Percutaneous mitral annuloplasty (PMA) represents a new treatment option for secondary mitral regurgitation (SMR) being associated with higher morbidity and mortality. The present study was aimed to evaluate whether or not acute effects on SMR severity can quantitatively be assessed after PMA. METHODS AND RESULTS: PMA was performed in 30 patients (mean age 76 ± 9; 37% males) with moderate (n = 14) or severe (n = 16) SMR. Vena contracta (VC), left ventricular (LV) velocity-time-integral ratio (VTIMV/LVOT ), effective regurgitant orifice area (EROA) by two-dimensional proximal isovelocity surface area (PISA), regurgitant volume (RVolPISA ) and regurgitant fraction (RFPISA ) by PISA, RVolvolume and RFvolume by LV volume analyses, and parameters describing LV morphology, function, and cardiac performance were assessed by transthoracic echocardiography prior to and after PMA. According to RFPISA /RFvolume , 14 patients showed mild, 15 moderate, and 1 severe SMR after PMA. Mean RF, RVol, EROA, VC, and VTIMV/LVOT were lower directly after PMA (RFPISA : 49% ± 11 vs. 34% ± 13, P < 0.001; RFvolume : 46% ± 10 vs. 34% ± 13, P < 0.001; RVolPISA : 33 mL ± 13 vs. 25 mL ± 12, P < 0.001; RVolvolume : 28 mL ± 17 vs. 20 mL ± 14, P < 0.05; EROAPISA : 0.24 cm2  ± 0.1 vs. 0.19 cm2  ± 0.1, P < 0.05; VC: 5.2 ± 0.1 vs. 4.1 ± 0.2, P < 0.001; VTIMV/LVOT : 1.9 ± 0.4 vs. 1.6 ± 0.5, P < 0.05). Parameters of LV morphology, function, and cardiac performance did not change directly after PMA. CONCLUSIONS: PMA leads to a reduction of MR severity in >80% of SMR patients. Acute effects of PMA can quantitatively be assessed by transthoracic echocardiography.

Rate of Cough During Treatment With Angiotensin-Converting Enzyme Inhibitors: A Meta-Analysis of Randomized Placebo-Controlled Trials.

Use of protective angiotensin-converting enzyme inhibitors (ACE-I) in patients with cardiovascular disease (CVD) is sometimes limited by incident coughing. In clinical trials, cough occurred also on placebo. We performed a meta-analysis including randomized, placebo-controlled trials reporting cough on ACE-I in patients with CVD. We evaluated the attributable fraction of cough on ACE-I accounting rate on placebo: placebo-adjusted ACE-I (%) = (ACE-I (%) - Placebo (%)) / ACE-I (%). In total, 65,054 patients from 22 included studies were analyzed. Placebo-adjusted ACE-I cough was 37% of 13.5% reported cases on ACE-I, while 8.5% reported cases on placebo were equivalent to 63% of cases on ACE-I, indicating potential other factors for cough than ACE-I in a substantial number of cough cases on ACE-I. Placebo-adjusted ACE-I cough had the highest rates of arterial hypertension (85%) and the lowest of heart failure (29%). Therefore, other causes of cough, particularly in heart failure, should be excluded before ACE-I withdrawal.

The non-steroidal mineralocorticoid receptor antagonist finerenone prevents cardiac fibrotic remodeling.

Mineralocorticoid receptor (MR) overactivation promotes cardiac fibrosis. We studied the ability of the non-steroidal MR antagonist finerenone to prevent fibrotic remodeling. In neonatal rat cardiac fibroblasts, finerenone prevented aldosterone-induced nuclear MR translocation. Treatment with finerenone decreased the expression of connective tissue growth factor (CTGF) (74 ±â€¯15% of control, p = 0.005) and prevented aldosterone-induced upregulation of CTGF and lysyl oxidase (LOX) completely. Finerenone attenuated the upregulation of transforming growth factor ß (TGF-ß), which was induced by the Rac1 GTPase activator l-buthionine sulfoximine. Transgenic mice with cardiac-specific overexpression of Rac1 (RacET) showed increased left ventricular (LV) end-diastolic (63.7 ±â€¯8.0 vs. 93.8 ±â€¯25.6 µl, p = 0.027) and end-systolic (28.0 ±â€¯4.0 vs. 49.5 ±â€¯16.7 µl, p = 0.014) volumes compared to wild-type FVBN control mice. Treatment of RacET mice with 100 ppm finerenone over 5 months prevented LV dilatation. Systolic and diastolic LV function did not differ between the three groups. RacET mice exhibited overactivation of MR and 11ß hydroxysteroid dehydrogenase type 2. Both effects were reduced by finerenone (reduction about 36%, p = 0.030, and 40%, p = 0.032, respectively). RacET mice demonstrated overexpression of TGF-ß, CTGF, LOX, osteopontin as well as collagen and myocardial fibrosis in the left ventricle. In contrast, expression of these parameters did not differ between finerenone-treated RacET and control mice. Finerenone prevented left atrial dilatation (6.4 ±â€¯1.5 vs. 4.7 ±â€¯1.4 mg, p = 0.004) and left atrial fibrosis (17.8 ±â€¯3.1 vs. 12.8 ±â€¯3.1%, p = 0.046) compared to vehicle-treated RacET mice. In summary, finerenone prevented from MR-mediated structural remodeling in cardiac fibroblasts and in RacET mice. These data demonstrate anti-fibrotic myocardial effects of finerenone.

Mitral valve pressure gradient after percutaneous mitral valve repair: every beat counts.

A patient presented with symptoms of decompensated heart failure 2 months after percutaneous mitral valve (MV) repair. Echocardiography demonstrated impaired left ventricular function with elevated MV pressure gradients and pulmonary pressures during rapid atrial fibrillation. Heart rate control was achieved by implantation of a biventricular pacemaker with subsequent His-bundle ablation because atrial fibrillation was refractory to medical treatment. During biventricular pacing at different rates (50-110 b.p.m.), heart rate correlated positively with both MV mean pressure gradient and global longitudinal strain and negatively with stroke volume. MV pressure gradients directly translated into elevated pulmonary pressures. Thus, rate control and biventricular pacing improved cardiac haemodynamics.

Long-Term Hemodynamic Improvement after Transcatheter Mitral Valve Repair.

BACKGROUND: Correction of mitral regurgitation (MR) alters the load on the left ventricle. There are few data on the long-term hemodynamic adaptations of the cardiovascular system after transcatheter mitral valve repair (TMVR). The aim of this study was to determine a comprehensive hemodynamic status using noninvasive pressure-volume analysis. METHODS: Pressure-volume parameters were calculated from echocardiography with simultaneous arm-cuff blood pressure measurements at baseline before TMVR and 12 months after TMVR. Eighty-eight consecutive patients undergoing edge-to-edge mitral clip implantation because of grade 3+ or 4+, symptomatic (79.5% in New York Heart Association functional class ≥III) MR were prospectively enrolled. The mean left ventricular (LV) ejection fraction was 42 ± 14%. Sixty-seven percent of the patients had secondary MR. RESULTS: Twelve months after TMVR, 17.7% of patients had died, and 19.0% were rehospitalized because of decompensated heart failure. MR grade was ≤2+ in 90% of surviving patients, and 77% were in New York Heart Association functional class ≤II. LV end-diastolic volume index decreased from 87 ± 38 to 77 ± 40 mL/m2 (P < .0001), end-systolic volume index changed from 54 ± 34 to 50 ± 36 mL/m2 (P = .018), hence total stroke volume index was reduced (from 34 ± 11 to 28 ± 7 ml/m2, P < .0001). Ejection fraction and global longitudinal peak systolic strain remained unchanged. Increased forward ejection fraction (30 ± 14% vs 41 ± 20%, P < .0001), cardiac index (from 1.7 ± 0.4 to 1.9 ± 0.5 mL/min/m2, P = .003), and peak power index (214 ± 114 vs 280 ± 149 mm Hg/sec, P = .0001) as well as similar end-systolic elastance at reduced LV volumes indicated improved LV performance. Cardiac efficiency, measured as cardiac index relative to myocardial energy, was improved (0.012 ± 0.008 vs 0.019 ± 0.010 mm Hg-1, P = .002). Logistic regression analysis revealed baseline values of total ejection fraction and diastolic pulmonary pressure gradient as predictors of clinical improvement (odds ratios, 1.076 [P = .009] and 0.812 [P = .015], respectively) after TMVR. CONCLUSIONS: One year after TMVR, patients showed reverse remodeling and improved LV performance that was associated with improved symptom status. This hemodynamic improvement supports TMVR as long-term effective therapy for patients with symptomatic MR.

Mitral valve interventions in heart failure.

Secondary mitral regurgitation (MR) results from left ventricular dilatation and dysfunction. Quantification of secondary MR is challenging because of the underlying myocardial disease. Clinical and echocardiographic evaluation requires a multi-parametric approach. Severe secondary MR occurs in up to one-fourth of patients with heart failure with reduced ejection fraction, which is associated with a mortality rate of 40% to 50% in 3 years. Percutaneous edge-to-edge mitral valve repair (MitraClip) has emerged as an alternative to surgical valve repair to improve symptoms, functional capacity, heart failure hospitalizations, and cardiac haemodynamics. Further new transcatheter strategies addressing MR are evolving. The Carillion, Cardioband, and Mitralign devices were designed to reduce the annulus dilatation, which is a frequent and important determinant of secondary MR. Several transcatheter mitral valve replacement systems (Tendyne, CardiAQ-Edwards, Neovasc, Tiara, Intrepid, Caisson, HighLife, MValve System, and NCSI NaviGate Mitral) are emerging because valve replacement might be more durable compared with valve repair. In small studies, these interventional therapies demonstrated feasibility and efficiency to reduce MR and to improve heart failure symptoms. However, neither transcatheter nor surgical mitral valve repair or replacement has been proven to impact on the prognosis of heart failure patients with severe MR, which remains high with a mortality rate of 14-20% at 1 year. To date, the primary indication for treatment of secondary severe MR is the amelioration of symptoms, reinforcing the value of a Heart Team discussion. Randomized studies to investigate the treatment effect and long-term outcome for any transcatheter or surgical mitral valve intervention compared with optimized medical treatment are urgently needed and underway.