Prediction of Mortality and Heart Failure Hospitalization After Transcatheter Tricuspid Valve Interventions: Validation of TRISCORE.

BACKGROUND: Data on the prognostic role of the TRI-SCORE in patients undergoing transcatheter tricuspid valve intervention (TTVI) are limited. OBJECTIVES: The aim of this study was to evaluate the performance of the TRI-SCORE in predicting outcomes of patients undergoing TTVI. METHODS: TriValve (Transcatheter Tricuspid Valve Therapies) is a large multicenter multinational registry including patients undergoing TTVI. The TRI-SCORE is a risk model recently proposed to predict in-hospital mortality after tricuspid valve surgery. The TriValve population was stratified based on the TRI-SCORE tertiles. The outcomes of interest were all-cause death and all-cause death or heart failure hospitalization. Procedural complications and changes in NYHA functional class were also reported. RESULTS: Among the 634 patients included, 223 patients (35.2%) had a TRI-SCORE between 0 and 5, 221 (34.8%) had 6 or 7, and 190 (30%) had ≥8 points. Postprocedural blood transfusion, acute kidney injury, new atrial fibrillation, and in-hospital mortality were more frequent in the highest TRI-SCORE tertile. Postprocedure length of stay increased with a TRI-SCORE increase. A TRI-SCORE ≥8 was associated with an increased risk of 30-day all-cause mortality and all-cause mortality and the composite endpoint assessed at a median follow-up of 186 days (OR: 3.00; 95% CI: 1.38-6.55; HR: 2.17; 95% CI: 1.78-4.13; HR: 2.08, 95% CI: 1.57-2.74, respectively) even after adjustment for procedural success and EuroSCORE II or Society of Thoracic Surgeons Predicted Risk of Mortality. The NYHA functional class improved across all TRI-SCORE values. CONCLUSIONS: In the TriValve registry, the TRI-SCORE has a suboptimal performance in predicting clinical outcomes. However, a TRISCORE ≥8 is associated with an increased risk of clinical events and a lack of prognostic benefit after successful TTVI.

[Catheter-based and surgical treatment of mitral valve diseases]. / Katheterbasierte und operative Therapie bei Mitralklappenvitien.

There is a broad spectrum of mitral valve diseases ranging from young patients with rheumatic mitral valve stenosis up to older patients with secondary mitral valve regurgitation and numerous comorbidities. A profound understanding of the etiology, anatomical characteristics of mitral valve diseases and current treatment options is necessary to be able to prepare a patient-centered treatment approach. The interdisciplinary collaboration of referring physicians, interventional cardiologists, cardiac surgeons, heart failure and imaging specialists as well as anesthesiologists is a cornerstone of optimal patient treatment.

One-Year Outcomes According to Mitral Regurgitation Etiology Following Transcatheter Edge-to-Edge Repair With the PASCAL System: Results From a Multicenter Registry.

BACKGROUND: We previously reported procedural and 30-day outcomes of a German early multicenter experience with the PASCAL system for severe mitral regurgitation (MR). This study reports 1-year outcomes of mitral valve transcatheter edge-to-edge repair with the PASCAL system according to MR etiology in a large all-comer cohort. METHODS AND RESULTS: Clinical and echocardiographic outcomes up to 1-year were investigated according to MR etiology (degenerative [DMR], functional [FMR], or mixed [MMR]) in the first 282 patients with symptomatic MR 3+/4+ treated with the PASCAL implant at 9 centers in 2019. A total of 282 patients were included (33% DMR, 50% FMR, 17% MMR). At discharge, MR reduction to ≤1+/2+ was achieved in 58%/87% of DMR, in 75%/97% of FMR, and in 78%/98% of patients with MMR (P=0.004). MR reduction to ≤1+/2+ was sustained at 30 days (50%/83% DMR, 67%/97% FMR, 74%/100% MMR) and at 1 year (53%/78% DMR, 75%/97% FMR, 67%/91% MMR) with significant differences between etiologies. DMR patients with residual MR 3+/4+ at 1-year had at least complex valve morphology in 91.7%. Valve-related reintervention was performed in 7.4% DMR, 0.7% FMR, and 0.0% MMR (P=0.010). At 1-year, New York Heart Association Functional Class was significantly improved irrespective of MR etiology (P<0.001). CONCLUSIONS: In this large all-comer cohort, mitral valve transcatheter edge-to-edge repair with the PASCAL system was associated with an acute and sustained MR reduction at 1-year in all causes. However, in patients with DMR, MR reduction was less pronounced, reflecting the high incidence of complex or very complex anatomies being referred for mitral valve transcatheter edge-to-edge repair.

Characteristics and outcomes of patients with atrial versus ventricular secondary tricuspid regurgitation undergoing tricuspid transcatheter edge-to-edge repair - Results from the TriValve registry.

AIM: Functional or secondary tricuspid regurgitation (STR) is the most common phenotype of tricuspid regurgitation (TR) with atrial STR (ASTR) and ventricular STR (VSTR) being recently identified as two distinct entities. Data on tricuspid transcatheter edge-to-edge repair (T-TEER) in patients with STR according to phenotype (i.e. ASTR vs. VSTR) are lacking. The aim of this study was to assess characteristics and outcomes of patients with ASTR versus VSTR undergoing T-TEER. METHODS AND RESULTS: Patients with STR undergoing T-TEER were selected from the Transcatheter Tricuspid Valve Therapies (TriValve) registry. ASTR was defined by (i) left ventricular ejection fraction ≥50%, (ii) atrial fibrillation, and (iii) systolic pulmonary artery pressure <50 mmHg. Patients not matching these criteria were classified as VSTR. Patients with primary TR and cardiac implantable electronic device were excluded. Key endpoints included procedural success and survival at follow-up. A total of 298 patients were enrolled in the study: 65 (22%) with ASTR and 233 (78%) with VSTR. Procedural success was similar in the two groups (80% vs. 83% for ASTR vs. VSTR, p = 0.56) and TEER was effective in reducing TR in both groups (from 97% of patients with baseline TR ≥3+ to 23% in ASTR and to 15% in VSTR, all p = 0.001). At 12-month follow-up, survival was significantly higher in the ASTR versus VSTR cohort (91% vs. 72%, log-rank p = 0.02), with VSTR being an independent predictor of mortality at multivariable analysis (hazard ratio 4.75). CONCLUSIONS: In a real-world, multicentre registry, T-TEER was effective in reducing TR grade in both ASTR and VSTR. At 12-month follow-up, ASTR showed better survival than VSTR.

Treatment response to spironolactone in patients with heart failure with preserved ejection fraction: a machine learning-based analysis of two randomized controlled trials.

BACKGROUND: Whether there is a subset of patients with heart failure with preserved ejection fraction (HFpEF) that benefit from spironolactone therapy is unclear. We applied a machine learning approach to identify responders and non-responders to spironolactone among patients with HFpEF in two large randomized clinical trials. METHODS: Using a reiterative cluster allocating permutation approach, patients from the derivation cohort (Aldo-DHF) were identified according to their treatment response to spironolactone with respect to improvement in E/e'. Heterogenous features of response ('responders' and 'non-responders') were characterized by an extreme gradient boosting (XGBoost) algorithm. XGBoost was used to predict treatment response in the validation cohort (TOPCAT). The primary endpoint of the validation cohort was a combined endpoint of cardiovascular mortality, aborted cardiac arrest, or heart failure hospitalization. Patients with missing variables for the XGboost model were excluded from the validation analysis. FINDINGS: Out of 422 patients from the derivation cohort, reiterative cluster allocating permutation identified 159 patients (38%) as spironolactone responders, in whom E/e' significantly improved (p = 0.005). Within the validation cohort (n = 525) spironolactone treatment significantly reduced the occurrence of the primary outcome among responders (n = 185, p log rank = 0.008), but not among patients in the non-responder group (n = 340, p log rank = 0.52). INTERPRETATION: Machine learning approaches might aid in identifying HFpEF patients who are likely to show a favorable therapeutic response to spironolactone. FUNDING: See Acknowledgements section at the end of the manuscript.

Stressed Blood Volume in Severe Tricuspid Regurgitation: Implications for Transcatheter Treatment.

BACKGROUND: Although tricuspid transcatheter edge-to-edge repair (TEER) has been suggested to improve outcomes in patients with tricuspid regurgitation (TR), patients remain at substantial residual risk after the intervention. Total blood volume is divided between the unstressed volume, filling the vascular space, and stressed blood volume (SBV), generating intravascular pressure. SBV is an important mediator of hemodynamic derangements in heart failure and might pose an attractive adjunctive treatment target. OBJECTIVES: The aim of this study was to investigate the role of SBV in patients with severe TR and its implications for tricuspid TEER. METHODS: In total, 279 patients underwent right heart catheterization prior to TEER. SBV was estimated from hemodynamic variables fit to a comprehensive cardiovascular model. RESULTS: Estimated stressed blood volume (eSBV) was associated with obesity, renal and hepatic dysfunction and cardiac remodeling (P < 0.05 for all). Hemodynamically, eSBV correlated with pulmonary artery and cardiac filling pressures as well as right ventricular-pulmonary artery coupling (P < 0.05 for all). After TEER, patients with eSBV greater than the median demonstrated less reduction in right atrial pressures, peripheral edema, and ascites compared with lower eSBV patients (P < 0.05 for all). Higher eSBV was an independent predictor of the occurrence of death and heart failure hospitalization during a median follow-up duration of 618 days (P < 0.05 for all). CONCLUSIONS: In patients with severe TR, eSBV is associated with obesity, renal and liver dysfunction, more severe heart failure, attenuated reduction of venous congestion after TEER, and adverse clinical outcomes. Estimation of SBV should be incorporated in future trials in the field to identify patients in need of adjunctive therapies.

Short-Term Effects of Different Transcatheter Edge-to-Edge Devices on Mitral Valve Geometry.

Background Short-term effects on mitral valve (MV) anatomy after transcatheter edge-to-edge repair using the PASCAL system remain unknown. Precise quantification might allow for an advanced analysis of predictors for mean transmitral gradients. Methods and Results Consecutive patients undergoing transcatheter edge-to-edge repair for secondary mitral regurgitation using PASCAL or MitraClip systems were included. Quantification of short-term MV changes throughout the cardiac cycle was performed using peri-interventional 3-dimensional MV images. Predictors for mean transmitral gradients were identified in univariable and multivariable regression analysis. Long-term results were described during 1-year follow-up. A total of 100 patients undergoing transcatheter edge-to-edge repair using PASCAL (n=50) or MitraClip systems (n=50) were included. Significant reductions of anterior-posterior diameter, annular circumference, and area throughout the cardiac cycle were found in both cohorts (P<0.05 for all). Anatomic MV orifice area remained larger in the PASCAL cohort in mid (2.8±1.0 versus 2.4±0.9 cm2; P=0.049) and late diastole (2.7±1.1 versus 2.2±0.8 cm2; P=0.036) compared with the MitraClip cohort. Besides a device-specific profile of independent predictor of mean transmitral gradients, reduction of middiastolic anatomic MV orifice area was identified as an independent predictor in both the PASCAL (ß=-0.410; P=0.001) and MitraClip cohorts (ß=-0.318; P=0.028). At follow-up, reduction of mitral regurgitation grade to mild or less was more durable in the PASCAL cohort (90% versus 72%; P=0.035). Conclusions PASCAL and MitraClip showed comparable short-term effects on MV geometry. However, PASCAL might better preserve MV function and demonstrated more durable mitral regurgitation reduction during follow-up. Identification of independent predictors for mean transmitral gradients might potentially help to guide device selection in the future.

Short-Term Outcomes of Tricuspid Edge-to-Edge Repair in Clinical Practice.

BACKGROUND: Severe tricuspid regurgitation (TR) is known to be associated with substantial morbidity and mortality. OBJECTIVES: The authors sought to study the acute outcomes of subjects treated by tricuspid transcatheter edge-to-edge repair with the TriClip system (Abbott) in a contemporary, real-world setting. METHODS: The bRIGHT (An Observational Real-World Study Evaluating Severe Tricuspid Regurgitation Patients Treated With the Abbott TriClip™ Device) postapproval study is a prospective, single-arm, open-label, multicenter, postmarket registry conducted at 26 sites in Europe. Echocardiographic assessment was performed at a core laboratory. RESULTS: Enrolled subjects were elderly (79 ± 7 years of age) with significant comorbidities. Eighty-eight percent had baseline massive or torrential TR, and 80% of subjects were in NYHA functional class III or IV. Successful device implantation occurred in 99% of subjects, and TR was reduced to ≤moderate at 30 days in 77%. Associated significant improvements in NYHA functional class (I/II, 20% to 79%; P < 0.0001) and Kansas City Cardiomyopathy Questionnaire score (19 ± 23 points improvement; P < 0.0001) were observed at 30 days. With baseline TR grade removed as a variable, smaller right atrial volume and smaller tethering distance at baseline were independent predictors of TR reduction to ≤moderate at discharge (OR: 0.679; 95% CI: 0.537-0.858; P = 0.0012; OR: 0.722; 95% CI: 0.564-0.924; P = 0.0097). Fourteen subjects (2.5%) experienced a major adverse event at 30 days. CONCLUSIONS: Transcatheter tricuspid valve repair was found to be safe and effective in treating significant TR in a diverse, real-world population. (An Observational Real-World Study Evaluating Severe Tricuspid Regurgitation Patients Treated With the Abbott TriClip™ Device [bRIGHT]; NCT04483089).

Impact of Transcatheter Edge-to-Edge Mitral Valve Repair on Guideline-Directed Medical Therapy Uptitration.

BACKGROUND: Guideline-directed medical therapy (GDMT) optimization is mandatory before transcatheter edge-to-edge mitral valve repair (M-TEER) in patients with secondary mitral regurgitation (SMR) and heart failure (HF) with reduced ejection fraction (HFrEF). However, the effect of M-TEER on GDMT is unknown. OBJECTIVES: The authors sought to evaluate frequency, prognostic implications and predictors of GDMT uptitration after M-TEER in patients with SMR and HFrEF. METHODS: This is a retrospective analysis of prospectively collected data from the EuroSMR Registry. The primary events were all-cause death and the composite of all-cause death or HF hospitalization. RESULTS: Among the 1,641 EuroSMR patients, 810 had full datasets regarding GDMT and were included in this study. GDMT uptitration occurred in 307 patients (38%) after M-TEER. Proportion of patients receiving angiotensin-converting enzyme inhibitors/angiotensin receptor blockers/angiotensin receptor-neprilysin inhibitors, beta-blockers, and mineralocorticoid receptor antagonists was 78%, 89%, and 62% before M-TEER and 84%, 91%, and 66% 6 months after M-TEER (all P < 0.001). Patients with GDMT uptitration had a lower risk of all-cause death (adjusted HR: 0.62; 95% CI: 0.41-0.93; P = 0.020) and of all-cause death or HF hospitalization (adjusted HR: 0.54; 95% CI: 0.38-0.76; P < 0.001) compared with those without. Degree of MR reduction between baseline and 6-month follow-up was an independent predictor of GDMT uptitration after M-TEER (adjusted OR: 1.71; 95% CI: 1.08-2.71; P = 0.022). CONCLUSIONS: GDMT uptitration after M-TEER occurred in a considerable proportion of patients with SMR and HFrEF and is independently associated with lower rates for mortality and HF hospitalizations. A greater decrease in MR was associated with increased likelihood for GDMT uptitration.

Staging Heart Failure Patients With Secondary Mitral Regurgitation Undergoing Transcatheter Edge-to-Edge Repair.

BACKGROUND: Secondary mitral regurgitation (SMR) is a progressive disease with characteristic pathophysiological changes that may influence prognosis. Although the staging of SMR patients suffering from heart failure with reduced ejection fraction (HFrEF) according to extramitral cardiac involvement has prognostic value in medically treated patients, such data are so far lacking for edge-to-edge mitral valve repair (M-TEER). OBJECTIVES: This study sought to classify M-TEER patients into disease stages based on the phenotype of extramitral cardiac involvement and to assess its impact on symptomatic and survival outcomes. METHODS: Based on echocardiographic and clinical assessment, patients were assigned to 1 of the following HFrEF-SMR groups: left ventricular involvement (Stage 1), left atrial involvement (Stage 2), right ventricular volume/pressure overload (Stage 3), or biventricular failure (Stage 4). A Cox regression model was implemented to investigate the impact of HFrEF-SMR stages on 2-year all-cause mortality. The symptomatic outcome was assessed with New York Heart Association functional class at follow-up. RESULTS: Among a total of 849 eligible patients who underwent M-TEER for relevant SMR from 2008 until 2019, 9.5% (n = 81) presented with left ventricular involvement, 46% (n = 393) with left atrial involvement, 15% (n = 129) with right ventricular pressure/volume overload, and 29% (n = 246) with biventricular failure. An increase in HFrEF-SMR stage was associated with increased 2-year all-cause mortality after M-TEER (HR: 1.39; CI: 1.23-1.58; P < 0.01). Furthermore, higher HFrEF-SMR stages were associated with significantly less symptomatic improvement at follow-up. CONCLUSIONS: The classification of M-TEER patients into HFrEF-SMR stages according to extramitral cardiac involvement provides prognostic value in terms of postinterventional survival and symptomatic improvement.

Fate of iatrogenic atrial septal defects following mitral transcatheter edge-to-edge repair - a subanalysis of the MITHRAS trial.

Persisting iatrogenic atrial septal defects (iASD) after transcatheter mitral edge-to-edge repair (M-TEER) are associated with impaired outcomes. We investigated the natural history of relevant iASDs with left-to-right shunting post-M-TEER, predictors of spontaneous closure of iASD between 1 and 6 months post-M-TEER, and outcomes (heart failure [HF] hospitalization) in patients with spontaneous closure versus those with persistent iASD 6 months post-M-TEER. Patients with a relevant iASD 1-month post-M-TEER, who were treated conservatively in the randomized controlled MITHRAS trial, underwent clinical follow-up including transesophageal echocardiography 6 months post-M-TEER. Overall, 36 patients (median 77 [interquartile range 65-81] years; 36% women) completed the 6-months follow-up. Six (17%) patients had a spontaneous closure of the iASD. The eccentricity index of the iASD 1-month after M-TEER was the strongest predictor for spontaneous closure (Odds ratio 3.78; 95% confidence interval 1.26-11.33, p = 0.01) and an eccentricity index of < 1.9 provided a sensitivity of 77% at a specificity of 83% for iASD persistence (Area under the curve 0.83, p < 0.001) within 6-months post M-TEER.At follow-up, a numerical difference in the endpoint of HF hospitalization between the spontaneous closure and the residual shunt group (0% vs. 20%, p = 0.25) was observed. The eccentricity of the iASD was the strongest predictor for spontaneous closure at 1-months and an eccentricity index of < 1.9 is associated with a high persistence rate for 6 month after M-TEER. Clinical Trial Registration ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03024268 Identifier: NCT03024268. a (red) is reflecting the mayor lengthwise dimension and b (blue) the mayor oblique dimension. The eccentricity index is calculated by dividing a through b. (Open circle) is depicting an example for a round iASD and (Open rhombus) an example for an eccentric iASD 1 month after M-TEER.

Early Outcomes of 2 Mitral Valve Transcatheter Leaflet Approximation Devices: A Propensity Score-Matched Multicenter Comparison.

BACKGROUND: In addition to the edge-to-edge MitraClip repair system, the edge-to-spacer PASCAL repair system was approved for percutaneous treatment of severe mitral regurgitation (MR). Comparative data are lacking. OBJECTIVES: The aim of this study was to compare procedural and short-term safety and efficacy of 2 leaflet-based transcatheter mitral valve repair systems. METHODS: Procedural and 30-day outcomes were investigated in a propensity score-matched cohort of 307 PASCAL and 307 MitraClip patients at 10 sites. Matching criteria included sex, age, left ventricular ejection fraction, New York Heart Association functional class, MR etiology, left ventricular end-diastolic diameter, left atrial volume index, and vena contracta width. The primary efficacy endpoints were technical success and degree of residual MR at discharge. The primary safety endpoint was the rate of major adverse events (MAE). RESULTS: Technical success was 97.0% in the PASCAL group and 98.0% in the MitraClip group (P = 0.624). MR ≤2+ at discharge was comparable in both groups (PASCAL: 93.8% vs MitraClip: 92.4%; P = 0.527), with more patients exhibiting MR ≤1+ in the PASCAL group (70.5% vs 56.6%; P < 0.001). The postprocedural mean gradient was significantly higher in the MitraClip group (3.3 ± 1.5 mm Hg vs 3.9 ± 1.7 mm Hg; P < 0.001). At 30 days, all-cause mortality and MAE rates were similar (mortality: 1.7% vs 3.3%; P = 0.299; MAE: 3.9% vs 5.2%; P = 0.562). CONCLUSIONS: In this first large propensity score-matched comparison, procedural success rates and MAE did not differ significantly between patients treated with the PASCAL or MitraClip valve repair system. Procedural results with less than moderate MR and no elevated transmitral gradient were more common in the PASCAL group, which might have an impact on long-term outcome.

Circulating Galectin-3 in Patients with Cardiogenic Shock Complicating Acute Myocardial Infarction Treated with Mild Hypothermia: A Biomarker Sub-Study of the SHOCK-COOL Trial.

Background: Galectin-3 (Gal-3) is considered a potential cardiovascular inflammatory marker that may provide additional risk stratification for patients with acute heart failure. It is unknown whether mild therapeutic hypothermia (MTH) impacts Gal-3 levels. Therefore, this biomarker study aimed to investigate the effect of MTH on Gal-3. Methods: In the randomized SHOCK-COOL trial, 40 patients with cardiogenic shock (CS) complicating acute myocardial infraction (AMI) were randomly assigned to the MTH (33 °C) or control group in a 1:1 ratio. Blood samples were collected on the day of admission/day 1, day 2, and day 3. Gal-3 level kinetics throughout these time points were compared between the MTH and control groups. Additionally, potential correlations between Gal-3 and clinical patient characteristics were assessed. Multiple imputations were performed to account for missing data. Results: In the control group, Gal-3 levels were significantly lower on day 3 than on day 1 (day 1 vs. day 3: 3.84 [IQR 2.04−13.3] vs. 1.79 [IQR 1.23−3.50] ng/mL; p = 0.049). Gal-3 levels were not significantly different on any day between the MTH and control groups (p for interaction = 0.242). Spearman's rank correlation test showed no significant correlation between Gal-3 levels and sex, age, smoking, body mass index (BMI), and levels of creatine kinase-MB, creatine kinase, C-reactive protein, creatinine, and white blood cell counts (all p > 0.05). Patients with lower Gal-3 levels on the first day after admission demonstrated a higher risk of all-cause mortality at 30 days (hazard ratio, 2.67; 95% CI, 1.11−6.42; p = 0.029). In addition, Gal-3 levels on day 1 had a good predictive value for 30-day all-cause mortality with an area under the receiver operating characteristic curve of 0.696 (95% CI: 0.513−0.879), with an optimal cut-off point of less than 3651 pg/mL. Conclusions: MTH has no effect on Gal-3 levels in patients with CS complicating AMI compared to the control group. In addition, Gal-3 is a relatively stable biomarker, independent of age, sex, and BMI, and Gal-3 levels at admission might predict the risk of 30-day all-cause mortality.

Tubulin expression and modification in heart failure with preserved ejection fraction (HFpEF).

Diastolic dysfunction in heart failure with preserved ejection fraction (HFpEF) is characterised by increased left ventricular stiffness and impaired active relaxation. Underpinning pathomechanisms are incompletely understood. Cardiac hypertrophy and end stage heart disease are associated with alterations in the cardiac microtubule (MT) network. Increased amounts and modifications of α-tubulin associate with myocardial stiffness. MT alterations in HFpEF have not been analysed yet. Using ZSF1 obese rats (O-ZSF1), a validated HFpEF model, we characterised MT-modifying enzymes, quantity and tyrosination/detyrosination pattern of α-tubulin at 20 and 32 weeks of age. In the left ventricle of O-ZSF1, α-tubulin concentration (20 weeks: 1.5-fold, p = 0.019; 32 weeks: 1.7-fold, p = 0.042) and detyrosination levels (20 weeks: 1.4-fold, p = 0.013; 32 weeks: 1.3-fold, p = 0.074) were increased compared to lean ZSF1 rats. Tyrosination/α-tubulin ratio was lower in O-ZSF1 (20 weeks: 0.8-fold, p = 0.020; 32 weeks: 0.7-fold, p = 0.052). Expression of α-tubulin modifying enzymes was comparable. These results reveal new alterations in the left ventricle in HFpEF that are detectable during early (20 weeks) and late (32 weeks) progression. We suppose that these alterations contribute to diastolic dysfunction in HFpEF and that reestablishment of MT homeostasis might represent a new target for pharmacological interventions.

Atrial Functional Tricuspid Regurgitation: Novel Definition and Impact on Prognosis.

BACKGROUND: Atrial functional tricuspid regurgitation (atrial TR) has received growing recognition as a TR entity with a distinct cause owing to its independence from valvular tethering as the predominant mechanism underlying TR. However, characterization of atrial TR varies, and a universal definition is lacking. METHODS: In total, 651 patients with significant functional TR were analyzed, including 438 conservatively treated individuals and 213 patients who received transcatheter tricuspid valve repair (TTVR). Based on a clustering approach, we defined atrial TR as tricuspid valve (TV) tenting height ≤10 mm, midventricular right ventricular diameter ≤38 mm, and left ventricular ejection fraction ≥50%. RESULTS: Patients with atrial TR were more often females, had higher right ventricular fractional area change, higher left ventricular ejection fraction, and lower LV end-diastolic diameter, TV tenting area and height, lower right ventricular and tricuspid annular size, enlarged, but lower right atrial area and lower TV effective regurgitant orifice area (all P<0.05). Patients with atrial TR had significantly better long-term survival than non-atrial TR in the conservatively treated TR cohort (P<0.01, n=438). Atrial TR was independently associated with a lower rate of the combined end point of mortality and heart failure hospitalization at 1-year follow-up in the TTVR cohort (hazard ratio, 0.39; P<0.05, n=213). TR degree was significantly reduced after TTVR in non-atrial and atrial TR (P<0.01). Functional parameters significantly improved following TTVR independent of TR cause (P<0.05). CONCLUSIONS: An echocardiography-based atrial TR definition is associated with prognostic relevance in patients with functional TR in conservatively treated TR and after TTVR.

Effects of homoarginine supplementation on heart and skeletal muscle of rats with heart failure with preserved ejection fraction.

AIM: Heart failure with preserved ejection fraction (HFpEF) is associated with left ventricular stiffness, impaired diastolic relaxation, and severe exercise intolerance. Decreased homoarginine (hArg) levels are an independent predictor of mortality in cardiovascular disease and correlate with impaired exercise performance. We recently reported alterations in arginine, hArg, and related amino acids in obese ZSF1 rats (O-ZSF1), with a HFpEF phenotype. Although low hArg is associated with diastolic dysfunction in humans, potential effects of hArg supplementation were not tested yet. METHODS AND RESULTS: At an age of 6 weeks, 12 O-ZSF1 were randomized into two groups: (1) O-ZSF1 rats supplemented with hArg in their drinking water (sO-ZSF1) or (2) O-ZSF1 rats receiving no hArg supplementation (O-ZSF1). At an age of 32 weeks, effects of primary prevention by hArg supplementation on echocardiographic, histological, and functional parameters of heart and skeletal muscle were determined. Lean ZSF1 rats (L-ZSF1) served as controls. hArg supplementation did not prevent impairment of diastolic relaxation (E/e': O-ZSF1 21 ± 3 vs. sO-ZSF1 22 ± 3, P = 0.954, L-ZSF1 18 ± 5) but resulted in more cardiac fibrosis (histological collagen staining: +57% in sO-ZSF1 vs. O-ZSF1, P = 0.027) and increased collagen gene expression (Col1a1: +48% in sO-ZSF1 vs. O-ZSF1, P = 0.026). In contrary, right ventricular function was preserved by hArg supplementation (TAPSE (mm): O-ZSF1 1.2 ± 0.3 vs. sO-ZSF1 1.7 ± 0.3, P = 0.020, L-ZSF1 1.8 ± 0.4). Musculus soleus maximal specific muscle force (N/cm2 ) in O-ZSF1 (30.4 ± 0.8) and sO-ZSF1 (31.9 ± 0.9) was comparable but significantly reduced compared with L-ZSF1 (36.4 ± 0.7; both P < 0.05). Maximal absolute muscle force (g) (O-ZSF1: 177.6 ± 7.8, sO-ZSF1: 187.8 ± 5.0, L-ZSF1: 181.5 ± 7.9, all P > 0.05) and cross-sectional fibre area (arbitrary units) (O-ZSF1: 1697 ± 57, sO-ZSF1: 1965 ± 121, L-ZSF1: 1691 ± 104, all P > 0.05) were not altered. CONCLUSIONS: Preservation of physiological hArg level in HFpEF may not be suited to prevent alterations in left ventricular and skeletal muscle function and structure. However, hArg supplementation may be beneficial for right ventricular function especially in pulmonary hypertension in HFpEF. We may speculate that clinically observed decreased hArg level are not the cause but the consequence of a yet unrecognized pathomechanism that underpins HFpEF.

ER-Stress and Senescence Coordinately Promote Endothelial Barrier Dysfunction in Diabetes-Induced Atherosclerosis.

Diabetes mellitus is hallmarked by accelerated atherosclerosis, a major cause of mortality among patients with diabetes. Efficient therapies for diabetes-associated atherosclerosis are absent. Accelerated atherosclerosis in diabetic patients is associated with reduced endothelial thrombomodulin (TM) expression and impaired activated protein C (aPC) generation. Here, we directly compared the effects of high glucose and oxidized LDL, revealing that high glucose induced more pronounced responses in regard to maladaptive unfolded protein response (UPR), senescence, and vascular endothelial cell barrier disruption. Ex vivo, diabetic ApoE-/- mice displayed increased levels of senescence and UPR markers within atherosclerotic lesions compared with nondiabetic ApoE-/- mice. Activated protein C pretreatment maintained barrier permeability and prevented glucose-induced expression of senescence and UPR markers in vitro. These data suggest that high glucose-induced maladaptive UPR and associated senescence promote vascular endothelial cell dysfunction, which-however-can be reversed by aPC. Taken together, current data suggest that reversal of glucose-induced vascular endothelial cell dysfunction is feasible.

Characteristics of Heart Failure With Preserved Ejection Fraction Across the Range of Left Ventricular Ejection Fraction.

BACKGROUND: Recent trial data suggest that stratification of patients with heart failure with preserved ejection fraction (HFpEF) according to left ventricular ejection fraction (LVEF) provides a means for dissecting different treatment responses. However, the differential pathophysiologic considerations have rarely been described. METHODS: This prospective, single-center study analyzed consecutive symptomatic patients with HFpEF diagnosed according to the 2016 European Society of Cardiology heart failure guidelines. Patients were grouped into LVEF 50% to 60% and LVEF >60% cohorts. All patients underwent cardiac magnetic resonance imaging. Transfemoral cardiac catheterization was performed to derive load-dependent and load-independent left ventricular (LV) properties on pressure-volume loop analyses. RESULTS: Fifty-six patients with HFpEF were enrolled and divided into LVEF 50% to 60% (n=21) and LVEF >60% (n=35) cohorts. On cardiac magnetic resonance imaging, the LVEF >60% cohort showed lower LV end-diastolic volumes (P=0.019) and end-systolic volumes (P=0.001) than the LVEF 50% to 60% cohort; stroke volume (P=0.821) did not differ between the cohorts. Extracellular volume fraction was higher in the LVEF 50% to 60% cohort than in the LVEF >60% cohort (0.332 versus 0.309; P=0.018). Pressure-volume loop analyses demonstrated higher baseline LV contractility (end-systolic elastance, 1.85 vs 1.33 mm Hg/mL; P<0.001) and passive diastolic stiffness (ß constant, 0.032 versus 0.018; P=0.004) in the LVEF >60% cohort. Ventriculo-arterial coupling (end-systolic elastance/arterial elastance) at rest was in the range of optimized stroke work in the LVEF >60% cohort but was impaired in the LVEF 50% to 60% cohort (1.01 versus 0.80; P=0.005). During handgrip exercise, patients with LVEF >60% had higher increases in end-systolic elastance (1.85 versus 0.82 mm Hg/mL; P=0.023), attenuated increases in indexed end-systolic volume (-1 versus 7 mL/m²; P<0.004), and more exaggerated increases in LV filling pressures (8 vs 5 mm Hg; P=0.023). LV stroke volume decreased in the LVEF >60% cohort (P=0.007) under exertion. CONCLUSIONS: Patients with HFpEF in whom LVEF ranged from 50% to 60% demonstrated reduced contractility, impaired ventriculo-arterial coupling, and higher extracellular volume fraction. In contrast, patients with HFpEF and a LVEF >60% demonstrated a hypercontractile state with excessive LV afterload and diminished preload reserve. A LVEF-based stratification of patients with HFpEF identified distinct morphologic and pathophysiologic subphenotypes.