Tadalafil for Treatment of Combined Postcapillary and Precapillary Pulmonary Hypertension in Patients With Heart Failure and Preserved Ejection Fraction: A Randomized Controlled Phase 3 Study.

BACKGROUND: We assessed the efficacy and safety of tadalafil, a phosphodiesterase type 5 inhibitor, in patients with heart failure with preserved ejection fraction and combined postcapillary and precapillary pulmonary hypertension. METHODS: In the double-blind PASSION study (Phosphodiesterase-5 Inhibition in Patients With Heart Failure With Preserved Ejection Fraction and Combined Post- and Pre-Capillary Pulmonary Hypertension), patients with heart failure with preserved ejection fraction and combined postcapillary and precapillary pulmonary hypertension were randomized 1:1 to receive tadalafil at a target dose of 40 mg or placebo. The primary end point was the time to the first composite event of adjudicated heart failure hospitalization or all-cause death. Secondary end points included all-cause mortality and improvements in New York Heart Association functional class or ≥10% improvement in 6-minute walking distance from baseline. RESULTS: Initially targeting 372 patients, the study was terminated early because of disruption in study medication supply. At that point, 125 patients had been randomized (placebo: 63; tadalafil: 62,). Combined primary end-point events occurred in 20 patients (32%) assigned to placebo and 17 patients (27%) assigned to tadalafil (hazard ratio, 1.02 [95% CI, 0.52-2.01]; P=0.95). There was a possible signal of higher all-cause mortality in the tadalafil group (hazard ratio, 5.10 [95% CI, 1.10-23.69]; P=0.04). No significant between-group differences were observed in other secondary end points. Serious adverse events occurred in 29 participants (48%) in the tadalafil group and 35 (56%) in the placebo group. CONCLUSIONS: The PASSION trial, terminated prematurely due to study medication supply disruption, does not support tadalafil use in patients with heart failure with preserved ejection fraction and combined postcapillary and precapillary pulmonary hypertension, with potential safety concerns and no observed benefits in primary and secondary end points. REGISTRATION: URL: https://www.clinicaltrialsregister.eu/; Unique identifier: 2017-003688-37. URL: https://drks.de; Unique identifier: DRKS -DRKS00014595.

Transcatheter aortic valve implantation in patients with high-risk symptomatic native aortic regurgitation (ALIGN-AR): a prospective, multicentre, single-arm study.

BACKGROUND: Surgery remains the only recommended intervention for patients with native aortic regurgitation. A transcatheter therapy to treat patients at high risk for mortality and complications with surgical aortic valve replacement represents an unmet need. Commercial transcatheter heart valves in pure aortic regurgitation are hampered by unacceptable rates of embolisation and paravalvular regurgitation. The Trilogy transcatheter heart valve (JenaValve Technology, Irvine, CA, USA) provides a treatment option for these patients. We report outcomes with transfemoral transcatheter aortic valve implantation (TAVI) in patients with pure aortic regurgitation using this dedicated transcatheter heart valve. METHODS: The ALIGN-AR trial is a prospective, multicentre, single-arm study. We recruited symptomatic patients (aged ≥18 years) with moderate-to-severe or severe aortic regurgitation at high risk for mortality and complications after surgical aortic valve replacement at 20 US sites for treatment with the Trilogy transcatheter heart valve. The 30-day composite primary safety endpoint was compared for non-inferiority with a prespecified performance goal of 40·5%. The primary efficacy endpoint was 1-year all-cause mortality compared for non-inferiority with a performance goal of 25%. This trial is registered with ClinicalTrials.gov, NCT04415047, and is ongoing. FINDINGS: Between June 8, 2018, and Aug 29, 2022, we screened 346 patients. We excluded 166 (48%) patients and enrolled 180 (52%) patients with symptomatic aortic regurgitation deemed high risk by the heart team and independent screening committee assessments. The mean age of the study population was 75·5 years (SD 10·8), and 85 (47%) were female, 95 (53%) were male, and 131 (73%) were White. Technical success was achieved in 171 (95%) patients. At 30 days, four (2%) deaths, two (1%) disabling strokes, and two (1%) non-disabling strokes occurred. Using standard Valve Academic Research Consortium-2 definitions, the primary safety endpoint was achieved, with events occurring in 48 (27% [97·5% CI 19·2-34·0]) patients (pnon-inferiority<0·0001), with new pacemaker implantation in 36 (24%) patients. The primary efficacy endpoint was achieved, with mortality in 14 (7·8% [3·3-12·3]) patients at 1 year (pnon-inferiority<0·0001). INTERPRETATION: This study shows the safety and effectiveness of treating native aortic regurgitation using a dedicated transcatheter heart valve to treat patients with symptomatic moderate-to-severe or severe aortic regurgitation who are at high risk for mortality or complications after surgical aortic valve replacement. The observed short-term clinical and haemodynamic outcomes are promising as are signs of left ventricular remodelling, but long-term follow-up is necessary. FUNDING: JenaValve Technology.

Advanced CT measures of coronary artery disease with intermediate stenosis in patients with severe aortic valve stenosis.

BACKGROUND: Coronary artery disease (CAD) and severe aortic valve stenosis (AS) frequently coexist. While pre-transcatheter aortic valve replacement (TAVR) computed tomography angiography (CTA) allows to rule out obstructive CAD, interpreting hemodynamic significance of intermediate stenoses is challenging. This study investigates the incremental value of CT-derived fractional flow reserve (CT-FFR), quantitative coronary plaque characteristics (e.g., stenosis degree, plaque volume, and composition), and peri-coronary adipose tissue (PCAT) density to detect hemodynamically significant lesions among those with AS and CAD. MATERIALS AND METHODS: We included patients with severe AS and intermediate coronary lesions (20-80% diameter stenosis) who underwent pre-TAVR CTA and invasive coronary angiogram (ICA) with resting full-cycle ratio (RFR) assessment between 08/16 and 04/22. CTA image analysis included assessment of CT-FFR, quantitative coronary plaque analysis, and PCAT density. Coronary lesions with RFR ≤ 0.89 indicated hemodynamic significance as reference standard. RESULTS: Overall, 87 patients (age 77.9 ± 7.4 years, 38% female) with 95 intermediate coronary artery lesions were included. CT-FFR showed good discriminatory capacity (area under receiver operator curve (AUC) = 0.89, 95% confidence interval (CI) 0.81-0.96, p < 0.001) to identify hemodynamically significant lesions, superior to anatomical assessment, plaque morphology, and PCAT density. Plaque composition and PCAT density did not differ between lesions with and without hemodynamic significance. Univariable and multivariable analyses revealed CT-FFR as the only predictor for functionally significant lesions (odds ratio 1.28 (95% CI 1.17-1.43), p < 0.001). Overall, CT-FFR ≤ 0.80 showed diagnostic accuracy, sensitivity, and specificity of 88.4% (95%CI 80.2-94.1), 78.5% (95%CI 63.2-89.7), and 96.2% (95%CI 87.0-99.5), respectively. CONCLUSION: CT-FFR was superior to CT anatomical, plaque morphology, and PCAT assessment to detect functionally significant stenoses in patients with severe AS. CLINICAL RELEVANCE STATEMENT: CT-derived fractional flow reserve in patients with severe aortic valve stenosis may be a useful tool for non-invasive hemodynamic assessment of intermediate coronary lesions, while CT anatomical, plaque morphology, and peri-coronary adipose tissue assessment have no incremental or additional benefit. These findings might help to reduce pre-transcatheter aortic valve replacement invasive coronary angiogram. KEY POINTS: • Interpreting the hemodynamic significance of intermediate coronary stenoses is challenging in pre-transcatheter aortic valve replacement CT. • CT-derived fractional flow reserve (CT-FFR) has a good discriminatory capacity in the identification of hemodynamically significant coronary lesions. • CT-derived anatomical, plaque morphology, and peri-coronary adipose tissue assessment did not improve the diagnostic capability of CT-FFR in the hemodynamic assessment of intermediate coronary stenoses.

Coronary angiography after cardiac arrest without ST-elevation myocardial infarction: a network meta-analysis.

AIMS: This network meta-analysis aimed to assess the effect of early coronary angiography (CAG) compared with selective CAG (late and no CAG) for patients after out-of-hospital cardiac arrest without ST-elevation myocardial infarction (NSTE-OHCA). METHODS AND RESULTS: A systematic literature search was performed using the EMBASE, MEDLINE and Web of Science databases without restrictions on publication date. The last search was performed on 15 July 2022. Randomized controlled trials (RCTs) and non-randomized studies (NRS) comparing the effect of early CAG to selective CAG after NSTE-OHCA on survival and/or neurological outcomes were included. Meta-analyses were performed based on a DerSimonian-Laird random effects model. A total of 18 studies were identified by the literature search. After the exclusion of two studies due to high risk of bias, 16 studies (six RCTs, ten NRS) were included in the final analyses. Meta-analyses showed a statistically significant increase in survival after early CAG compared with selective CAG in the overall analysis [OR: 1.40, 95% confidence interval (CI): (1.12-1.76), P < 0.01, I2 = 68%]. This effect was lost in the subgroup analysis of RCTs [OR: 0.89, 95% CI: (0.73-1.10), P = 0.29, I2 = 0%]. Random effects model network meta-analysis of NRS based on a Bayesian method showed statistically significant increased survival after late compared with early CAG [OR: 4.20, 95% CI: (1.22, 20.91)]. CONCLUSION: The previously reported superiority of early CAG after NSTE-OHCA is based on NRS at high risk of selection and survivorship bias. The meta-analysis of RCTs does not support routinely performing early CAG after NSTE-OHCA.

A Controlled Trial of Rivaroxaban after Transcatheter Aortic-Valve Replacement.

BACKGROUND: Whether the direct factor Xa inhibitor rivaroxaban can prevent thromboembolic events after transcatheter aortic-valve replacement (TAVR) is unclear. METHODS: We randomly assigned 1644 patients without an established indication for oral anticoagulation after successful TAVR to receive rivaroxaban at a dose of 10 mg daily (with aspirin at a dose of 75 to 100 mg daily for the first 3 months) (rivaroxaban group) or aspirin at a dose of 75 to 100 mg daily (with clopidogrel at a dose of 75 mg daily for the first 3 months) (antiplatelet group). The primary efficacy outcome was the composite of death or thromboembolic events. The primary safety outcome was major, disabling, or life-threatening bleeding. The trial was terminated prematurely by the data and safety monitoring board because of safety concerns. RESULTS: After a median of 17 months, death or a first thromboembolic event (intention-to-treat analysis) had occurred in 105 patients in the rivaroxaban group and in 78 patients in the antiplatelet group (incidence rates, 9.8 and 7.2 per 100 person-years, respectively; hazard ratio with rivaroxaban, 1.35; 95% confidence interval [CI], 1.01 to 1.81; P = 0.04). Major, disabling, or life-threatening bleeding (intention-to-treat analysis) had occurred in 46 and 31 patients, respectively (4.3 and 2.8 per 100 person-years; hazard ratio, 1.50; 95% CI, 0.95 to 2.37; P = 0.08). A total of 64 deaths occurred in the rivaroxaban group and 38 in the antiplatelet group (5.8 and 3.4 per 100 person-years, respectively; hazard ratio, 1.69; 95% CI, 1.13 to 2.53). CONCLUSIONS: In patients without an established indication for oral anticoagulation after successful TAVR, a treatment strategy including rivaroxaban at a dose of 10 mg daily was associated with a higher risk of death or thromboembolic complications and a higher risk of bleeding than an antiplatelet-based strategy. (Funded by Bayer and Janssen Pharmaceuticals; GALILEO ClinicalTrials.gov number, NCT02556203.).

Myeloperoxidase is a critical mediator of anthracycline-induced cardiomyopathy.

Cardiotoxicity is a major complication of anthracycline therapy that negatively impacts prognosis. Effective pharmacotherapies for prevention of anthracycline-induced cardiomyopathy (AICM) are currently lacking. Increased plasma levels of the neutrophil-derived enzyme myeloperoxidase (MPO) predict occurrence of AICM in humans. We hypothesized that MPO release causally contributes to AICM. Mice intravenously injected with the anthracycline doxorubicin (DOX) exhibited higher neutrophil counts and MPO levels in the circulation and cardiac tissue compared to saline (NaCl)-treated controls. Neutrophil-like HL-60 cells exhibited increased MPO release upon exposition to DOX. DOX induced extensive nitrosative stress in cardiac tissue alongside with increased carbonylation of sarcomeric proteins in wildtype but not in Mpo-/- mice. Accordingly, co-treatment of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) with DOX and MPO aggravated loss of hiPSC-CM-contractility compared to DOX treatment alone. DOX-treated animals exhibited pronounced cardiac apoptosis and inflammation, which was attenuated in MPO-deficient animals. Finally, genetic MPO deficiency and pharmacological MPO inhibition protected mice from the development of AICM. The anticancer efficacy of DOX was unaffected by MPO deficiency. Herein we identify MPO as a critical mediator of AICM. We demonstrate that DOX induces cardiac neutrophil infiltration and release of MPO, which directly impairs cardiac contractility through promoting oxidation of sarcomeric proteins, cardiac inflammation and cardiomyocyte apoptosis. MPO thus emerges as a promising pharmacological target for prevention of AICM.

Enforced viral replication activates adaptive immunity and is essential for the control of a cytopathic virus.

The innate immune system limits viral replication via type I interferon and also induces the presentation of viral antigens to cells of the adaptive immune response. Using infection of mice with vesicular stomatitis virus, we analyzed how the innate immune system inhibits viral propagation but still allows the presentation of antigen to cells of the adaptive immune response. We found that expression of the gene encoding the inhibitory protein Usp18 in metallophilic macrophages led to lower type I interferon responsiveness, thereby allowing locally restricted replication of virus. This was essential for the induction of adaptive antiviral immune responses and, therefore, for preventing the fatal outcome of infection. In conclusion, we found that enforced viral replication in marginal zone macrophages was an immunological mechanism that ensured the production of sufficient antigen for effective activation of the adaptive immune response.

Echocardiographic Progression of Calcific Aortic Valve Disease in Patients with Preexisting Aortic Valve Sclerosis.

Background: We aimed to evaluate echocardiographic parameters to predict calcific aortic valve disease (CAVD) progression. CAVD ranges from aortic valve sclerosis (ASc) with no functional impairment of the aortic valve to severe aortic stenosis (AS). It remains uncertain, which patients with ASc have a particularly high risk of developing AS. Methods: We included a total of 153 patients with visual signs of ASc and peak flow velocity (Vmax) below 2.5 m/s at baseline echocardiography. Progression of CAVD to AS was defined as an increase in Vmax ≥ 2.5 m/s with a delta of ≥ 0.1 m/s; stable ASc was defined as Vmax below 2.5 m/s and a delta < 0.1 m/s. Finally, we compared clinical and echocardiographic parameters between these two groups. Results: The mean age at baseline was 73.5 ( ± 8.2) years and 66.7% were of male sex. After a mean follow-up of 1463 days, 57 patients developed AS, while 96 patients remained in the ASc group. The AS group showed significantly more calcification (p < 0.001) and thickening (p < 0.001) of the aortic valve cusps at baseline, although hemodynamics showed no evidence of AS in both groups (ASc group: Vmax 1.6 ± 0.3 m/s versus AS group: Vmax 1.9 ± 0.3 m/s; p < 0.001). Advanced calcification (odds ratio [OR]: 4.8, 95% confidence interval [CI]: 1.5-15.9; p = 0.009) and a cusp thickness > 0.26 cm (OR: 16.6, 95% CI: 5.4-50.7; p < 0.001) were independent predictors for the development of AS. Conclusions: The acquisition of simple echocardiographic parameter may help to identify patients with particularly high risk of developing AS.

Surgical Versus Interventional Treatment of Major Access Site Complications During Transfemoral TAVI Procedures at a Large Volume Center.

PURPOSE: Access-related vascular complications in transfemoral transcatheter aortic valve implantation (TAVI) can be treated endovascularly or surgically. The aim of this study was to evaluate the short- and long-term outcomes of endovascular treatment compared with surgical repair for access-related vascular complications. METHODS: This retrospective study was performed from January 1, 2018, to December 31, 2020. All transfemorally treated TAVI patients in whom a surgical or endovascular treatment for an access site complication was needed were included. The primary outcome was the need for any related vascular re-operation. RESULTS: In total, 1219 transfemoral TAVI procedures were conducted during the study period. 19 patients suffered an access complication requiring endovascular treatment, while 54 patients required surgical repair. No differences were seen with regard to re-operations (endovascular 15.8% vs surgical 14.8%; p=0.919), wound infections (endovascular 0% vs surgical. 11.1%; p=0.129), and wound healing disorders (endovascular 15.8% vs surgical 29.6%; p=0.237). Patients undergoing endovascular treatment were discharged earlier (endovascular 11.2 vs surgical 14.9 days; p=0.028). After surgical repair, patients received significantly more blood transfusions than endovascularly treated patients (endovascular 1.00 vs surgical 3.1 red blood cell concentrate bags; p<0.001). No differences were found regarding the new onset of walking pain, rest pain, and ischemic ulcers during follow-up. CONCLUSION: In this retrospective cohort, endovascular treatment of access-related vascular complications of transfemoral TAVI procedures was safe and feasible. During the hospital stay, endovascularly treated patients received fewer blood transfusions and were discharged faster than surgically treated patients. No differences regarding clinical outcomes and re-intervention rates were seen during the follow-up. CLINICAL IMPACT: Given the in this retrospective study demonstrated safety and feasibility of endovascular treatment for major access-related vascular complications, along with the in-hospital benefits and absence of follow-up disadvantages compared to surgical treatment, endovascular treatment should be considered in cases of major access-related vascular complications in transfemoral TAVI patients.

Surgical versus Interventional Treatment of Concomitant Aortic Valve Stenosis and Coronary Artery Disease.

BACKGROUND: Coronary artery disease (CAD) is frequently diagnosed in patients with aortic valve stenosis. Treatment options include surgical and interventional approaches. We therefore analyzed short-term outcomes of patients undergoing either coronary artery bypass grafting with simultaneous aortic valve replacement (CABG + AVR) or staged percutaneous coronary intervention and transcatheter aortic valve implantation (PCI + TAVI). METHODS: From all patients treated since 2017, we retrospectively identified 237 patients undergoing TAVI within 6 months after PCI and 241 patients undergoing combined CABG + AVR surgery. Propensity score matching was performed, resulting in 101 matched pairs. RESULTS: Patients in the CABG + AVR group were younger compared with patients in the PCI + TAVI group (71.9 ± 4.9 vs 81.4 ± 3.6 years; p < 0.001). The overall mortality at 30 days before matching was higher after CABG + AVR than after PCI + TAVI (7.8 vs 2.1%; p = 0.012). The paired cohort was balanced for both groups regarding demographic variables and the risk profile (age: 77.2 ± 3.7 vs78.5 ± 2.7 years; p = 0.141) and EuroSCORE II (6.2 vs 7.6%; p = 0.297). At 30 days, mortality was 4.9% in the CABG + AVR group and 1.0% in the PCI + TAVI group (p = 0.099). Rethoracotomy was necessary in 7.9% in the CABG + AVR, while conversion to open heart surgery was necessary in 2% in the PCI + TAVI group. The need for new pacemaker was lower after CABG + AVR than after PCI + TAVI (4.1 vs 6.9%; p = 0.010). No paravalvular leak (PVL) was noted in the CABG + AVR group, while the incidence of moderate-to-severe PVL after PCI + TAVI was 4.9% (p = 0.027). CONCLUSION: A staged interventional approach comprises a short-term survival advantage compared with combined surgery for management of CAD and aortic stenosis. However, PCI + TAVI show a significantly higher risk of atrioventricular block and PVL. Further long-term trials are warranted.

Valve-in-Valve TAVR versus Redo Surgical Aortic Valve Replacement: Early Outcomes.

OBJECTIVE: This study aimed to assess short-term outcomes of patients with failed aortic valve bioprosthesis undergoing valve-in-valve transcatheter aortic valve replacement (ViV-TAVR) or redo surgical aortic valve replacement (rSAVR). METHODS: Between 2009 and 2019, 90 patients who underwent ViV-TAVR (n = 73) or rSAVR (n = 17) due to failed aortic valve bioprosthesis fulfilled the inclusion criteria. Groups were compared regarding clinical end points, including in-hospital all-cause mortality. Patients with endocarditis and in a need of combined cardiac surgery were excluded from the study. RESULTS: ViV-TAVR patients were older (78.0 ± 7.4 vs. 62.1 ± 16.2 years, p = 0.012) and showed a higher prevalence of baseline comorbidities such as atrial fibrillation, diabetes mellitus, hyperlipidemia, and arterial hypertension. In-hospital all-cause mortality was higher for rSAVR than in the ViV-TAVR group (17.6 vs. 0%, p < 0.001), whereas intensive care unit stay was more often complicated by blood transfusions for rSAVR patients without differences in cerebrovascular events. The paravalvular leak was detected in 52.1% ViV-TAVR patients compared with 0% among rSAVR patients (p < 0.001). CONCLUSION: ViV-TAVR can be a safe and feasible alternative treatment option in patients with degenerated aortic valve bioprosthesis. The choice of treatment should include the patient's individual characteristics considering ViV-TAVR as a standard of care.

Outcomes and Characteristics of Patients with Intraprocedural Cardiopulmonary Resuscitation during TAVR.

BACKGROUND: Transcatheter aortic valve replacement (TAVR) has become an established alternative to surgical aortic valve replacement (AVR) for higher risk patients. Periprocedural TAVR complications decreased with a growing expertise of implanters. Yet, TAVR can be accompanied by life-threatening adverse events such as intraprocedural cardiopulmonary resuscitation (CPR). This study retrospectively analyzed predictors and outcomes in a cohort of patients from a high-volume center undergoing periprocedural CPR during TAVR. METHODS: A total of 729 patients undergoing TAVR, including 59 with intraprocedural CPR, were analyzed with respect to peri- and postprocedural outcomes. RESULTS: Patients undergoing CPR showed a significantly lower left ventricular ejection fraction (LVEF) and lower baseline transvalvular mean and peak pressure gradients. The systolic blood pressure measured directly preoperatively was significantly lower in the CPR cohort. CPR patients were in a higher need for intraprocedural defibrillation, heart-lung circulatory support, and conversion to open heart surgery. Further, they showed a higher incidence of atrioventricular block grade III , valve malpositioning, and pericardial tamponade. The in-hospital mortality was significantly higher after intraprocedural CPR, accompanied by a higher incidence of disabling stroke, new pacemaker implantation, more red blood cell transfusion, and longer stay in intensive care unit. CONCLUSION: Impaired preoperative LVEF and instable hemodynamics before valve deployment are independent risk factors for CPR and are associated with compromised outcomes. Heart rhythm disturbances, malpositioning of the prosthesis, and pericardial tamponade are main causes of the high mortality of 17% reported in the CPR group. Nevertheless, mechanical circulatory support and conversion to open heart surgery reduce mortality rates of CPR patients.

Pulmonary hypertension associated with left heart disease.

Pulmonary hypertension (PH) is a common condition in patients with left heart disease (LHD) that is highly relevant for morbidity and mortality. While post-capillary in nature, the pathophysiology of PH in patients with LHD (heart failure/cardiomyopathy, valvular heart disease; other: congenital/acquired) is complex, and decisions about management strategies are challenging. Recently, the updated European Society of Cardiology/European Respiratory Society guidelines on the diagnosis and treatment of PH revisited hemodynamic definitions and the sub-classification of post-capillary PH, and provided numerous new recommendations on the diagnosis and management of PH associated with various types of LHD. Here, we review several novel aspects that focus on: (a) updated hemodynamic definitions, including the distinction between isolated post-capillary PH (IpcPH) and combined post- and pre-capillary PH (CpcPH); (b) the pathogenesis of PH-LHD, considering various components contributing to PH, such as pulmonary congestion, vasoconstriction, and vascular remodeling; (c) the prognostic relevance of PH and hemodynamic markers; (d) the diagnostic approach to PH-LHD; (e) management strategies in PH-LHD, distinguishing between targeting the underlying left heart condition, the pulmonary circulation, and/or impaired right ventricular function. In conclusion, precise clinical and hemodynamic characterization and detailed phenotyping are essential for prognostication and the management of patients with PH-LHD.

Diagnostic yield of repeat screening colonoscopy ten years after an adenoma-negative index screening endoscopy.

In Germany, colonoscopy was introduced as a screening instrument about 20 years ago. Ten years after an adenoma-negative index endoscopy, a second screening colonoscopy can be performed in younger persons, but this approach is based on limited evidence. We therefore prospectively analyzed the diagnostic yield of second screening colonoscopies in clinical routine.Ten years following adenoma-negative screening endoscopy a second screening colonoscopy was performed in 401 persons (210 women and 191 men); mean age was 70 years. A total of 244 benign neoplastic lesions were removed in 135 persons (34%). Eight persons had three or more small tubular adenomas removed; 19 persons had at least one tubular adenoma measuring ≥ 10 mm; 14 persons had adenomas with villous characteristics; 19 persons had serrated adenomas; one person had an adenoma with high grade dysplasia. Thus 61 persons (33 men and 28 women) were classified as bearing a significant risk for the development of colorectal cancer (15%). An additional patient had a low-risk malignant polyp removed endoscopically.We conclude that a significant number of small and advanced adenomas can be identified in a second screening colonoscopy ten years after an adenoma-negative index screening endoscopy, but malignant lesions are rare. Whether or not removal of the benign lesions in a second screening colonoscopy will reduce incidence and mortality of colorectal carcinoma remains to be seen in this elderly group.

Clinical results and 30-day outcomes of self-expanding transcatheter aortic valves: comparative case-matched analysis of CoreValve® versus ACURATE neo™.

BACKGROUND: Transcatheter aortic valve replacement (TAVR) is associated with excellent results in patients with severe aortic stenosis. In highly calcified aortic anuli with increased risk of annulus rupture and in favor of the supra-annular design, self-expandable prostheses are frequently used. In this regard, we aimed to perform a comparative analysis of clinical and 30-day outcomes after TAVR using the self-expanding CoreValve® Evolut R or ACURATE neo™ prosthesis. METHODS: Out of 343 consecutive patients treated with either CoreValve® Evolut R or ACURATE neo™ from January 2014 to December 2017, 76 patients were assigned each per group after 1:1 propensity score matching in regard of preoperative characteristics. Pre- and periprocedural outcomes were retrospectively collected and assessed. Outcomes at 30 days are reported according to the established Valve Academic Research Consortium (VARC-2) criteria. RESULTS: Device success and 30-day survival accounted for 93.4% (n = 71), respectively 97.4% (n = 74) in both groups (p = 1.00). No statistically significant differences regarding clinical parameters were observed. The combined safety endpoint at 30 days was comparable (84.2% (n = 64) CoreValve® vs 85.5% (n = 65) ACURATE neo™; p = 0.848). Except a trend toward higher stroke (p = 0.08) and pacemaker (p = 0.07) rate in the CoreValve® group, major vascular complications, incidence of life-threatening or disabling bleeding, and incidence of postoperative acute kidney injury were comparable. Postoperative hemodynamic parameters showed no significant differences between the implanted valves. CONCLUSION: Both self-expandable prostheses showed good postoperative hemodynamic performance with a low incidence of severe paravalvular leakage, all- cause mortality, and comparable clinical outcomes.

Vascular Ultrasound for In Vivo Assessment of Arterial Pathologies in a Murine Model of Atherosclerosis and Aortic Aneurysm.

Vascular diseases like atherosclerosis and abdominal aortic aneurysm (AAA) are common pathologies in the western world, promoting various potentially fatal conditions. Here, we evaluate high-resolution (HR) ultrasound in mouse models of atherosclerosis and AAA as a useful tool for noninvasive monitoring of early vascular changes in vivo. We used Apolipoprotein E-deficient (ApoE-/-) mice as an atherosclerosis model and induced AAA development by the implementation of Angiotensin II-releasing osmotic minipumps. HR ultrasound of the carotid artery or the abdominal aorta was performed to monitor vascular remodeling in vivo. Images were analyzed by speckle tracking algorithms and correlated to histological analyses and subsequent automated collagen quantification. Consistent changes were observed via ultrasound in both models: Global radial strain (GRS) was notably reduced in the AAA model (23.8 ± 2.8% vs. 12.5 ± 2.5%, p = 0.01) and in the atherosclerotic mice (20.6 ± 1.3% vs. 15.8 ± 0.9%, p = 0.02). In mice with AAA, vessel distensibility was significantly reduced, whereas intima-media thickness was increased in atherosclerotic mice. The area and collagen content of the tunica media were increased in diseased arteries of both models as measured by automated image analysis of Picrosirius Red-stained aortic sections. Correlation analysis revealed a strong correlation of multiple parameters, predicting early vascular damage in HR ultrasound and histological examinations. In conclusion, our findings underscore the potential of HR ultrasound in effectively tracing early alterations in arterial wall properties in murine models of atherosclerosis and AAA.

Myeloid leukocytes' diverse effects on cardiovascular and systemic inflammation in chronic kidney disease.

Chronic kidney disease's prevalence rises globally. Whereas dialysis treatment replaces the kidney's filtering function and prolongs life, dreaded consequences in remote organs develop inevitably over time. Even milder reductions in kidney function not requiring replacement therapy associate with bacterial infections, cardiovascular and heart valve disease, which markedly limit prognosis in these patients. The array of complications is diverse and engages a wide gamut of cellular and molecular mechanisms. The innate immune system is profoundly and systemically altered in chronic kidney disease and, as a unifying element, partakes in many of the disease's complications. As such, a derailed immune system fuels cardiovascular disease progression but also elevates the propensity for serious bacterial infections. Recent data further point towards a role in developing calcific aortic valve stenosis. Here, we delineate the current state of knowledge on how chronic kidney disease affects innate immunity in cardiovascular organs and on a systemic level. We review the role of circulating myeloid cells, monocytes and neutrophils, resident macrophages, dendritic cells, ligands, and cellular pathways that are activated or suppressed when renal function is chronically impaired. Finally, we discuss myeloid cells' varying responses to uremia from a systems immunology perspective.

Multiparametric MRI identifies subtle adaptations for demarcation of disease transition in murine aortic valve stenosis.

Aortic valve stenosis (AS) is the most frequent valve disease with relevant prognostic impact. Experimental model systems for AS are scarce and comprehensive imaging techniques to simultaneously quantify function and morphology in disease progression are lacking. Therefore, we refined an acute murine AS model to closely mimic human disease characteristics and developed a high-resolution magnetic resonance imaging (MRI) approach for simultaneous in-depth analysis of valvular, myocardial as well as aortic morphology/pathophysiology to identify early changes in tissue texture and critical transition points in the adaptive process to AS. AS was induced by wire injury of the aortic valve. Four weeks after surgery, cine loops, velocity, and relaxometry maps were acquired at 9.4 T to monitor structural/functional alterations in valve, aorta, and left ventricle (LV). In vivo MRI data were subsequently validated by histology and compared to echocardiography. AS mice exhibited impaired valve opening accompanied by significant valve thickening due to fibrotic remodelling. While control mice showed bell-shaped flow profiles, AS resulted not only in higher peak flow velocities, but also in fragmented turbulent flow patterns associated with enhanced circumferential strain and an increase in wall thickness of the aortic root. AS mice presented with a mild hypertrophy but unaffected global LV function. Cardiac MR relaxometry revealed reduced values for both T1 and T2 in AS reflecting subtle myocardial tissue remodelling with early alterations in mitochondrial function in response to the enhanced afterload. Concomitantly, incipient impairments of coronary flow reserve and myocardial tissue integrity get apparent accompanied by early troponin release. With this, we identified a premature transition point with still compensated cardiac function but beginning textural changes. This will allow interventional studies to explore early disease pathophysiology and novel therapeutic targets.

Transcatheter valve repair of tricuspid regurgitation with the PASCAL system: TriCLASP study 30-day results.

BACKGROUND: Severe tricuspid regurgitation (TR) is independently associated with increased morbidity and mortality. Percutaneous transcatheter approaches may offer an alternative for patients not amenable to surgery. METHODS: TriCLASP is a prospective, single-arm, multicenter European post-market clinical follow-up study (NCT04614402) to evaluate the safety and performance of the PASCAL system (Edwards Lifesciences) in patients with severe or greater TR. At 30 days, a composite of major adverse events (MAEs) adjudicated by a clinical events committee, echocardiographic parameters adjudicated by core laboratory, and clinical, functional, and quality-of-life measures were evaluated. RESULTS: Mean age of the 74 enrolled patients was 80.3 years, with 58.1% female, 90.5% systemic hypertension, and 77.0% in New York Heart Association (NYHA) class III/IV. Mean Society for Thoracic Surgeons score (MV repair) was 9.0%. TR severity was significantly reduced at discharge (p < 0.001) and sustained at 30 days (p < 0.001), and 90.0% of patients achieved ≤moderate TR. The composite MAE rate at 30 days was 3.0%, including 4 events in 2 patients: cardiovascular mortality 1.5%, stroke 1.5%, renal complications requiring unplanned dialysis or renal replacement therapy 1.5%, and severe bleeding 1.5%. There were no nonelective tricuspid valve reinterventions, major access site and vascular complications, major cardiac structural complications, or device embolizations. NYHA class I/II was achieved in 55.8%, 6-minute walk distance improved by 38.2 m (p < 0.001), and Kansas City cardiomyopathy questionnaire scores improved by 13.4 points (p < 0.001). CONCLUSION: Experience with the PASCAL transcatheter valve repair system in a European post-market setting confirms favorable safety and effectiveness at 30 days. TR significantly reduced, and clinical, functional, and quality-of-life outcomes significantly improved. This study is ongoing. Clinical Trial Registration: The study is ongoing and registered on ClinicalTrials.gov as NCT04614402. The current analysis is an interim report.

Two-year clinical outcomes after successful transcatheter aortic valve implantation with balloon-expandable versus self-expanding valves: A subanalysis of the GALILEO trial.

BACKGROUND: Midterm data comparing clinical outcomes after successful implantation of self-expanding and balloon-expandable transcatheter heart valves (THV) are limited. We aimed to compare 2-year outcomes after successful transcatheter aortic valve implantation (TAVI) with the Edwards balloon-expandable or the Medtronic self-expanding THV. METHODS: Two-year outcomes were analyzed according to the implanted THV in the GALILEO trial. Major adverse cardiac and cerebrovascular events (MACCE) was a composite of all-cause death or thromboembolic events including stroke, myocardial infarction, symptomatic valve thrombosis, systemic embolism, deep-vein thrombosis, or pulmonary embolism. RESULTS: Among 1644 patients recruited in 136 centers across 16 countries between 2015 and 2018, 499 received a self-expanding and 757 patients received a balloon-expandable THV. Patients treated with a self-expanding THV were more likely to be female, and had higher surgical risk, lower hemoglobin levels, and more frequent valve-in-valve procedures than those with a balloon-expandable THV. After multivariable adjustment, there were no significant differences in major clinical outcomes between self-expanding versus balloon-expandable THV: MACCE (17.0% vs. 13.4%, adjusted-hazard ratios [HR] 1.18, 95% confidence intervals [CI]: 0.82-1.69); all-cause death (11.4% vs. 9.3%, adjusted-HR 1.26; 95% CI: 0.78-2.05); cardiovascular death (8.5% vs. 4.0%, adjusted-HR 1.53; 95% CI: 0.82-2.86), any stroke (5.1% vs. 3.7%, adjusted-HR 0.86; 95% CI: 0.43-1.73); major or life-threatening bleeding (5.9% vs. 6.8%, adjusted-HR 0.93; 95% CI: 0.53-1.63). CLINICAL TRIAL REGISTRATION: https://www. CLINICALTRIALS: gov. NCT02556203. CONCLUSIONS: Two-year follow-up data from the GALILEO trial indicate that successful TAVI either with self-expanding or balloon-expandable THVs according to physician discretion did not show difference in rates of MACCE.