Transcatheter aortic valve implantation in severe calcified annulus using the Lotus valve system: Increased incidence of fatal major vascular complications.

OBJECTIVES: This study reports the outcome of a highly selected transcatheter aortic valve implantation (TAVI) population. BACKGROUND: In patients with aortic valve stenosis and severe calcification of the left ventricular outflow tract and/or the annulus, the Boston Scientific Lotus valve provided a low paravalvular leakage rate omitting the risk of annular rupture. METHODS: Until now more than 3,600 TAVI procedures were performed at our institution. Between 8/2015 and 2/2017, 634 TAVI procedures were performed, of which 80 TAVI patients with severe calcifications consecutively received the Lotus valve. Valve Academic Research Consortium (VARC)-2 criteria of these procedures were prospectively documented in our institutional TAVI registry. One year follow-up for the Lotus treated patients was completed. RESULTS: Mean age was 82.0 ± 5.5 years. Device success was 95.0%. Conversion was required in two cases (2.5%). New permanent pacemaker implantation rate was 33.3%. Vascular complications occurred more frequent in comparison to non-Lotus treated patients (13.8 vs. 8.1%; p < .05): five minor and six major vascular complications (6.3 and 7.5%), including four fatal aortic injuries (three acute aortic dissections type A, one rupture of the aortic arch). Seventy-two-hour and 30-day mortality rates were also higher in Lotus patients (6.3 and 12.5% vs. 0.3 and 2.5%; each p < .05). One-year mortality in Lotus patients was 22.5%. CONCLUSIONS: In TAVI procedures with the Lotus valve occurrence of vascular complications including lethal aortic injuries and mortality rates were considerably high. Furthermore, in every TAVI procedure careful examination of the aorta should be mandatory and be a part of planning it.

Contractile properties of the right atrial myofilaments in patients with myxomatous mitral valve degeneration.

BACKGROUND: Myxomatous degeneration of the mitral valve is a common pathological finding in mitral valve surgery and the most common reason for severe mitral valve regurgitation. Considering the importance of right ventricular remodeling and global function after mitral valve surgery we tried to elucidate a possible association of myxomatous mitral valve and impairment of right atrial and ventricular function, which might have an impact on global ventricular performance after mitral valve surgery. METHODS: Right atrial tissue was harvested from 47 patients undergoing mitral valve surgery. We took the trabeculae from the right auricle, which was resected at the right auricle for implementation of extracorporal circulation. The tissue was skinned and prepared in a 24 h-lasting procedure to create small fibers for hinging them in the "muscle machine", an experimental set-up, created for pCa-force measurements. RESULTS: Patients without myxomatous mitral valve developed significantly more force (4.0 mN ± 0.8 mN) at the highest step of calcium concentration compared to 2.7 mN ± 0.4 mN in group of patients with myxomatous valve degeneration (p 0.03). Calcium sensitivity in the myxomatous valve group was at pCa 6.0 and in the non-myxomatous group at pCa 5. Furthermore we observed a significant difference in ejection fraction (EF) among the groups: 49% in the non-myxomatous group versus 57% in the myxomatous group (p 0.03). In the non-myxomatous group 5 patients had diastolic dysfunction grade I-II (22,7%), in group I 10 patients (40%). This was also significant (p 0.04). CONCLUSIONS: Patients with myxomatous mitral valve degeneration seem to have reduced force capacities. Calcium sensitivity is higher compared to the non-myxomatous group, which might be a compensatory mechanism to cover the physiological demand. Furthermore we suggest a higher incidence of diastolic dysfunction in patients with myxomatous mitral valve degeneration, which might have an impact on ventricular remodeling after mitral valve surgery.

Elucidation of the genetic causes of bicuspid aortic valve disease.

AIMS: The present study aims to characterize the genetic risk architecture of bicuspid aortic valve (BAV) disease, the most common congenital heart defect. METHODS AND RESULTS: We carried out a genome-wide association study (GWAS) including 2236 BAV patients and 11 604 controls. This led to the identification of a new risk locus for BAV on chromosome 3q29. The single nucleotide polymorphism rs2550262 was genome-wide significant BAV associated (P = 3.49 × 10-08) and was replicated in an independent case-control sample. The risk locus encodes a deleterious missense variant in MUC4 (p.Ala4821Ser), a gene that is involved in epithelial-to-mesenchymal transformation. Mechanistical studies in zebrafish revealed that loss of Muc4 led to a delay in cardiac valvular development suggesting that loss of MUC4 may also play a role in aortic valve malformation. The GWAS also confirmed previously reported BAV risk loci at PALMD (P = 3.97 × 10-16), GATA4 (P = 1.61 × 10-09), and TEX41 (P = 7.68 × 10-04). In addition, the genetic BAV architecture was examined beyond the single-marker level revealing that a substantial fraction of BAV heritability is polygenic and ∼20% of the observed heritability can be explained by our GWAS data. Furthermore, we used the largest human single-cell atlas for foetal gene expression and show that the transcriptome profile in endothelial cells is a major source contributing to BAV pathology. CONCLUSION: Our study provides a deeper understanding of the genetic risk architecture of BAV formation on the single marker and polygenic level.

Impact of Dialysis on the Prognosis of Patients Undergoing Transcatheter Aortic Valve Implantation.

End-stage renal disease (ESRD) affects approximately 2% to 4% of patients with severe aortic stenosis. It is because these patients have been excluded from clinical trials, the impact of transcatheter aortic valve implantation (TAVI) in this patient group has not been thoroughly investigated. Between April 2008 and March 2015, 2,000 patients (dialysis group, n = 56 [2.8%]) were consecutively enrolled when diagnosed with severe aortic stenosis and eligible to undergo TAVI. Procedural and longer-term outcomes were analyzed and adjusted for differences in baseline characteristics. Patients on dialysis had a higher periprocedural mortality (10.7% vs 1.7%; adjusted odds ratio [adjOR] 5.65, 95% confidence interval [CI] 1.91 to 16.67; p = 0.002) and a lower Valve Academic Research Consortium (VARC)-II (VARC) defined device success (adjOR 0.34, 95% CI 0.15 to 0.79; p = 0.012). At 30 days, there was an increased rate of all-cause mortality (21.4 vs 4.8%; adjOR 4.90, 95% CI 1.96 to 12.26; p = 0.001), cardiovascular (adjOR 3.67, 95% CI 1.43 to 9.41; p = 0.007) and noncardiovascular mortality (adjOR 6.28, 95% CI 1.36 to 9.41; p = 0.019), myocardial infarction (adjOR 9.39, 95% CI 1.84 to 48.03; p = 0.007), bleeding (adjOR 2.48, 95% CI 1.06 to 5.83; p = 0.036) as well as the VARC-II defined early safety combined end point (adjOR 2.97, 95% CI 1.28 to 6.90; p = 0.012) associated with dialysis. Dialysis was associated with poor survival at one (57.1% vs 84.2%) and 3 years (26.8% vs 66.9%) with or without the consideration of the first 72 hours (p <0.001; adjusted p <0.001). Although, in the multivariable regression analysis, reduced ejection fraction, peripheral arterial disease, pulmonary hypertension (PH), frailty and dialysis were associated with 1-year mortality, only PH (>60 mm Hg) remained significant in an analysis restricted to the dialysis patients (adjusted hazard ratio 2.68; 95% CI 1.18 to 5.88; p = 0.018). PH had a sensitivity of 45.8%, a specificity of 81.3%, and a positive predictive value of 64.7%. In conclusion, dialysis is an independent predictor of mortality in patients who underwent TAVI. Long-term mortality in dialysis patients appears to be largely determined by the kidney disease and/or dialysis itself whereas VARC-II defined complications are largely unaffected. An increased short-term mortality still calls for (pre-) procedural optimization.

The adenosine deaminase inhibitor erythro-9-[2-hydroxyl-3-nonyl]-adenine decreases intestinal permeability and protects against experimental sepsis: a prospective, randomised laboratory investigation.

INTRODUCTION: The treatment of septic conditions in critically ill patients is still one of medicine's major challenges. Cyclic nucleotides, adenosine and its receptors play a pivotal role in the regulation of inflammatory responses and in limiting inflammatory tissue destruction. The aim of this study was to verify the hypothesis that adenosine deaminase-1 and cyclic guanosine monophosphate-stimulated phosphodiesterase inhibition by erythro-9-[2-hydroxyl-3-nonyl]-adenine could be beneficial in experimental endotoxicosis/sepsis. METHOD: We used two established animal models for endotoxicosis and sepsis. Twenty-four male Wistar rats that had been given intravenous endotoxin (Escherichia coli lipopolysaccharide) were treated with either erythro-9-[2-hydroxyl-3-nonyl]-adenine infusion or 0.9% saline during a study length of 120 minutes. Sepsis in 84 female C57BL/6 mice was induced by caecal ligation and puncture. Animals were treated with repeated erythro-9-[2-hydroxyl-3-nonyl]-adenine injections after 0, 12 and 24 hours or 4, 12 and 24 hours for delayed treatment. RESULTS: In endotoxaemic rats, intestinal production of hypoxanthine increased from 9.8 +/- 90.2 micromol/l at baseline to 411.4 +/- 124.6 micromol/l and uric acid formation increased from 1.5 +/- 2.3 mmol/l to 13.1 +/- 2.7 mmol/l after 120 minutes. In endotoxaemic animals treated with erythro-9-[2-hydroxyl-3-nonyl]-adenine, we found no elevation of adenosine metabolites. The lactulose/L-rhamnose ratio (14.3 versus 4.2 in control animals; p = 2.5 x 10(-7)) reflects a highly permeable small intestine and through the application of erythro-9-[2-hydroxyl-3-nonyl]-adenine, intestinal permeability could be re-established. The lipopolysaccharide animals had decreased L-rhamnose/3-O-methyl-D-glucose urine excretion ratios. Erythro-9-[2-hydroxyl-3-nonyl]-adenine reduced this effect. The mucosa damage score of the septic animals was higher compared with control and therapy animals (p < 0.05). Septic shock induction by caecal ligation and puncture resulted in a 160-hour survival rate of about 25%. In contrast, direct adenosine deaminase-1 inhibition resulted in a survival rate of about 75% (p = 0.0018). A protective effect was still present when erythro-9-[2-hydroxyl-3-nonyl]-adenine treatment was delayed for four hours (55%, p = 0.029). CONCLUSIONS: We present further evidence of the beneficial effects achieved by administering erythro-9-[2-hydroxyl-3-nonyl]-adenine, an adenosine deaminase-1 and cyclic guanosine monophosphate-stimulated phosphodiesterase inhibitor, in an endotoxicosis and sepsis animal model. This suggests a potential therapeutic option in the treatment of septic conditions.

Two-Year Outcomes of Transcatheter Compared With Surgical Aortic Valve Replacement in "Minimal-Risk" Patients Lacking EuroSCORE Co-morbidities (from the TAVIK Registry).

We aimed to compare the outcomes of transcatheter aortic valve implantation (TAVI) with surgical aortic valve replacement (SAVR) in an elderly but nonfrail, minimally co-morbid population. Although data comparing these 2 procedures in intermediate- and low-risk patients are mounting, no distinction has been made between co-morbidity and age/gender as driving forces for surgical risk. Patients undergoing isolated TAVI or SAVR between May 2008 and March 2015 were documented. Data for 225 patients (TAVI 132, SAVR 93) aged ≥75 and <86 years and fulfilling minimal-risk criteria were analyzed. Patients who underwent TAVI were older (80.7 vs 77.4 years, p <0.0001) and had a higher mean Society of Thoracic Surgeons score (2.16% vs 1.72%, p <0.0001). Mild prosthetic valve regurgitation (odds ratio [OR] 4.9, 95% confidence interval [CI] 3.34 to 7.20) was more likely after TAVI, as were renal complications (predominantly stage I acute kidney injury; OR 2.86, 95% CI 1.79 to 4.55) and new pacemaker implantation (OR 3.33, 95% CI 1.76 to 6.26) at 30 days; however, life-threatening bleeding (OR 0.58, 95% CI 0.36 to 0.93) and reintervention for bleeding (OR 0.03, 95% CI 0.01 to 0.13) were less likely. Survival was comparable between groups at 30 days (99.2% vs 100%, p = 1.0) and 1 year (96.2% vs 96.8%, OR 0.85, 95% CI 0.20 to 3.63, p = 0.823), but it was poorer for patients who underwent TAVI at 2 years (OR 0.31, 95% CI 0.16 to 0.61). In conclusion, the short-term outcomes of TAVI in elderly, low-risk, minimally co-morbid patients appear to be similar to those of SAVR, with access-specific complications. Although these results point toward the potential for more liberal use of TAVI in minimal-risk patients, poorer midterm survival remains a concern, requiring further exploration.

Reduced right atrial contractile force in patients with left ventricular diastolic dysfunction: A study in human atrial fibers-contractile force and diastolic dysfunction.

BACKGROUND/OBJECTIVE: The aim of our study was to evaluate right heart contractile force in patients with diastolic dysfunction (DD) with preserved left heart ejection fraction undergoing cardiac surgery. We examined the contractile properties of skinned human fibers obtained from the right auricle in two groups (DD and controls). METHODS: Right atrial tissue from 64 patients, who were undergoing cardiac surgery, were collected before extracorporal circulation. Tissue was conserved and prepared as "skinned fibers". We exposed the dissected fibers to increasing calcium concentrations and recorded the force values. RESULTS: Patients with DD develop significantly less force at middle and higher calcium concentrations pCa 4.0: DD 2.58 ± 0.4 mN, controls 5.32 ± 0.4 mN, p = 0.02; pCa 5.5: DD 1.14 ± 0.3 mN, controls 1.45 ± 0.3 mN, p = 0.03. DD significantly correlates with left ventricular hypertrophy (LVH; p = 0.03). DD did not significantly occur more often in patients with mitral valve insufficiency, aortic insufficiency or stenosis, or coronary heart disease (all p > 0.10). LVH, which was associated with DD, correlated significantly with mitral valve prolapse (p = 0.05), aortic valve stenosis (p = 0.02), and mitral valve insufficiency (p = 0.03). CONCLUSION: Contractile force is significantly reduced in right atrial skinned human fibers with DD. DD is significantly associated with LVH, but emerges independently from underlying pathologies like valve diseases or coronary heart disease. This underlines the hypothesis that impairment of contractile capacity directly results from DD-independent from volume or pressure overload due to valvular or ischemic heart disease.

Transcatheter aortic valve implantation in patients with a reduced left ventricular ejection fraction: a single-centre experience in 2000 patients (TAVIK Registry).

BACKGROUND: Previous studies into the effect of a reduced left ventricular ejection fraction (EF) on the short- and long-term prognosis of patients undergoing transcatheter aortic valve implantation (TAVI) have reported conflicting findings. We analysed data from the Karlsruhe TAVI registry with the aim of addressing this question. METHODS AND RESULTS: Patients with aortic stenosis undergoing TAVI were divided into sub-groups according to EF: severely reduced (<30%; n = 109), reduced (≥30 and ≤40%; n = 201), and mid-range/preserved (>40%; n = 1690). VARC complications at 30 days for the population with severely reduced EF did not differ in comparison to the patients with mid-range/preserved EF. Patients with severely reduced EF had a significantly lower survival at 48 h (91.7 vs. 99.0%; p < 0.001), at 30 days (84.4 vs. 95.8%; p < 0.001) and at 1 year (66.1 vs. 85.0%, p < 0.001) compared to those with mid-range/preserved EF. The risk of death increased with age, peripheral arterial disease, poor self-care and chronic renal failure in patients with severely reduced EF. CONCLUSIONS: Mortality post-TAVI was higher for patients with a reduced EF, although the excess comorbidity burden likely contributed to this. A reduced EF should not be considered a contraindication for TAVI per se, but the additional presence of comorbidity indicates increased risk for these patients.

Mortality in patients with acute aortic dissection type A: analysis of pre- and intraoperative risk factors from the German Registry for Acute Aortic Dissection Type A (GERAADA).

OBJECTIVES: Acute aortic dissection type A (AADA) is an emergency with excessive mortality if surgery is delayed. Knowledge about independent predictors of mortality on surgically treated AADA patients is scarce. Therefore, this study was conducted to identify pre- and intraoperative risk factors for death. METHODS: Between July 2006 and June 2010, 2137 surgically treated patients with AADA were enrolled in a multicentre, prospective German Registry for Acute Aortic Dissection type A (GERAADA), presenting perioperative status, operative strategies, postoperative outcomes and AADA-related risk factors for death. Multiple logistic regression analysis was performed to identify the influence of different parameters on 30-day mortality. RESULTS: Overall 30-day mortality (16.9%) increased with age [adjusted odds ratio (OR) = 1.121] and among patients who were comatose (adjusted OR = 3.501) or those who underwent cardiopulmonary resuscitation (adjusted OR = 3.751; all P < 0.0001). The higher the number of organs that were malperfused, the risk for death was (adjusted OR for one organ = 1.651, two organs = 2.440, three organs or more = 3.393, P < 0.0001). Mortality increased with longer operating times (total, cardiopulmonary bypass, cardiac ischaemia and circulatory arrest; all P < 0.02). Arterial cannulation site for extracorporeal circulation, operative techniques and arch interventions had no significant impact on 30-day mortality (all P > 0.1). No significant risk factors, but relevant increases in mortality, were determined in patients suffering from hemiparesis pre- and postoperatively (each P < 0.01), and in patients experiencing paraparesis after surgery (P < 0.02). CONCLUSIONS: GERAADA could detect significant disease- and surgery-related risk factors for death in AADA, influencing the outcome of surgically treated AADA patients. Comatose and resuscitated patients have the poorest outcome. Cannulation sites and operative techniques did not seem to affect mortality. Short operative times are associated with better outcomes.

Analysis of risk factors for neurological dysfunction in patients with acute aortic dissection type A: data from the German Registry for Acute Aortic Dissection type A (GERAADA).

OBJECTIVES: Acute aortic dissection type A (AADA) is associated with major adverse events, such as transient or persistent neurological dysfunction (ND), which may be patient-, disease- or surgery-related. There is a lack of consensus regarding risk factors for ND in AADA patients. The aim of this study was to analyse and identify risk factors for new postoperative ND after aortic repair for AADA. METHODS: Between July 2006 and June 2010, 2137 AADA patients were enrolled in the multi-centre, prospective German Registry of AADA (GERAADA). Perioperative data were prospectively gathered from 50 institutes in Austria, Switzerland and Germany, and multivariate logistic regression analysis was performed to determine the independent predictors of new onset ND. RESULTS: ND occurred in 20.3% of all patients prior to surgery, 12.6% of which resolved postoperatively and 7.7% persisted. New ND after AADA surgery occurred in 9.5% of patients. Risk factors for an increased rate of postoperative new ND were malperfusion syndrome of three or more territories prior to surgery [odds ratio (OR) = 2.206, P = 0.0065], dissection of the supraaortic vessels (OR = 1.468, P = 0.0103) and longer operating time (OR = 1.002 per min, P = 0.0001). New postoperative ND was associated with an increased rate of mortality (22.5 vs. 16.1%, P = 0.0087). Arterial cannulation site had no statistically significant impact on neurological outcomes. CONCLUSIONS: Neurological complications are associated with increased mortality post-AADA repair. New onset ND is associated with extensive malperfusion syndrome, supraaortic vessel dissection and operative time and does not seem to be affected by choice of arterial cannulation site.