TIMP-1 as a biomarker in obstructive sleep apnea: screening, monitoring, risk stratification, and a step towards precision medicine.

OBJECTIVE: The diagnosis of obstructive sleep apnea (OSA) is a complex time- and resource-intensive diagnostic procedure. Since tissue inhibitors of matrix metalloproteinases (TIMP's) are involved in various pathophysiological processes and are correlated with a high cardiovascular risk, TIMP's appear to be a suitable candidate for an OSA-biomarker. PATIENTS AND METHODS: In a prospective controlled diagnostic study, TIMP-1 serum levels of 273 OSA-patients and controls were analyzed for correlation with OSA severity, BMI, age, sex, cardio-/ cerebrovascular comorbidities. Furthermore, longitudinal medium- and long-term effects of CPAP-treatment (n=15) on TIMP-1-levels were investigated. RESULTS: TIMP-1 was clearly linked to OSA as well as to disease severity (mild, moderate, severe; each p<0.001) and was not influenced by age, gender, BMI, or cardio-/cerebrovascular comorbidities. ROC curve analysis revealed an AUC of 0.91 ± 0.017 SE (p<0.001), suggesting a TIMP-1 cut-off value of 75 ng/ml (sensitivity 0.78; specificity 0.91) being especially sensitive for patients with severe OSA (sensitivity 0.89; specificity 0.91). The likelihood ratio was 8.88, while the diagnostic odds ratio was 37.14. CPAP-treatment led to a significant decrease of TIMP-1 after 6-8 months (p=0.008). CONCLUSIONS: TIMP-1 seems to fulfill the preconditions for a circulating OSA-biomarker: disease-specific with a mandatory presence in affected patients, reversible on treatment, reflects disease severity and provides a cutoff value between the healthy state and disease. In the clinical routine, TIMP 1 may help to stratify the individual OSA-associated cardiovascular risk and to monitor the treatment response to CPAP-therapy as a further step towards providing a personalized therapy.

Predictors of olfactory improvement after endoscopic sinus surgery in chronic rhinosinusitis with nasal polyps.

OBJECTIVE: This study aimed to determine the predictors of olfactory improvement after endoscopic sinus surgery among patients with chronic rhinosinusitis with nasal polyps. METHOD: This prospective cohort study included patients admitted to a university hospital between 2006 and 2012. Assessment using odour identification testing, a sinonasal symptom questionnaire, the Rhinosinusitis Disability Index and mucus biomarker levels was performed at various time points. Correlation of variables with identification score differences at six post-operative time points and at baseline was performed, followed by multiple linear regression to determine significant predictors at each of the six post-operative time points. RESULTS: Baseline absence of acute sinusitis, elevated serpin F2 and anterior rhinorrhoea predict early olfactory improvement, whereas baseline allergic rhinitis predicts late olfactory improvement. Baseline odour identification score was the strongest predictor across all time points. CONCLUSION: Patients with chronic rhinosinusitis and nasal polyps with worse disease or baseline olfactory function may benefit more from endoscopic sinus surgery in terms of olfactory improvement.

Timing of peptide receptor radiotargeted therapy in relation to cardiac valve surgery for carcinoid heart disease in patients with neuroendocrine metastases and cardiac syndrome. A single-centre study from a centre of excellence.

INTRODUCTION: Perioperative mortality of patients who undergo heart valve surgery for carcinoid heart valve disease has been observed to be high (5%-10%). We investigated whether peptide receptor radiotherapy with lutetium-177 dotatate can be used safely in patients with neuroendocrine neoplasm carcinoid heart valve disease and if there is associated survival advantage by reducing overall exposure of the valves to high doses of vasoactive peptides. METHOD: Retrospective case notes review was performed on 18 neuroendocrine neoplasm patients (mean 60 years), who underwent heart valve surgery between 2003 and 2017 for carcinoid heart valve disease, 9 of whom received peptide receptor radiotherapy in addition to surgery. RESULTS: All patients were treated with somatostatin receptor antagonists and underwent cardiac valvular surgery (mean two valves replaced) and three benefitted from additional coronary bypass grafting. Nine patients underwent surgery alone: in this group, the time from surgery to progression was 14 months (mean; SD 13.5 months). Nine were treated with peptide receptor radiotherapy in addition to surgery. Six underwent surgery with peptide receptor radiotherapy on progression. Time to progression from surgery to first peptide receptor radiotherapy was mean 25.1 months (SD 23.6 months). No patients developed peritreatment cardiac complications. There were no deaths within the 30-day postoperative period. Average time from surgery to last follow-up/death was 41 months (6-79) in the surgery + lutetium group and in the surgery only group 17 months (1-24). Nine patients died, five in the surgery + lutetium group and four in the surgery only group, all at greater than 1-year postsurgery. DISCUSSION: Peptide receptor radiotherapy is safe in the setting of Carcinoid valvular heart disease in patients with controlled heart failure, PPRT can be use in the pre- and post-valve surgery period. There appears to be a survival benefit of having peptide receptor radiotherapy. Further evidence for peptide receptor radiotherapy in the neoadjuvant setting prior to cardiothoracic surgery is required.

[Anesthesiological concepts in fast-track arthroplasty]. / Anästhesiologische Konzepte in der Fast-Track-Endoprothetik.

Whereas only a few years ago the only expectation of skilful anesthesia was an undisturbed execution of surgical procedures, today this has changed to a perioperative responsibility in which all physicians involved in the treatment process try to optimize the existing circumstances and risks of the patient before, during and after surgery. Thus, the tasks for the anesthesiologist have been mainly extended to a rapid recovery strategy with as few side effects as possible, such as nausea and vomiting or postoperative cognitive deficits (POCD). The establishment of evident structures and the introduction of suitable perioperative procedures with the goal of maintaining homeostasis, adequate opioid-sparing pain treatment and rapid postoperative convalescence determine the anesthesiological fast-track concept.

S100B in serum and saliva: a valid invasive or non-invasive biomarker in obstructive sleep apnea?

OBJECTIVE: The aim of this prospective study was to determine whether serum or saliva S100B could be established as an invasive or non-invasive biomarker of cerebrovascular stress due to chronic intermittent hypoxia in obstructive sleep apnea (OSA). PATIENTS AND METHODS: S100B levels in serum and saliva were measured by an enzyme-linked immunosorbent assay (ELISA) in 40 patients with polysomnographically confirmed OSA (n=34) or ronchopathy (n=6) and 20 control subjects (n=20). We also investigated four healthy volunteers (n=4) to determine whether the S100B levels in serum and saliva are dependent on the time of day. RESULTS: Serum S100B was significantly higher in OSA than in healthy control subjects (p=0.007), although it was not related to the severity of OSA and was independent of age, sex, and subjective daytime symptoms. Values of S100B in saliva showed a marked scatter, so there was no significant difference between the OSA group and controls (p=0.62). We did not find that S100B levels in either serum or saliva depended on the time of day (p=0.53; p=0.91). CONCLUSIONS: Serum S100B allows us to discriminate healthy subjects from patients with OSA. However, it does not live up to its promise as a valid invasive predictor of OSA, since it does not correlate with the severity of the disease. Also, S100B in saliva is not suitable for use as a non-invasive biomarker to detect hypoxia-induced cerebrovascular stress in OSA. This finding prevents an S100B saliva-based assessment of risk or possible extent of structural brain damage, ruling out the possibility of non-invasive home monitoring of compliance and therapeutic efficacy in cases of OSA on treatment.

Impact of mitral geometry and global afterload on improvement of mitral regurgitation after trans-catheter aortic valve implantation.

OBJECTIVE: To assess the impact of mitral geometry, left ventricular (LV) remodelling and global LV afterload on mitral regurgitation (MR) after trans-catheter aortic valve implantation (TAVI). METHODS: In this study, 60 patients who underwent TAVI were evaluated by 3D echocardiography at baseline, 1 month and 6 months after procedure. The proportional change in MR following TAVI was determined by examining the percentage change in vena contracta (VC) at 6 months. Patients having a significant reduction of at least 30% in VC were defined as good responders (GR) and the remaining patients were defined as poor responders (PR). RESULTS: After 6 months of TAVI, 27 (45%) patients were GR and 33 (55%) were PR. There was a significant decrease in 3DE-derived mitral annular diameter and area (P = 0.001), mitral valve tenting area (TA) (P = 0.05), and mitral papillary muscle dyssynchrony index (DSI) (P = 0.05) in the GR group. 3DE-derived LVESV (P = 0.016), LV mass (P = 0.001) and LV DSI, (P = 0.001) were also improved 6 months after TAVI. In addition, valvulo-arterial impedance (ZVA) was significantly higher at baseline in patients with PR (P = 0.028). 3DE-derived mitral annular area (ß: 0.47, P = 0.04), mitral papillary DSI (ß: -0.65, P = 0.012) and ZVA (ß: 0.45, P = 0.028) were the strongest independent parameters that could predict the reduction of functional MR after TAVI. CONCLUSION: GR patients demonstrate more regression in mitral annulus area and diameter after significant decrease in high LVEDP and trans-aortic gradients with TAVI. PR patients appear to have increased baseline ZVA, mitral valve tenting and restriction in mitral valve coaptation. These factors are important for predicting the impact of TAVI on pre-existing MR.

Arterial blood pressure and vascular function in human saphenous vein.

Hypertension is a risk factor for accelerated saphenous vein (SV) graft disease and endothelial dysfunction in a number of vascular territories. We examined the relationship between blood pressure (BP) and vascular function in SV from 94 male patients undergoing coronary artery bypass grafting (CABG). Patients were pretreated with respect to cholesterol (3.4±1.2 mmol/L) and BP (systolic 139±22 mmHg, diastolic 74±13 mmHg). All patients were taking aspirin, 85% statins, 50% angiotensin-converting enzyme inhibitors and 70% beta-blockers. We demonstrate in human SV rings ex vivo that increased BP has no effect on acetylcholine-mediated vasodilatation (p=0.58), nor on the constrictor response to L-NMMA (p=0.98), but has a positive association with the constrictor response to phenylephrine (p=0.008) and a negative correlation with the vasodilator response to sodium nitroprusside (p=0.03). These results may provide further explanation for the high incidence of early vein graft failure after CABG in hypertensive patients and support an aggressive approach to optimize BP before surgery.

2012 update on the Edwards SAPIENTM transcatheter heart valve.

Last year was the 10th anniversary of the first transcatheter aortic valve implantation (TAVI) performed by Alain Cribier using the Cribier-Edwards transcatheter heart valve (THV). The Edwards SAPIENTM THV (Edwards Lifesciences, Irvine, CA, USA) was the first commercially available balloon-expandable THV to receive CE-Mark certification in Europe for transfemoral and transapical aortic valve implantation in 2007/2008. Outcome of the prospective randomized PARTNER-US trial resulted in FDA approval for TAVI using the Edwards SAPIENTM THV in patients unsuitable for surgery in 2011 and high-risk patients in 2012. This experience, together with results from the SOURCE Registry and National Registries, has resulted in further modifications of valve design and delivery systems, but also improvement in patient selection and procedural techniques. In this manuscript we review the changes made to the newest model of the Edwards SAPIENTM and its delivery systems over time with an emphasis on the SAPIEN XTTM. We also summarize the recent experience presented on the Edwards SAPIENTM and SAPIEN XTTM, new access routes and lessons learned for patient assessment, as well as opportunities for future development of the device.

My rules of a perfect SAPIEN™ transcatheter aortic valve implantation.

Transcatheter aortic valve implantation has been established as an alternative treatment option for those patients with aortic stenosis (AO), who are high risk or unsuitable for surgical aortic valve replacement. Since its introduction, transcatheter aortic valve implantation has been mainly performed either by a percutaneous approach through the femoral arteries or by using a transapical approach via a left-sided mini-thoracotomy. More recently, experience on alternative access routes such as the subclavian artery and the ascending aorta has been reported in a small number of patients. The Edwards SAPIENTM transcatheter heart valve (Edwards Lifesciences, Irvine, CA, USA) was the first balloon-expandable transcatheter heart valve to receive CE-Mark certification in Europe for transfemoral and transapical aortic valve implantation in 2007/2008. However, it also has been used for transcatheter procedures using access through ascending aorta and subclavian artery. Appropriate patient selection is key for a successful transcatheter aortic valve program and should be in the responsibility of the heart team of interventional cardiologists, cardiac surgeons, cardiac imaging specialists, anesthetists and geriatrists. Their mixture of skills will enable the team to build patient care pathways in which patients are assessed regarding cardiac and non-cardiac comorbidities, the most appropriate type of treatment is jointly agreed, and finally various treatment options are delivered. In this review we highlight the cornerstones of a successful transcatheter aortic valve program using the Edwards SAPIENTM valve. We focus in particular on preoperative diagnostics, patient selection and potential strengths and weaknesses of the various access routes to offer a guideline for future experience.

The combined treatment of aortic stenosis and abdominal aortic aneurysm using transcatheter techniques: a case report.

We describe the case of an 85 year old lady with symptomatic aortic stenosis (AS) with a history of previous coronary artery bypass grafting (CABG), who was referred for consideration of aortic valve replacement (AVR). Echocardiography revealed severe AS with peak gradient of 92 mmHg, orifice area of 0.6 cm2 and preserved left ventricular function. Computed tomography (CT) aortogram revealed a diffusely calcified aorta and an infrarenal abdominal aortic aneurysm (AAA) measuring 6.5 cm. For symptomatic and prognostic reasons she needed treatment of both the AAA and AS. Her calculated logistic EuroSCORE for AVR was 39%. Following discussion at a multidisciplinary forum, it was agreed that the best way to offer her treatment with the lowest risk was by using transcatheter techniques for both pathologies. She subsequently underwent transcatheter aortic valve implantation (TAVI) via the transapical approach to treat her AS, and 3 months later, endovascular stenting of her infrarenal AAA. She recovered well from both procedures. At 6 week follow up, her cardiac symptoms had improved considerably, and echocardiography revealed a mean AV gradient of 7 mmHg with good left ventricular function. Ultrasound of her abdomen revealed exclusion of the aneurysm sac with no endoleak. This is the first described case of TAVI and endovascular treatment of an AAA as a staged procedure.

A rare case of an aberrant anterior mitral valve chord resulting in severe mitral regurgitation.

A 49 year old female presented with severe dyspnoea due to mitral regurgitation. Echocardiography revealed an aberrant mitral valve chord causing severe mitral regurgitation. The aberrant chord extended between the anterior mitral valve leaflet (AMVL) and the atrial septum causing AMVL prolapse. Resection of the aberrant chord and correction of the AMVL using synthetic Gore-Tex sutures was performed. The patient made an uneventful recovery with post-op echocardiography demonstrating normal mitral valve function.

Transcatheter valve-in-valve implantation for failed bioprosthetic heart valves.

BACKGROUND: The majority of prosthetic heart valves currently implanted are tissue valves that can be expected to degenerate with time and eventually fail. Repeat cardiac surgery to replace these valves is associated with significant morbidity and mortality. Transcatheter heart valve implantation within a failed bioprosthesis, a "valve-in-valve" procedure, may offer a less invasive alternative. METHODS AND RESULTS: Valve-in-valve implantations were performed in 24 high-risk patients. Failed valves were aortic (n=10), mitral (n=7), pulmonary (n=6), or tricuspid (n=1) bioprostheses. Implantation was successful with immediate restoration of satisfactory valve function in all but 1 patient. No patient had more than mild regurgitation after implantation. No patients died during the procedure. Thirty-day mortality was 4.2%. Mortality was related primarily to learning-curve issues early in this high-risk experience. At baseline, 88% of patients were in New York Heart Association functional class III or IV; at the last follow-up, 88% of patients were in class I or II. At a median follow-up of 135 days (interquartile range, 46 to 254 days) and a maximum follow-up of 1045 days, 91.7% of patients remained alive with satisfactory valve function. CONCLUSIONS: Transcatheter valve-in-valve implantation is a reproducible option for the management of bioprosthetic valve failure. Aortic, pulmonary, mitral, and tricuspid tissue valves were amenable to this approach. This finding may have important implications with regard to valve replacement in high-risk patients.

Expression of collagen types I, II and III in juvenile angiofibromas.

Extracellular matrix components have rarely been the focus of interest in juvenile angiofibroma (JA) studies. Although JAs are known to be collagen-rich tumours, single collagens have not been analysed so far. This investigation aimed to study the expression of the fibrillar collagen types I, II and III in JAs using quantitative RT-PCR (n = 15), Western blot analysis (n = 7) and immunohistochemical staining (n = 9). Nasal mucosa (NM) specimens were used as control tissues. ELISA investigation (n = 3) was performed to determine the concentration of C-terminal propeptide of type I collagen in blood serum before and after JA resection. Quantitative RT-PCR found significantly elevated Col1A1 (p < 0.001), Col1A2 (p < 0.001) and Col3A1 (p < 0.001) mRNA levels in JAs, compared with NM. Western blot analysis and immunohistochemical staining proved that there is a significant collagen type I and III protein expression in JAs. In none out of 3 patients, ELISA investigation found evidence for elevated concentrations of C-terminal propeptide of type I collagen before tumour resection, compared with postsurgical measurements. Results of the findings using quantitative RT-PCR, Western blot analysis and immunohistochemistry determined that type II collagen is practically absent in JAs. Based on these findings, type I and III collagen are confirmed as being major components of the extracellular matrix in JAs. However, our findings are not encouraging as regards the use of C-terminal Col I propeptide as a suitable serum tumour marker. Our findings confirming that collagen type II expression is practically absent in JAs refutes the theory that JAs originate in cartilage tissue.

Mid-term results of aortic valve preservation: remodelling vs. reimplantation.

OBJECTIVE: Valve-preserving root replacement has become an accepted alternative to composite replacement both in dissection and in aneurysmal disease. We retrospectively analysed 5-year results comparing root remodelling and reimplantation procedures. METHODS: From October 1995 to January 2001, 119 patients underwent either root remodelling (group A; n = 98; age: 61 +/- 14 years) or valve reimplantation within a vascular graft (group B; n = 21; age: 47 +/- 17 years). In group A, 26 patients were operated for aortic dissection type A and 72 for aortic valve regurgitation and aneurysmal disease. In group B, 8 patients were operated for aortic dissection type A, 13 for aortic valve regurgitation and aneurysm. Concomitant arch surgery was performed in 65 patients (group A: 57; group B: 8). RESULTS: Time on cardiopulmonary bypass was 121 +/- 30 min in group A, 143 +/- 24 min in group B, and aortic cross-clamp time was 87 +/- 19 min in group A and 113 +/- 24 min in group B. Average duration was therefore longer in group B (p = n.s.) Hospital mortality was 3.1 % in group A and 0 % in group B. Following elective procedures, hospital mortality was 1.1 % in group A. Freedom from aortic regurgitation over grade 2 at 4 years was 86 % in group A and 94.7 % in group B. At 4 years, freedom from proximal reoperation was 97.8 % in group A and 100 % in group B. There was no deterioration of valve function or need for reoperation observed after 1 year in either group. CONCLUSION: Five-year results are comparable and encouraging for remodelling and reimplantation procedures. If the initial valve function and geometry is adequate, the chance of secondary failure beyond the first year is minimal.

Aortic valve replacement with a stentless bioprosthesis using the full-root technique.

BACKGROUND: In aortic valve replacement stentless bioprostheses results in improved hemodynamic function compared to stented valves. Using the root replacement technique even larger prostheses are implantable. We present our experience with stentless bioprostheses implanted in the "full-root" technique. PATIENTS AND METHODS: Between 01/1997 and 12/2000, 149 patients underwent root replacement with a stentless xenograft (age 70 +/- 9y, women 52 %, ejection-fraction 58 +/- 15 %). Isolated stenosis was present in 34 %, incompetence in 24 %, and mixed disease in 42 % of patients. Bacterial endocarditis was found in 16 %, and 3 patients suffered from acute aortic dissection. RESULTS: Mean bypass time was 118 +/- 45 min, ischemic time 83 +/- 26 min and operating time 201 +/- 62 min. Concomitant procedures were CABG (32 %), replacement of ascending aorta (22 %) and aortic arch (13 %), mitral valve repair (6.7 %), and carotid thrombendarterectomy (1.3 %). Total in-hospital mortality was 6.7 %, with a 1.8 % mortality rate for patients with isolated aortic valve disease. CONCLUSION: Aortic valve replacement using stentless bioprostheses in the root replacement technique is a safe surgical option. In patients with small aortic roots or ring abscesses it guarantees remodelling of the aortic annulus.

Complete arterial revascularisation in patients older than 70 years.

BACKGROUND: Coronary artery bypass grafting (CABG) using left internal thoracic artery and vein grafts is standard in patients of advanced age. A number of these patients, however, present without suitable vein grafting material and thus require the use of arterial conduits. In order to investigate the safety and efficacy of complete arterial revascularisation, we have compared the perioperative results of patients older than 70 years with conventional CABG and complete arterial revascularisation. PATIENTS AND METHODS: Group I (n = 172) with conventional CABG in 1999 was compared with 152 patients (group II) with complete arterial CABG between 1996 and July 2000. There were no significant differences regarding age, gender, left ventricular ejection fraction or incidence of three-vessel disease or left main stenosis. The proportion of reoperations was significantly higher in group II (16 %) vs. group I (4 %). RESULTS: A mean of 3.7 +/- 0.7 anastomoses (I) versus 4.0 +/- 0.9 (II) were performed per patient (p = n. s.). Mean operating time (I: 210 +/- 46 min; II: 194 +/- 46 min) and bypass time (I: 87 +/- 25 min; II: 78 +/- 29 min) were significantly lower in group II. Ischemic time (I: 46 +/- 22 min; II: 49 +/- 21 min) was not significantly different. The incidence of sternal dehiscence was 2.9 % (I: n = 5) vs. 1.3 % (II: n = 2). Hospital mortality was 4.6 % in group I vs. 3.9 % (II). CONCLUSION: Complete arterial revascularisation is a safe option in patients aged over 70. It remains to be shown whether it may also have advantage in the long term.