The role of impaired cGMP homeostasis in cone photoreceptor degeneration

Achromatopsia (ACHM) is a currently untreatable inherited eye disease that severely impairs daylight vision. The clinical manifestation results from cone photoreceptor dysfunction and is characterized by poor visual acuity, lack of colour discrimination and photophobia. In addition, a progressive degeneration and loss of macular cone photoreceptors is observed. In total six disease genes are known, but the majority of patients carries mutations in CNGA3 (29% of cases) or CNGB3 (48% of cases); the two genes encoding the cone cyclic nucleotide-gated (CNG) channel. This ion channel is directly gated by the second messenger cyclic GMP (cGMP) and is an integral part of the so called phototransduction cascade that translates light signals into electrical stimuli. Interestingly, genetic deletion of the CNG channel subunit CNGA3 in mice leads to high cellular levels of cGMP in affected cone photoreceptors. The aim of this thesis was to characterize the role of impaired cGMP signalling during cone photoreceptor degeneration in the Cnga3 knockout (KO) mouse model for ACHM. First, the developmental time course of cGMP accumulation was investigated using a cGMP-specific antibody. One point worthy of note is that elevated cGMP levels could be observed as early as four days after birth. Using a virus-mediated in vivo gene knockdown (KD) approach it was possible to identify guanylate cyclase 2E (Gucy2e) as the main source of cGMP. Moreover, Gucy2e KD resulted in prolonged survival of cones in Cnga3 KO mice suggesting a toxic role of sustained cGMP overload in affected photoreceptors. Given the absence of CNG channels in Cnga3 KO cones this toxic effect has to be mediated by other cGMP targets. Promising candidates that were further investigated were the cGMP-dependent kinases (cGKs). To investigate the impact of elevated cGK signalling for photoreceptor viability a constitutively active cGK was overexpressed in wildtype mouse photoreceptors using viral vectors. This induced a dramatic decrease of the photoreceptor layer and demonstrated that these kinases can induce cell death. To verify this and to define the effect of the two kinase types, Cnga3 KO mice were cross-bread with cGKI and cGKII KO mice and further examined morphologically. Global loss of cGKII but not cGKI significantly protected cone photoreceptors resulting in lower levels of degeneration and cell death. This finding was confirmed using viral vector-mediated delivery of a cGKII specific shRNA into cone photoreceptors of Cnga3 KO mice. Expression of cGKII-shRNA in adult Cnga3 KO mice again showed a decrease of degeneration suggesting cGKII as a novel target for neuroprotection in cone degeneration. Finally, to further unravel the cGMP signalling triggering cell death in cones two proteomic approaches were performed to identify potential downstream targets of cGKII. These screens could identify a link between a cGMP-cGK-signalling pathway and the serine/threonine kinase Atr. In conclusion this thesis presents strong evidence that cGMP-signalling accelerates retinal degeneration and identifies cGMP/cGKII signalling as a novel target for neuroprotective therapies to prolong cone survival in ACHM and other cone degenerations.Achromatopsie (ACHM) ist eine bis heute nicht heilbare erblich bedingte Augenkrankheit, die das Sehvermögen bei Tageslicht erheblich beeinträchtigt. Die Symptome entstehen durch eine Dysfunktion der Zapfen und sind geprägt von einem vollständigen Ausfall des Farbsinns, einer geringen Sehschärfe und einer extremen Blendungsempfindlichkeit der Betroffenen. Außerdem ist eine schnell fortschreitende Degeneration der Zapfen in der Makula zu beobachten. Mutationen in sechs Genen werden mit ACHM assoziiert, die meisten Patienten tragen jedoch eine Mutation in den Genen, die den in den Zapfen exprimierten zyklisch-Nukleotid gesteuerten (CNG) Kanal kodieren: CNGA3 (29 % der Fälle) und CNGB3 (48 % der Fälle). Dieser Ionenkanal wird durch Bindung des zellulären Botenstoffes - dem zyklischen GMP (cGMP) - geöffnet und ist zudem ein wichtiger Bestandteil der „Sehkaskade“ (sog. Phototransduktionskaskade), die Lichtsignale in elektrische Impulse umwandelt. Interessanterweise führt eine genetische Deletion der Untereinheit CNGA3 bei Mäusen zu einem erhöhten zellulären Level von cGMP in betroffenen Zapfen. Ziel dieser Arbeit war es, die Rolle der beeinträchtigten cGMP-Signalwege während der Zapfendegeneration des Cnga3 Knockout (KO) Mausmodelles zu charakterisieren. Zunächst wurde der entwicklungsspezifische Verlauf der cGMP Akkumulation untersucht. Überraschenderweise war bereits vier Tage nach der Geburt ein erhöhtes cGMP Level festzustellen. Mit Hilfe eines Virus-vermittelten Gen-Knockdowns (KD) war es möglich die Guanylatzyklase 2E (Gucy2E) als die Hauptquelle des cGMP in Zapfen zu identifizieren. Therapierte Augen zeigten eine erhöhte Zapfendichte, was darauf hinweist, dass eine cGMP-Überlastung toxische Auswirkungen auf die betroffenen Zapfen hat. Ohne den CNG-Kanal in Cnga3 KO Zapfen kann die toxische Wirkung nur durch andere cGMP-Targets herbeigeführt werden. Vielversprechend für weitere Experimente erschienen dabei die cGMP-abhängigen Kinasen (cGKs), die weiter untersucht wurden. Um die Auswirkungen von erhöhten cGK-Signalwegen zu untersuchen, wurde in Wildtypmäusen durch virale Vektoren eine konstitutiv aktive cGK überexprimiert. Dies hatte einen drastischen Verlust der Photorezeptorschicht zur Folge und zeigte, dass diese Kinasen Zelltod auslösen können. Um dies zu verifizieren wurden Cnga3 KO Mäuse mit cGKI und cGKII KO Mäusen gekreuzt und morphologisch untersucht. Ein globaler Verlust der cGKII nicht aber der cGKI schützte die Zapfen vor Zelltod und führte zu einer signifikant verminderten Degeneration. Dieses Ergebnis wurde durch die Applikation einer cGKII-shRNA in Cnga3 KO Mäusen bestätigt, die ebenfalls einen signifikanten Rückgang des Zellsterbens zeigte. Diese Anwendung zeigt, dass cGKII ein möglicher neuer Anknüpfungspunkt für neuroprotektive Mechanismen in Zapfendegenerationen sein kann. Um letztendlich den cGMP Signalweg, der zum Zelltod führt, besser verstehen zu können, wurden mögliche Targets der cGKII durch zwei Massenspektrometrie-Ansätze identifiziert. Die Ergebnisse dieser Experimente weisen auf einen Zusammenhang zwischen dem cGMP-cGK-Signalweg und der Serin/threonine Kinase Atr hin. Zusammenfassend liefert diese Arbeit aussagekräftige Nachweise, dass cGMP-Signalwege die retinale Degeneration beschleunigen und identifiziert einen cGMP-cGK Signalweg als neuen Anknüpfungspunkt für neuroprotektive Therapien um die Lebensdauer der Zapfen in ACHM und anderen Zapfendegenerationen zu verlängern

Directed PCR-free engineering of highly repetitive DNA sequences

Background: Highly repetitive nucleotide sequences are commonly found in nature e.g. in telomeres, microsatellite DNA, polyadenine (poly(A)) tails of eukaryotic messenger RNA as well as in several inherited human disorders linked to trinucleotide repeat expansions in the genome. Therefore, studying repetitive sequences is of biological, biotechnological and medical relevance. However, cloning of such repetitive DNA sequences is challenging because specific PCR-based amplification is hampered by the lack of unique primer binding sites resulting in unspecific products.Results: For the PCR-free generation of repetitive DNA sequences we used antiparallel oligonucleotides flanked byrestriction sites of Type IIS endonucleases. The arrangement of recognition sites allowed for stepwise and seamless elongation of repetitive sequences. This facilitated the assembly of repetitive DNA segments and open reading frames encoding polypeptides with periodic amino acid sequences of any desired length. By this strategy wecloned a series of polyglutamine encoding sequences as well as highly repetitive polyadenine tracts. Such repetitive sequences can be used for diverse biotechnological applications. As an example, the polyglutamine sequences were expressed as His6-SUMO fusion proteins in Escherichia coli cells to study their aggregation behavior in vitro. The His6-SUMO moiety enabled affinity purification of the polyglutamine proteins, increased their solubility, and allowed controlled induction of the aggregation process. We successfully purified the fusions proteins and provide an example for their applicability in filter retardation assays.Conclusion: Our seamless cloning strategy is PCR-free and allows the directed and efficient generation of highlyrepetitive DNA sequences of defined lengths by simple standard cloning procedures

The role of impaired cGMP homeostasis in cone photoreceptor degeneration

Achromatopsia (ACHM) is a currently untreatable inherited eye disease that severely impairs daylight vision. The clinical manifestation results from cone photoreceptor dysfunction and is characterized by poor visual acuity, lack of colour discrimination and photophobia. In addition, a progressive degeneration and loss of macular cone photoreceptors is observed. In total six disease genes are known, but the majority of patients carries mutations in CNGA3 (29% of cases) or CNGB3 (48% of cases); the two genes encoding the cone cyclic nucleotide-gated (CNG) channel. This ion channel is directly gated by the second messenger cyclic GMP (cGMP) and is an integral part of the so called phototransduction cascade that translates light signals into electrical stimuli. Interestingly, genetic deletion of the CNG channel subunit CNGA3 in mice leads to high cellular levels of cGMP in affected cone photoreceptors. The aim of this thesis was to characterize the role of impaired cGMP signalling during cone photoreceptor degeneration in the Cnga3 knockout (KO) mouse model for ACHM. First, the developmental time course of cGMP accumulation was investigated using a cGMP-specific antibody. One point worthy of note is that elevated cGMP levels could be observed as early as four days after birth. Using a virus-mediated in vivo gene knockdown (KD) approach it was possible to identify guanylate cyclase 2E (Gucy2e) as the main source of cGMP. Moreover, Gucy2e KD resulted in prolonged survival of cones in Cnga3 KO mice suggesting a toxic role of sustained cGMP overload in affected photoreceptors. Given the absence of CNG channels in Cnga3 KO cones this toxic effect has to be mediated by other cGMP targets. Promising candidates that were further investigated were the cGMP-dependent kinases (cGKs). To investigate the impact of elevated cGK signalling for photoreceptor viability a constitutively active cGK was overexpressed in wildtype mouse photoreceptors using viral vectors. This induced a dramatic decrease of the photoreceptor layer and demonstrated that these kinases can induce cell death. To verify this and to define the effect of the two kinase types, Cnga3 KO mice were cross-bread with cGKI and cGKII KO mice and further examined morphologically. Global loss of cGKII but not cGKI significantly protected cone photoreceptors resulting in lower levels of degeneration and cell death. This finding was confirmed using viral vector-mediated delivery of a cGKII specific shRNA into cone photoreceptors of Cnga3 KO mice. Expression of cGKII-shRNA in adult Cnga3 KO mice again showed a decrease of degeneration suggesting cGKII as a novel target for neuroprotection in cone degeneration. Finally, to further unravel the cGMP signalling triggering cell death in cones two proteomic approaches were performed to identify potential downstream targets of cGKII. These screens could identify a link between a cGMP-cGK-signalling pathway and the serine/threonine kinase Atr. In conclusion this thesis presents strong evidence that cGMP-signalling accelerates retinal degeneration and identifies cGMP/cGKII signalling as a novel target for neuroprotective therapies to prolong cone survival in ACHM and other cone degenerations.Achromatopsie (ACHM) ist eine bis heute nicht heilbare erblich bedingte Augenkrankheit, die das Sehvermögen bei Tageslicht erheblich beeinträchtigt. Die Symptome entstehen durch eine Dysfunktion der Zapfen und sind geprägt von einem vollständigen Ausfall des Farbsinns, einer geringen Sehschärfe und einer extremen Blendungsempfindlichkeit der Betroffenen. Außerdem ist eine schnell fortschreitende Degeneration der Zapfen in der Makula zu beobachten. Mutationen in sechs Genen werden mit ACHM assoziiert, die meisten Patienten tragen jedoch eine Mutation in den Genen, die den in den Zapfen exprimierten zyklisch-Nukleotid gesteuerten (CNG) Kanal kodieren: CNGA3 (29 % der Fälle) und CNGB3 (48 % der Fälle). Dieser Ionenkanal wird durch Bindung des zellulären Botenstoffes - dem zyklischen GMP (cGMP) - geöffnet und ist zudem ein wichtiger Bestandteil der „Sehkaskade“ (sog. Phototransduktionskaskade), die Lichtsignale in elektrische Impulse umwandelt. Interessanterweise führt eine genetische Deletion der Untereinheit CNGA3 bei Mäusen zu einem erhöhten zellulären Level von cGMP in betroffenen Zapfen. Ziel dieser Arbeit war es, die Rolle der beeinträchtigten cGMP-Signalwege während der Zapfendegeneration des Cnga3 Knockout (KO) Mausmodelles zu charakterisieren. Zunächst wurde der entwicklungsspezifische Verlauf der cGMP Akkumulation untersucht. Überraschenderweise war bereits vier Tage nach der Geburt ein erhöhtes cGMP Level festzustellen. Mit Hilfe eines Virus-vermittelten Gen-Knockdowns (KD) war es möglich die Guanylatzyklase 2E (Gucy2E) als die Hauptquelle des cGMP in Zapfen zu identifizieren. Therapierte Augen zeigten eine erhöhte Zapfendichte, was darauf hinweist, dass eine cGMP-Überlastung toxische Auswirkungen auf die betroffenen Zapfen hat. Ohne den CNG-Kanal in Cnga3 KO Zapfen kann die toxische Wirkung nur durch andere cGMP-Targets herbeigeführt werden. Vielversprechend für weitere Experimente erschienen dabei die cGMP-abhängigen Kinasen (cGKs), die weiter untersucht wurden. Um die Auswirkungen von erhöhten cGK-Signalwegen zu untersuchen, wurde in Wildtypmäusen durch virale Vektoren eine konstitutiv aktive cGK überexprimiert. Dies hatte einen drastischen Verlust der Photorezeptorschicht zur Folge und zeigte, dass diese Kinasen Zelltod auslösen können. Um dies zu verifizieren wurden Cnga3 KO Mäuse mit cGKI und cGKII KO Mäusen gekreuzt und morphologisch untersucht. Ein globaler Verlust der cGKII nicht aber der cGKI schützte die Zapfen vor Zelltod und führte zu einer signifikant verminderten Degeneration. Dieses Ergebnis wurde durch die Applikation einer cGKII-shRNA in Cnga3 KO Mäusen bestätigt, die ebenfalls einen signifikanten Rückgang des Zellsterbens zeigte. Diese Anwendung zeigt, dass cGKII ein möglicher neuer Anknüpfungspunkt für neuroprotektive Mechanismen in Zapfendegenerationen sein kann. Um letztendlich den cGMP Signalweg, der zum Zelltod führt, besser verstehen zu können, wurden mögliche Targets der cGKII durch zwei Massenspektrometrie-Ansätze identifiziert. Die Ergebnisse dieser Experimente weisen auf einen Zusammenhang zwischen dem cGMP-cGK-Signalweg und der Serin/threonine Kinase Atr hin. Zusammenfassend liefert diese Arbeit aussagekräftige Nachweise, dass cGMP-Signalwege die retinale Degeneration beschleunigen und identifiziert einen cGMP-cGK Signalweg als neuen Anknüpfungspunkt für neuroprotektive Therapien um die Lebensdauer der Zapfen in ACHM und anderen Zapfendegenerationen zu verlängern

RAS-NOTECHS: validity and reliability of a tool for measuring non-technical skills in robotic-assisted surgery settings

BACKGROUND Non-technical skills (NTS) are essential for safe surgical practice as they impact workflow and patient outcomes. Observational tools to measure operating room (OR) teams' NTS have been introduced. However, there are none that account for the specific teamwork challenges introduced by robotic-assisted surgery (RAS). We set out to develop and content-validate a tool to assess multidisciplinary NTS in RAS. METHODOLOGY Stepwise, multi-method procedure. Observations in different surgical departments and a scoping literature review were first used to compile a set of RAS-specific teamwork behaviours. This list was refined and expert validated using a Delphi consensus approach consisting of qualitative interviews and a quantitative survey. Then, RAS-specific behaviours were merged with a well-established assessment tool on OR teamwork (NOTECHS II). Finally, the new tool-RAS-NOTECHS-was applied in standardized observations of real-world procedures to test its reliability (inter-rater agreement via intra-class correlations). RESULTS Our scoping review revealed 5242 articles, of which 21 were included based on pre-established inclusion criteria. We elicited 16 RAS-specific behaviours from the literature base. These were synthesized with further 18 behavioural markers (obtained from 12 OR-observations) into a list of 26 behavioural markers. This list was reviewed by seven RAS experts and condensed to 15 expert-validated RAS-specific behavioural markers which were then merged into NOTECHS II. For five observations of urologic RAS procedures (duration: 13~h and 41~min), inter-rater agreement for identification of behavioural markers was strong. Agreement of RAS-NOTECHS scores indicated moderate to strong agreement. CONCLUSIONS RAS-NOTECHS is the first observational tool for multidisciplinary NTS in RAS. In preliminary application, it has been shown to be reliable. Since RAS is rapidly increasing and challenges for effective and safe teamwork remain at the forefront of quality and safety of surgical care, RAS-NOTECHS may contribute to training and improvement efforts in technology-facilitated surgeries

ACEMg-mediated hearing preservation in cochlear implant patients receiving different electrode lengths (PROHEARING): study protocol for a randomized controlled trial

Abstract Background The indications for a cochlear implant (CI) have been extended to include patients with some residual hearing. Shorter and thinner atraumatic electrodes have been designed to preserve the residual hearing in the implanted ear. However, the insertion of the electrode array into the cochlea, with potential mechanical trauma and the presence of this foreign body inside the cochlea, may lead to free radical formation and reduced blood perfusion of the cochlea which can result in the loss of residual hearing. Methods/design In this single-center, randomized, placebo-controlled, double-blind phase II clinical trial the effect of free radical scavengers and a vasodilator on the residual hearing of 140 CI patients will be evaluated. The formulation is composed of β-carotene (vitamin A), ascorbic acid (vitamin C), dl-α-tocopherol acetate (vitamin E) and the vasodilator magnesium (Mg), or ACEMg. Medication is administered twice daily per os for approximately 3 months. The primary measure is based upon the reduction in postoperative low-frequency air-conducted pure-tone thresholds compared to preoperative thresholds in ACEMg-treated patients compared to those of a placebo group. Additionally, the effect of different electrode lengths (20, 24 and 28 mm) is analyzed. Study visits are scheduled 2 days before surgery, at first fitting, which is the adjustment and start of stimulation via CI 4 weeks after surgery and 3, 6, 9 and 12 months after first fitting. The primary endpoint is the air-conduction hearing loss at 500 Hz 3 months after first fitting. Additionally, speech recognition tests, hearing aid benefit in the implanted ear and electrophysiological measurements of implant function are assessed. Since this is a blinded clinical trial and recruitment is still ongoing, data continue to accrue and we cannot yet analyze the outcome of the ACEMg treatment. Discussion There is an unfulfilled need for new strategies to preserve acoustic hearing in CI patients. This study will provide first-in-man data on ACEMg-mediated protection of residual hearing in CI patients. Performing all surgeries and patient follow-up at one study site improves consistency in diagnosis and therapy and less variability in surgery, audiological test techniques and fitting. This approach will allow investigation of the influence of ACEMg on residual hearing in CI patients. Trial registration The German Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM) application number 4039192, was registered on 6 December 2013 with protocol amendment version 3.0 from 19 August 2014. EudraCT number: 2012-005002-22 .http://deepblue.lib.umich.edu/bitstream/2027.42/134623/1/13063_2016_Article_1526.pd

Reduced early visual processing of own body images in anorexia nervosa: An event-related potentials study

Introduction. Although body image distortion in anorexia nervosa (AN) has been extensively studied over the past decades, its underlying mechanisms are not yet fully understood. Neuro-imaging studies have identified functional and structural alterations in brain areas involved in visual body perception, but the time course of visual body processing in AN remains mostly unexplored. The current study used event-related brain potentials (ERPs) to investigate single processing steps along the time course, particularly the visual processing of physical body image characteristics (featural processing, P1) and the recognition of a body as such (configural processing, N1). Methods. Twenty in-patients with AN, and 20 healthy women viewed photographs of themselves, of another woman’s body and of their own and another woman’s standardized object (cup) with concurrent EEG recording. Results. Body images elicited an accentuation of the P1 component (105-160 ms), which was absent for the comparison between own-body and own-cup images in the AN group. Results regarding the N1 component suggest alterations in object processing in AN. Conclusions. Our results demonstrate that individuals with AN show reduced featural processing of their own body image, a process which, due to its position early in the visual processing stream, is unlikely to involve higher cognitive stimulus processing. This suggests a possible role of previously undetected pre-conscious mechanisms in body image disturbance

Assessing health-related quality of life in COPD: comparing generic and disease-specific instruments with focus on comorbidities

Background: Chronic Obstructive Pulmonary Disease (COPD) influences different aspects of patient's health-related quality of life (HRQL). While disease-specific HRQL instruments focus on symptoms and functional impairments, generic instruments cover a broader view on health. This study compares the generic EQ-5D-3 L and two disease-specific questionnaires (St.-George's Respiratory Questionnaire (SGRQ-C), COPD Assessment Test (CAT)) in a comprehensive spectrum of COPD disease grades with particular attention on comorbidities and assesses the discriminative abilities of these instruments. Methods: Using data from the baseline visit of the German COPD cohort COSYCONET, mean HRQL scores in different COPD grades were compared by linear regression models adjusting for age, sex, education, smoking status, BMI, and low vs. high number of comorbidities or a list of several self-reported comorbid conditions. Discriminative abilities of HRQL instruments to differentiate between COPD grades were assessed by standardized mean differences. Results: In 2,291 subjects in COPD GOLD grades 1-4 EQ-5D-3 L utility, EQ-5D VAS, SGRQ, and CAT were found able to discriminate between COPD grades, with some limitations for the EQ-5D utility in mild disease. Both generic and disease-specific HRQL instruments reflected the burden of comorbid conditions. The SGRQ showed the best discrimination between COPD grades and was less influenced by comorbidities, while EQ-5D utility put a higher weight on comorbid conditions. For all instruments, psychiatric disorders and peripheral artery disease showed the strongest negative associations with HRQL. Conclusion: All HRQL instruments considered reflect considerable impairment of HRQL in COPD patients, worsening with increasing COPD grade and number of comorbidities. Findings may support clinical assessment, choice of HRQL instrument in future studies, and parameterization of decision-analytic models

Cardiovascular risk in patients with alpha-1-antitrypsin deficiency

Background: Alpha-1-antitrypsin deficiency (AATD) is a rare inherited condition caused by mutations of the SERPINA1 gene that is associated with the development of a COPD like lung disease. The comorbidities in patients with AATDrelated lung diseases are not well defined. The aim of this study was to analyze the clinical phenotype of AATD patients within the German COPD cohort study COSYCONET (“COPD and SYstemic consequences-COmorbidities NETwork”) cohort focusing on the distribution of comorbidities. Method and results: The data from 2645 COSYCONET patients, including 139 AATD patients (110 with and 29 without augmentation therapy), were analyzed by descriptive statistics and regression analyses. We found significantly lower prevalence of cardiovascular comorbidities in AATD patients as compared to non-AATD COPD patients. After correction for age, pack years, body mass index, and sex, the differences were still significant for coronary artery disease (p = 0.002) and the prevalence of peripheral artery disease as determined by an ankle-brachial-index <= 0.9 (p = 0.035). Also the distribution of other comorbidities such as bronchiectasis differed between AATD and non-deficient COPD. Conclusion: AATD is associated with a lower prevalence of cardiovascular disease, the underlying mechanisms need further investigation

Chronotype is associated with psychological well-being depending on the composition of the study sample

Past studies examining the effect of chronotype and social jetlag on psychological well-being have been inconsistent so far. Here, we recruited participants from the general population and enquired about their natural sleeping behavior, sleep quality, depressive symptoms, and perceived stress. Partial correlations were computed between sleep variables and indicators of psychological well-being, controlling for age and sex. Less sleep during work days was found a good indicator for impairments in psychological well-being. In exploratory follow-up analyses, the same correlations were calculated within groups of early, intermediate, and late chronotype. We observed that the composition of the sample in terms of chronotype influenced whether associations between sleep variables and psychological well-being could be observed, a finding that is advised to be taken into account in future studies.Peer Reviewe

Cardiovascular risk in patients with alpha-1-antitrypsin deficiency

Background: Alpha-1-antitrypsin deficiency (AATD) is a rare inherited condition caused by mutations of the SERPINA1 gene that is associated with the development of a COPD like lung disease. The comorbidities in patients with AATD-related lung diseases are not well defined. The aim of this study was to analyze the clinical phenotype of AATD patients within the German COPD cohort study COSYCONET (“COPD and SYstemic consequences-COmorbidities NETwork”) cohort focusing on the distribution of comorbidities. Method and results: The data from 2645 COSYCONET patients, including 139 AATD patients (110 with and 29 without augmentation therapy), were analyzed by descriptive statistics and regression analyses. We found significantly lower prevalence of cardiovascular comorbidities in AATD patients as compared to non-AATD COPD patients. After correction for age, pack years, body mass index, and sex, the differences were still significant for coronary artery disease (p = 0.002) and the prevalence of peripheral artery disease as determined by an ankle-brachial-index <= 0.9 (p = 0.035). Also the distribution of other comorbidities such as bronchiectasis differed between AATD and non-deficient COPD. Conclusion: AATD is associated with a lower prevalence of cardiovascular disease, the underlying mechanisms need further investigation