Sleep-time predictors of cardiovascular complications in surgical peripheral arterial disease

ABSTRACT Patients with peripheral arterial disease (PAD) undergoing surgical revascularisation are in high risk of postoperative cardiovascular complications and death, due to advancing age and multiple comorbidities in the population. In addition, PAD needing surgery represents a severe form of systemic atherosclerosis but the exact underlying pathophysiology of acute myocardial infarction (AMI) in these patients is unclear and predicting outcome especially in the long-term is challenging. Obstructive sleep apnoea (OSA) is increasingly common in the general population and independently associated with various manifestations of cardiovascular disease or their risk factors; OSA is highly prevalent in patients with coronary artery disease (CAD), stroke, hypertension and diabetes. To expand this knowledge, we determined the prevalence and severity (in terms of the apnoeahypopnoea index, AHI) of OSA in surgical PAD as well as its impact on the incidence of major adverse cardiovascular and cerebrovascular events (MACCE) in this patient group. Heart rate variability (HRV) reflects fluctuations in sympathetic and parasympathetic activation responsible for neurocirculatory control in various physiological and pathophysiological situations. Depressed HRV is associated with increased cardiovascular morbidity and mortality following AMI and major surgery. In this study, the alterations of nocturnal HRV and their association with the severity of OSA and incidence of MACCE in patients with PAD was assessed, including the fractal correlation properties of HRV. HRV in a control group of 15 healthy subjects was also examined. Patients scheduled for sub-inguinal vascular surgery (n=84, age 67±9 years) underwent polysomnography and HRV analyses. OSA was detected in 86% of patients and in 56% it was moderate or severe. Age, male gender, depressed left ventricular function and decreasing high density lipoprotein/cholesterol ratio (HDL/Chol) predicted the presence and severity of OSA. The latter two remained significant after adjusting for age and gender. OSA with AHI ≥20/hour, used as a cut-off in the outcome analyses, predicted a higher risk of MACCE (p=0.001) along with pre-existing CAD (p=0.001), decreasing HDL/Chol (p=0.048) and <4 years history of PAD (p=0.018). HRV was altered in patients with PAD when compared to controls but the time domain measures were mostly unchanged. In the frequency domain, low frequency power was generally lower, high frequency power was mostly higher and fractal correlation was consistently lower. Very low frequency power was increased the most in patients with AHI 10-20/hour when compared to <10/hour while those with AHI ≥20/hour had lower fractal correlation in the morning. Patients suffering a MACCE had lower high frequency power during S3-4 and rapid eye movement sleep. In conclusion, OSA is associated with worsening atherosclerosis and predicts MACCE after vascular surgery. HRV alterations, although associated with PAD, have limited predictive value. Keywords: atherosclerosis, peripheral arterial disease, sleep apnoea, heart rate variabilityTIIVISTELMÄ Unenaikaiset sydänkomplikaatioiden ennustetekijät kirurgista hoitoa vaativassa perifeerisessä valtimotaudissa Perifeeristä valtimotautia sairastavilla potilailla on suuri leikkauksenjälkeisten sydänkomplikaatioiden riski johtuen yhä iäkkäämmästä väestöstä sekä lukuisista rinnakkaissairauksista. Lisäksi perifeerinen valtimotauti merkitsee vaikea-asteista yleistynyttä ateroskleroosia, mutta sydäninfarktin tarkka syntymekanismi näillä potilailla on epäselvä ja erityisesti pitkän aikavälin ennusteen arviointi on haastavaa. Obstruktiivinen uniapnea yleistyy väestössä ja sillä on itsenäinen yhteys useisiin sydän- ja verisuonisairauksiin ja niiden riskitekijöihin; uniapnea on erittäin yleinen sepelvaltimotauti-, aivohalvaus-, verenpainetauti- ja diabetespotilailla. Tämän tietopohjan laajentamiseksi tässä tutkimuksessa määritettiin uniapnean esiintyvyys ja vaikeusaste (määrittäjänä apnea-hypopneaindeksi, AHI) vaikea-asteista yleistynyttä ateroskleroosia sairastavilla potilailla sekä sen vaikutus vakavien sydän- ja aivotapahtumien ilmaantuvuuteen. Sydämen sykevaihtelu kuvastaa autonomisen hermoston toiminnan muutoksia, jotka puolestaan vastaavat verenkierron säätelystä erilaisissa fysiologisissa ja patofysiologisissa tilanteissa. Alentunut sykevaihtelu on yhteydessä lisääntyneeseen kardiovaskulaariseen sairastuvuuteen ja kuolleisuuteen sairastetun sydäninfarktin tai suuren leikkauksen jälkeen. Tässä tutkimuksessa arvioitiin yöllisen sydämen sykevaihtelun muutosten yhteyttä uniapnean vaikeusasteeseen sekä vakavien sydän- ja aivotapahtumien ilmaantuvuuteen, mukaan lukien sykevaihtelun fraktaalikorrelaatio-ominaisuudet. Tutkimuksessa analysoitiin sykevaihtelu myös 15 terveen henkilön vertailuryhmältä. Nivustason alapuoliseen verisuonileikkaukseen meneville potilaille (n=84, ikä 67±9 vuotta) tehtiin unipolygrafia ja sykevaihteluanalyysi. Uniapnea todettiin 86 %:lla potilaista ja 56 %:lla se oli kohtalainen tai vaikea. Ikä, miessukupuoli, heikentynyt vasemman kammion toiminta ja alentunut HDL-kolesterolin suhde kokonaiskolesteroliin ennustivat uniapneaa ja sen vaikeutumista; 2 viimeksi mainittua säilyivät merkitsevinä ikä- ja sukupuolivakioinnin jälkeen. AHI ≥20/tunti, joka valittiin kynnysarvoksi päätetapahtumaanalyyseihin, ennusti merkitsevästi vakavia sydän- ja aivotapahtumia (p=0.001). Muita merkitseviä tekijöitä olivat sepelvaltimotauti (p=0.001), alentunut HDL-suhde (p=0.048) ja lyhyt (alle 4 vuotta) perifeerisen valtimotaudin kesto ennen leikkaushoidon tarvetta (p=0.018). Sykevaihtelu oli muuttunut valtimotautipotilailla verrattuna kontrolleihin, mutta aikakenttäparametrit säilyivät lähes ennallaan. Pienitaajuuksinen sykevaihtelu oli yleisesti vähäisempää, suuritaajuuksinen enimmäkseen voimakkaampaa ja fraktaalikorrelaatio johdonmukaisesti heikompaa. Hyvin pienitaajuuksinen vaihtelu oli eniten lisääntynyt AHI 10-20/tunti -alaryhmässä verrattuna AHI <10/tunti -ryhmään, mutta AHI ≥20/tunti -potilailla aamun fraktaalikorrelaatio oli heikompaa. Potilaiden, jotka saivat vakavia sydän- ja aivotapahtumia, suuritaajuusvaihtelu oli heikompaa syvän unen ja vilkeunen aikana. Johtopäätöksinä todetaan, että uniapnea on yhteydessä vaikeutuvaan valtimotautiin sekä ennustaa vakavia sydän- ja aivotapahtumia verisuonileikkauksen jälkeen sykevaihtelun muutosten ennustearvon ollessa tässä aineistossa hyvin rajallinen. Avainsanat: ateroskleroosi, perifeerinen valtimotauti, uniapnea, sykevaihtel

Ustekinumab for Crohn's disease: a nationwide real-life cohort study from Finland (FINUSTE)

Background: Ustekinumab (UST), a human anti-IL12/23p40 monoclonal antibody, has been approved for treatment of Crohn's Disease (CD) since the end of 2016. This nationwide noninterventional, retrospective chart review explored real-life data in patients receiving UST to provide guidance in UST treatment in the era of increasing prevalence of CD. Methods: The study assessed UST treatment patterns such as dosing frequency, concomitant medication and persistence in 48 CD patients commencing UST therapy in 12 Finnish hospitals during 2017. Clinical remission and response rates were explored using a modified Harvey-Bradshaw index (mHBI) and endoscopic response via the simple endoscopic score for Crohn's disease (SES-CD) as proportions of patients at week 16 and at the end of follow-up. Results: Forty patients (83%) continued UST-treatment at the end of follow-up. At week 16, clinical response and endoscopic healing was observed, where data were available; mHBI decreased from 9 to 3 (p = .0001) and SES-CD from 12 to 3 (p = .009). Clinical benefit was achieved by 83% (19/23) at week 16 and by 76% (16/21) at the end of follow-up. The proportion of patients using corticosteroids decreased from 48% to 25% at week 16 and to 13% at the end of the follow-up. Conclusion: UST showed to be effective and persistent, inducing short-term clinical benefit and endoscopic response in this real-life nationwide study of CD patients. Significant corticosteroid tapering in patients with highly treatment refractory and long-standing CD was observed

Ustekinumab for Crohn’s disease: a nationwide real-life cohort study from Finland (FINUSTE)

Background: Ustekinumab (UST), a human anti-IL12/23p40 monoclonal antibody, has been approved for treatment of Crohn?s Disease (CD) since the end of 2016. This nationwide noninterventional, retrospective chart review explored real-life data in patients receiving UST to provide guidance in UST treatment in the era of increasing prevalence of CD.Methods: The study assessed UST treatment patterns such as dosing frequency, concomitant medication and persistence in 48?CD patients commencing UST therapy in 12 Finnish hospitals during 2017. Clinical remission and response rates were explored using a modified Harvey?Bradshaw index (mHBI) and endoscopic response via the simple endoscopic score for Crohn?s disease (SES-CD) as proportions of patients at week 16 and at the end of follow-up.Results: Forty patients (83%) continued UST-treatment at the end of follow-up. At week 16, clinical response and endoscopic healing was observed, where data were available; mHBI decreased from 9 to 3 (p?=?.0001) and SES-CD from 12 to 3 (p?=?.009). Clinical benefit was achieved by 83% (19/23) at week 16 and by 76% (16/21) at the end of follow-up. The proportion of patients using corticosteroids decreased from 48% to 25% at week 16 and to 13% at the end of the follow-up.Conclusion: UST showed to be effective and persistent, inducing short-term clinical benefit and endoscopic response in this real-life nationwide study of CD patients. Significant corticosteroid tapering in patients with highly treatment refractory and long-standing CD was observed.Peer reviewe

Alterations in heart rate variability in patients with peripheral arterial disease requiring surgical revascularization have limited association with postoperative major adverse cardiovascular and cerebrovascular events.

OBJECTIVE:Obstructive sleep apnea (OSA) is common in peripheral arterial disease (PAD) and associates with high mortality after surgery. Since abnormal heart rate variability (HRV) is predictive of postoperative complications, we investigated the relations of HRV with PAD, OSA and major adverse cardiovascular and cerebrovascular events (MACCE). MATERIALS AND METHODS:Seventy-five patients (67±9 years) scheduled for sub-inguinal revascularization and 15 controls (63±6 years) underwent polysomnography and HRV analyses. OSA with an apnea-hypopnea index (AHI) ≥20/hour was considered significant. HRV was measured during wakefulness, S2, S3-4 and rapid eye movement (REM) sleep with time and frequency domain methods including beat-to-beat variability, low frequency (LF) and high frequency (HF) power, and detrended fluctuation analysis (DFA). MACCE was defined as cardiac death, myocardial infarction, coronary revascularization, hospitalized angina pectoris and stroke. RESULTS:Thirty-six patients (48%) had AHI≥20/hour. During follow-up (median 52 months), 22 patients (29%) suffered a MACCE. Compared to controls, fractal correlation of HRV (scaling exponent alpha 1 measured with DFA) was weaker during S2 and evening wakefulness in all subgroups (+/-AHI≥20/hour, +/-MACCE) but only in patients with AHI≥20/hour during morning wakefulness. The LF/HF ratio was lower in all subgroups during S2 but only in patients with AHI ≥20/hour during evening or morning wake. In the covariance analysis adjusted for age, body mass index, coronary artery disease and PAD duration, the alpha 1 during morning wakefulness remained significantly lower in patients with AHI≥20/hour than in those without (1.12 vs. 1.45; p = 0.03). Decreased HF during REM (p = 0.04) and S3-4 sleep (p = 0.03) were predictive of MACCE. In analyses with all sleep stages combined, mean heart rate as well as very low frequency, LF, HF and total power were associated with OSA of mild-to-moderate severity (AHI 10-20/hour). CONCLUSIONS:HRV is altered in patients with PAD. These alterations have a limited association with OSA and MACCE

Distributed experiments in design sciences, a next step in design observation studies?

This paper describes and proposes a new method for conducting globally distributed design research. Instead of using e.g. a software we tried out a completely analogue approach: Five carefully prepared packages, containing all the necessary materials and instructions for a design challenge, were sent out to supervisors in Norway, Finland, Italy, and Australia. These local supervisors then conducted the egg-drop exercise with students that are part of an international course held at CERN. As the task is conducted according to a previously tested protocol, the results gathered with this new method can then be benchmarked with this available data. This new approach to globally conducted engineering design activities avoids local bias and enables for gathering large amounts of diverse data points. One can also think of a research community where every member can send out one experiment per year and, in return, receives data points from across the world. Based on the feedback from the supervisors we can say that from an organisational standpoint of view, this method works well. The comparison to the existing data has yet to be done