Cardiogenic shock; focus on ventilatory strategies, the elderly, and biomarker-based risk stratification

Cardiogenic shock (CS) is the most severe form of acute heart failure (HF) characterized by hypotension and systemic hypoperfusion caused by cardiac dysfunction. Prolonged hypotension provokes neurohumoral compensatory mechanisms and systemic inflammatory responses, leading to organ injury followed by multiorgan failure and poor prognosis. CS may be caused by various etiological factors, acute coronary syndromes (ACS) being the most common cause. In addition to prompt recognition of CS, the cause of shock should be treated urgently, as by means of immediate revascularization in the case of ACS-related CS. Although aggressive therapy options, such as mechanical circulatory devices and ventilatory support, may be used, this approach is demanding on the patient, carries risk for complications, and requires additional healthcare resources. Despite advanced therapy options, prognosis in CS is still very poor with a short-term mortality rate up to 40%. Appropriate risk assessment in the early stage of shock is crucial to identify patients most likely to benefit from intensive and costly treatment. The aim of this thesis was to assess the treatment of respiratory failure in CS, focusing on the use of different ventilatory strategies and their impact on outcome; to evaluate the contemporary clinical picture, prognosis, and risk assessment of elderly (≥ 75 years) CS patients; and to investigate prognostic properties of two novel biomarkers in the early phase of CS. The study population consisted of the multinational, observational, prospective CardShock study, which included 219 patients with both ACS and non-ACS etiologies. Study I evaluated the use of different ventilatory strategies in CS. Although most patients (63%) were treated with invasive mechanical ventilation (IMV), a fair number were successfully treated with non-invasive ventilation (NIV) (12%). The intensity of respiratory support required was dependent on the severity of shock; those treated with IMV suffered from more severe shock and had higher 90-day mortality compared with those treated with NIV (49% vs. 27%). However, after balancing the IMV and NIV groups with shock severity and clinical characteristics, the choice of ventilatory strategy itself did not influence the outcome. Study II assessed the key features of elderly (≥ 75 years) CS patients. The elderly constituted a quarter of the population. Despite similar etiology and treatment of shock, they had a higher in-hospital mortality rate compared with younger patients (46% vs. 33%). However, those elderly patients who survived to hospital discharge had a prognosis comparable to that of the younger. The two contemporary risk prediction scores, the CardShock risk score and the IABP-SHOCK II risk score, proved to be useful in the early risk stratification in the elderly patients as well. Furthermore, by incorporating the novel biomarkers into the scores, the risk prediction ability of the scores improved markedly. Study III evaluated concentrations of a novel biomarker, growth differentiation factor 15 (GDF-15), in CS. GDF-15 is a stress-responsive cytokine that is expressed under acute and chronic stressful conditions and it has shown prognostic potential in various diseases. In this study GDF-15 levels were already very high at the beginning of CS and associated with markers of hypoperfusion (high lactate, low pH) and various acute organ dysfunctions (heart, renal, liver) indicating severe circulatory failure. High and increasing levels of GDF-15 were associated with a worse outcome, while low and decreasing levels were indicative of better prognosis. Furthermore, GDF-15 improved the early risk stratification of CS beyond the clinical risk score. Study IV investigated the levels of soluble urokinase-type plasminogen activator receptor (suPAR) in the early stage of CS. suPAR is a novel biomarker secreted in response to inflammatory stimuli and thought to reflect the level of immunoactivation. suPAR has prognostic ability in many acute and chronic diseases, including cardiovascular diseases, cancer, and sepsis. In this study, suPAR levels were clearly elevated during the first days of CS. High levels were associated with both acute and chronic organ dysfunctions. suPAR had independent prognostic potential in CS and improved the risk stratification, especially in the patients with intermediate risk. In conclusion, NIV can be used safely in the treatment of respiratory failure in suitable CS patients. The choice of ventilation strategy did not appear to influence outcome. Elderly patients constitute a considerable portion of CS patients with high mortality. Contemporary risk scores are also useful for early risk prediction in this age group. High levels of the novel biomarkers GDF-15 and suPAR are indicative of severe circulatory failure and end-organ injury, suggesting poor prognosis. These biomarkers may be new prognostic tools in the risk assessment of CS.Sydänperäinen sokki on monitahoinen oireyhtymä, jossa sydämen akuutti toimintahäiriö aiheuttaa sen supistumiskyvyn merkittävän heikentymisen johtaen vaikeaan verenkiertovajaukseen, kudosten hapenpuutteeseen ja monielinvaurioon sekä lopulta hoitamattomana kuolemaan. Oireyhtymän patogeneesissä myös elimistön neurohumoraalisilla vasteilla sekä systeemisen tulehdusreaktion kehittymisellä on oma roolinsa. Mikä tahansa sydämen toimintaa heikentävä sairaus voi olla syynä sydänperäiseen sokkiin, useimmiten kyseessä on laaja sydäninfarkti. Hoidon kulmakivenä on sydämen toimintahäiriön aiheuttaneen syyn tunnistaminen ja välitön korjaaminen. Sokkiin liittyvää verenkierto- ja hengitysvajausta hoidetaan tarvittaessa mekaanisia tukilaitteita avuksi käyttäen tehohoito-olosuhteissa, mikä on kuitenkin potilaille raskasta, altistaa komplikaatioille ja vaatii runsaasti terveydenhuollon resursseja. Kehittyneistä hoitotoimenpiteistä huolimatta kuolleisuus sydänperäiseen sokkiin on edelleen korkea noin 40 %. Hoidossa oleellista on sokin tunnistaminen, raskaista hoidoista hyötyvien korkean riskin potilaiden tunnistaminen ja hoitotoimenpiteiden aloittaminen riittävän varhaisessa vaiheessa ennen peruuttamattomien pääte-elinvaurioiden syntymistä. Tämän väitöskirjan tavoitteena oli selvittää sokkiin liittyvän hengitysvajauksen hoitoa keskittyen eri hengitystukimuotojen käyttöön ja niiden mahdolliseen ennustevaikutukseen sekä tutkia iäkkäiden (≥ 75-vuotiaiden) sokkipotilaiden taudin kliinistä kuvaa ja selvittää ajankohtaisten riskipisteytysmallien käyttökelpoisuutta tämän ikäryhmän ennusteen arvioimisessa. Lisäksi tavoitteena oli arvioida kahden uuden biomarkkerin käyttökelpoisuutta sydänperäisen sokin ennustearviossa. Väitöskirjan tutkimusaineisto on peräisin 219 potilasta käsittävästä monikansallisesta, havainnoivasta CardShock –tutkimuksesta. Ensimmäisessä osatyössä tutkittiin sydänperäiseen sokkiin sairastuneiden potilaiden hengitysvajauksen hoitoa ja eri hengitystukimuotojen käyttöä keskittyen non-invasiiviseen (NIV) hengitystukihoitoon. Tutkimuksessa havaittiin, että sydänperäiseen sokkiin sairastuneiden hengitystuen tarve riippui sokin vaikeusasteesta. Suurin osa potilaista (63%) hoidettiin invasiivisella mekaanisella ventilaatiolla (IMV) keinoilmatien kera, mutta merkittävä osa (12%) pärjäsi pelkästään non-invasiivisella ventilaatiolla (NIV). IMV:lla hoidetut potilaat kärsivät vaikeammasta sokin taudinkuvasta ja heillä oli korkeampi 90 päivän kuolleisuus NIV:llä hoidettuihin verrattuna (49% vs. 27%). Hengitystukistrategian valinnalla ei kuitenkaan ollut vaikutusta ennusteeseen. Toisessa osatyössä selvitettiin iäkkäiden (≥ 75-vuotiaiden) sydänperäiseen sokkiin sairastuneiden potilaiden kliinistä taudinkuvaa, hoitoa ja ennustearviota. Neljäsosa potilaista oli yli 75-vuotiaita. Huolimatta sokin samankaltaisesta etiologiasta ja hoidosta iäkkäiden potilaiden sairaalakuolleisuus oli selvästi nuorempia korkeampi (46% vs. 33%). Toisaalta sokista selvinneiden iäkkäiden ennuste ei eronnut nuorempien ennusteesta. Tutkimuksen mukaan sydänperäiseen sokkiin sairastuneille kehitetyt riskipisteytysmallit toimivat hyvin myös iäkkäillä ja niiden ennustearviota voidaan parantaa yhdistämällä ne biomarkkereiden kanssa. Kolmannessa osatyössä tutkittiin biomerkkiaine GDF-15 pitoisuuksia sydänperäisen sokin alkuvaiheessa sekä niiden yhteyttä ennusteeseen. GDF-15-pitoisuuksien tiedetään nousevan elimistön erilaisissa akuuteissa sekä kroonisissa stressitilanteissa ja GDF-15 omaa ennustearvoa useissa eri sairauksissa. Tutkimuksessa havaittiin, että GDF-15–pitoisuudet olivat hyvin korkeita jo sokin ensivaiheessa. Korkeat pitoisuudet olivat yhteydessä kudosten riittämätöntä verenkiertoa kuvastaviin biomarkkereihin (korkea laktaatti ja matala pH) ja elintoimintahäiriöihin (sydän, maksa, munuaiset) sekä huonompaan ennusteeseen. Lisäksi todettiin, että nouseva GDF-15 –taso oli merkki huonosta ennusteesta, kun taas laskevat pitoisuudet kuvastivat parempaa ennustetta. Yhdistettynä kliiniseen riskipisteytysmalliin GDF-15 paransi sokkipotilaiden ennustearviota huomattavasti. Neljännessä osatyössä määritettiin biomerkkiaine suPAR:n pitoisuuksia sydänperäisen sokin alkuvaiheessa. SuPAR on biomerkkiaine, jonka pitoisuus nousee sekä akuuttien että kroonisten tulehduksellisten tilojen yhteydessä kuvastaen elimistön immunoaktivaatiota. Sen on todettu omaavan ennustearvoa useissa eri sairauksissa, kuten syövissä, sepsiksessä sekä sydän- ja verisuonisairauksissa. Tässä tutkimuksessa suPAR-tasot olivat selvästi koholla sydänperäiseen sokkiin sairastuneilla. Korkeat pitoisuudet olivat yhteydessä eri elintoimintahäiriöihin ja suurempaan kuolemanriskiin. Tutkimuksessa todettiin, että suPAR oli itsenäinen sydänperäisen sokin ennustetekijä ja yhdistettynä kliinisen riskipisteytysmallin kanssa se paransi erityisesti keskiriskin potilaiden ennustearviota. Yhteenvetona voidaan todeta, että sydänperäiseen sokkiin liittyvää hengitysvajausta voidaan hoitaa voidaan turvallisesti myös NIV:lla oikein valikoiduilla potilailla, eikä hengitysvajauksen hoitomuodolla ole merkitystä potilaan ennusteen kannalta. Iäkkäät muodostavat merkittävän osan sydänperäiseen sokkiin sairastuneista potilaista ja sokin ennustearvioon luodut kliiniset riskipisteytysmallit toimivat hyvin myös tässä ikäryhmässä. Tutkitut biomerkkiaineet, GDF-15 ja suPAR, kuvastavat sydänperäiseen sokkiin liittyvää vaikeaa verenkiertovajausta sekä siihen liittyviä elintoimintahäiriöitä ja voivat olla avuksi sokkipotilaiden ennustearviossa

Soluble Urokinase Plasminogen Activator Receptor (suPAR) in the Emergency Department (Ed): A Tool for the Assessment of Elderly Patients

Emergency department (ED) overcrowding is a global issue setting challenges to all care providers. Elderly patients are frequent visitors of the ED and their risk stratification is demanding due to insufficient assessment methods. A prospective cohort study was conducted to determine the risk-predicting value of a prognostic biomarker, soluble urokinase plasminogen activator receptor (suPAR), in the ED, concentrating on elderly patients. SuPAR levels were determined as part of standard blood sampling of 1858 ED patients. The outcomes were assessed in the group o

MicroRNA in combination with HER2-targeting drugs reduces breast cancer cell viability in vitro

HER2-positive (HER2+) breast cancer patients that do not respond to targeted treatment have a poor prognosis. The effects of targeted treatment on endogenous microRNA (miRNA) expression levels are unclear. We report that responsive HER2+breast cancer cell lines had a higher number of miRNAs with altered expression after treatment with trastuzumab and lapatinib compared to poorly responsive cell lines. To evaluate whether miRNAs can sensitize HER2+cells to treatment, we performed a high-throughput screen of 1626 miRNA mimics and inhibitors in combination with trastuzumab and lapatinib in HER2+breast cancer cells. We identified eight miRNA mimics sensitizing cells to targeted treatment, miR-101-5p, mir-518a-5p, miR-19b-2-5p, miR-1237-3p, miR-29a-3p, miR-29c-3p, miR-106a-5p, and miR-744-3p. A higher expression of miR-101-5p predicted better prognosis in patients with HER2+breast cancer (OS: p=0.039; BCSS: p=0.012), supporting the tumor-suppressing role of this miRNA. In conclusion, we have identified miRNAs that sensitize HER2+breast cancer cells to targeted therapy. This indicates the potential of combining targeted drugs with miRNAs to improve current treatments for HER2+breast cancers.Peer reviewe

High-throughput screen in vitro identifies dasatinib as a candidate for combinatorial treatment with HER2-targeting drugs in breast cancer

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Prognostic impact of angiographic findings, procedural success, and timing of percutaneous coronary intervention in cardiogenic shock

Abstract Aims Urgent revascularization is the mainstay of treatment in acute coronary syndrome (ACS) related cardiogenic shock (CS). The aim was to investigate the association of angiographic results with 90-day mortality. Procedural complications of percutaneous coronary intervention (PCI) were also examined. Methods and results This CardShock (NCT01374867) substudy included 158 patients with ACS aetiology and data on coronary angiography and complications during PCI procedure. Survival analysis was conducted with Kaplan?Meier curves and Cox regression analysis. Median age was 67 ± 11 years, and 77% were men. During 90-day follow-up, 66 (42%) patients died. Patients with one-vessel disease (n = 49) had lower mortality than patients with two-vessel (n = 59) or three-vessel (n = 50) disease (25% vs. 48% vs. 52%, P = 0.011). Successful revascularization [Thrombolysis in Myocardial Infarction (TIMI) Flow 3 post-PCI) was achieved more often in survivors than non-survivors (81% vs. 60%, P = 0.019). The median symptom-to-balloon time was 340 (196?660) minutes, with no difference between survivors and non-survivors. In multivariable mortality analysis, multivessel disease (HR 2.59, CI95% 1.29?5.18) and TIMI flowPeer reviewe

Hypoalbuminemia is a frequent marker of increased mortality in cardiogenic shock

Altres ajuts: VPH was supported by the Aarne Koskelo Foundation (no grant number): http://www. aarnekoskelonsaatio.fi/, and the Finnish Cardiac Foundation (no grant number): https://www. fincardio.fi/. Laboratory kits were provided by Roche Diagnostics. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Introduction The prevalence of hypoalbuminemia, early changes of plasma albumin (P-Alb) levels, and their effects on mortality in cardiogenic shock are unknown. Materials and methods P-Alb was measured from serial blood samples in 178 patients from a prospective multinational study on cardiogenic shock. The association of hypoalbuminemia with clinical characteristics and course of hospital stay including treatment and procedures was assessed. Theprimary outcome was all-cause 90-day mortality. Results Hypoalbuminemia (P-Alb < 34g/L) was very frequent (75%) at baseline in patients with cardiogenic shock. Patients with hypoalbuminemia had higher mortality than patients with normal albumin levels (48% vs. 23%, p = 0.004). Odds ratio for death at 90 days was 2.4 [95% CI 1.5-4.1] per 10 g/L decrease in baseline P-Alb. The association with increased mortality remained independent in regression models adjusted for clinical risk scores developed for cardiogenic shock (CardShock score adjusted odds ratio 2.0 [95% CI 1.1-3.8], IABPSHOCK II score adjusted odds ratio 2.5 [95%CI 1.2-5.0]) and variables associated with hypoalbuminemia at baseline (adjusted odds ratio 2.9 [95%CI 1.2-7.1]). In serial measurements,albumin levels decreased at a similar rate between 0h and 72h in both survivors andnonsurvivors (ΔP-Alb -4.6 g/L vs. 5.4 g/L, p = 0.5). While the decrease was higher for patients with normal P-Alb at baseline (p 0.001 compared to patients with hypoalbuminemia at baseline), the rate of albumin decrease was not associated with outcome. Conclusions Hypoalbuminemia was a frequent finding early in cardiogenic shock, and P-Alb levels decreased during hospital stay. Low P-Alb at baseline was associated with mortality independently of other previously described risk factors. Thus, plasma albumin measurement should be part of the initial evaluation in patients with cardiogenic shock

Predictive value of plasma proenkephalin and neutrophil gelatinase-associated lipocalin in acute kidney injury and mortality in cardiogenic shock

Background: Acute kidney injury (AKI) is a frequent form of organ injury in cardiogenic shock. However, data on AKI markers such as plasma proenkephalin (P-PENK) and neutrophil gelatinase-associated lipocalin (P-NGAL) in cardiogenic shock populations are lacking. The objective of this study was to assess the ability of P-PENK and P-NGAL to predict acute kidney injury and mortality in cardiogenic shock. Results: P-PENK and P-NGAL were measured at different time points between baseline and 48 h in 154 patients from the prospective CardShock study. The outcomes assessed were AKI defined by an increase in creatinine within 48 h and all-cause 90-day mortality. Mean age was 66 years and 26% were women. Baseline levels of P-PENK and P-NGAL (median [interquartile range]) were 99 (71-150) pmol/mL and 138 (84-214) ng/mL. P-PENK > 84.8 pmol/mL and P-NGAL > 104 ng/mL at baseline were identified as optimal cut-offs for AKI prediction and independently associated with AKI (adjusted HRs 2.2 [95% CI 1.1-4.4, p = 0.03] and 2.8 [95% CI 1.2-6.5, p = 0.01], respectively). P-PENK and P-NGAL levels at baseline were also associated with 90-day mortality. For patients with oliguria 6 h before study enrollment, 90-day mortality differed significantly between patients with low and high P-PENK/P-NGAL at baseline (5% vs. 68%, p 105.7 pmol/L and P-NGAL(24h) > 151 ng/mL had unadjusted hazard ratios of 5.6 (95% CI 3.1-10.7, p <0.001) and 5.2 (95% CI 2.8-9.8, p <0.001) for 90-day mortality. The association remained significant despite adjustments with AKI and two risk scores for mortality in cardiogenic shock. Conclusions: High levels of P-PENK and P-NGAL at baseline were independently associated with AKI in cardiogenic shock patients. Furthermore, oliguria before study inclusion was associated with worse outcomes only if combined with high baseline levels of P-PENK or P-NGAL. High levels of both P-PENK and P-NGAL at 24 h were found to be strong and independent predictors of 90-day mortality.Peer reviewe

Predictive value of plasma proenkephalin and neutrophil gelatinase-associated lipocalin in acute kidney injury and mortality in cardiogenic shock

Background: Acute kidney injury (AKI) is a frequent form of organ injury in cardiogenic shock. However, data on AKI markers such as plasma proenkephalin (P-PENK) and neutrophil gelatinase-associated lipocalin (P-NGAL) in cardiogenic shock populations are lacking. The objective of this study was to assess the ability of P-PENK and P-NGAL to predict acute kidney injury and mortality in cardiogenic shock. Results: P-PENK and P-NGAL were measured at different time points between baseline and 48 h in 154 patients from the prospective CardShock study. The outcomes assessed were AKI defined by an increase in creatinine within 48 h and all-cause 90-day mortality. Mean age was 66 years and 26% were women. Baseline levels of P-PENK and P-NGAL (median [interquartile range]) were 99 (71-150) pmol/mL and 138 (84-214) ng/mL. P-PENK > 84.8 pmol/mL and P-NGAL > 104 ng/mL at baseline were identified as optimal cut-offs for AKI prediction and independently associated with AKI (adjusted HRs 2.2 [95% CI 1.1-4.4, p = 0.03] and 2.8 [95% CI 1.2-6.5, p = 0.01], respectively). P-PENK and P-NGAL levels at baseline were also associated with 90-day mortality. For patients with oliguria 6 h before study enrollment, 90-day mortality differed significantly between patients with low and high P-PENK/P-NGAL at baseline (5% vs. 68%, p 105.7 pmol/L and P-NGAL(24h) > 151 ng/mL had unadjusted hazard ratios of 5.6 (95% CI 3.1-10.7, p <0.001) and 5.2 (95% CI 2.8-9.8, p <0.001) for 90-day mortality. The association remained significant despite adjustments with AKI and two risk scores for mortality in cardiogenic shock. Conclusions: High levels of P-PENK and P-NGAL at baseline were independently associated with AKI in cardiogenic shock patients. Furthermore, oliguria before study inclusion was associated with worse outcomes only if combined with high baseline levels of P-PENK or P-NGAL. High levels of both P-PENK and P-NGAL at 24 h were found to be strong and independent predictors of 90-day mortality.Peer reviewe

Soluble urokinase-type plasminogen activator receptor improves early risk stratification in cardiogenic shock

Aims Soluble urokinase-type plasminogen activator receptor (suPAR) is a biomarker reflecting the level of immune activation. It has been shown to have prognostic value in acute coronary syndrome and heart failure as well as in critical illness. Considering the complex pathophysiology of cardiogenic shock (CS), we hypothesized suPAR might have prognostic properties in CS as well. The aim of this study was to assess the kinetics and prognostic utility of suPAR in CS. Methods and results SuPAR levels were determined in serial plasma samples (0-96 h) from 161 CS patients in the prospective, observational, multicentre CardShock study. Kinetics of suPAR, its association with 90-day mortality, and additional value in risk-stratification were investigated. The median suPAR-level at baseline was 4.4 [interquartile range (IQR) 3.2-6.6)] ng/mL. SuPAR levels above median were associated with underlying comorbidities, biomarkers reflecting renal and cardiac dysfunction, and higher 90-day mortality (49% vs. 31%; P = 0.02). Serial measurements showed that survivors had significantly lower suPAR levels at all time points compared with nonsurvivors. For risk stratification, suPAR at 12 h (suPAR(12h)) with a cut-off of 4.4 ng/mL was strongly associated with mortality independently of established risk factors in CS: OR 5.6 (95% CI 2.0-15.5); P = 0.001) for death by 90 days. Adding suPAR(12h) > 4.4 ng/mL to the CardShock risk score improved discrimination identifying high-risk patients originally categorized in the intermediate-risk category. Conclusion SuPAR associates with mortality and improves risk stratification independently of other previously known risk factors in CS patients.Peer reviewe