Steigerung profibrotischer Signaltransduktion unter arrhythmischer Stimulation in Kardiomyozyten

Vorhofflimmern ist die häufigste Herzrhythmusstörung 1. Durch das Vorhofflimmern kommt es zu elektrischem und strukturellem Remodelling des Vorhofes. Das wichtigste Kennzeichen dieses strukturellen Remodellings ist die Fibrose. Die genaue Pathogenese der profibrotischen Signaltransduktion ist nicht vollständig bekannt. Viele Arbeiten konnten bereits zeigen, dass es durch Vorhofflimmern zu einer Verstärkung der profibrotischen Signaltransduktion kommt. Die besondere Bedeutung der Arrhythmie für diese Prozesse ist hingegen bisher nur teilweise erforscht. Daher entwickelten wir ein Zellkulturmodell mit neonatalen Rattenkardiomyozyten, um den singulären Einfluss der Arrhythmie auf die profibrotische Signaltransduktion weiter zu charakterisieren. Wir isolierten neonatale Kardiomyozyten aus Rattenherzen und stimulierten diese für 24 bzw. 48 Stunden in den Vergleichsgruppen rhythmisch und arrhythmisch, wobei beide Gruppen mit der gleichen Frequenz von 3Hz stimuliert wurden. Zunächst untersuchten wir den Connective Tissue Growth Factor (CTGF) als zentralen Mediator der Fibrose. Dabei zeigte sich bereits nach 24 Stunden unter arrhythmischer Stimulierung eine gesteigerte Proteinexpression auf 182±16%. Nach 48 Stunden Stimulation stieg diese Expression weiter auf 223±32%. In beiden Gruppen konnten wir keine Steigerung der CTGF Expression unter rhythmischer Stimulierung feststellen. Die 5´-AMP-aktivierte Kinase (AMPK), als Indikator für erhöhte energieverbrauchende Stoffwechselprozesse, war ebenfalls nach 24 und 48 Stunden arrhythmischer Stimulation auf 205±16% bzw. 192±21% erhöht. Des Weiteren konnten wir zeigen, dass es unter Arrhythmie und selektiver Ausschaltung der AMPK mit Compound C zu einer signifikanten Erniedrigung der CTGF Expression auf 83±10% kommt. Außerdem konnten wir zeigen, dass Arrhythmie zu einer signifikanten Steigerung der Expression von oxidativem Stress führt. Es zeigte sich eine Steigerung der Konzentration von reaktiven Sauerstoffspezies (ROS) auf 131±18%. Diese Erkenntnisse konnten wir durch eine Anfärbung des 8-oH-Desoxyguanosin untermauern. In dieser Färbung zeigte sich unter Arrhythmie eine deutlich stärkere Expression von 285±57%. Dem entgegen steht eine Aktivierung des antioxidativen Systems unter Arrhythmie. Es zeigte sich eine verstärkte Konzentration der Katalase mRNA von 119±6%. Außerdem waren die Konzentrationen der Superoxiddismutasen signifikant gesteigert. Nrf2, ein diesen Antioxidatien übergeordneter Transkriptionsfaktor, war in unseren Untersuchungen unter Arrhythmie nicht signifikant gesteigert. Als Verbindung zwischen oxidativem Stress und Fibrose zeigten wir, dass es zu einer Erhöhung von sST2 unter Arrhythmie kommt und somit die antifibrotischen Effekte von IL-33 und ST2L abgeschwächt werden. Fibrose äußert sich in einer Vermehrung der Extrazellulärmatrix (ECM). Dazu untersuchten wir die Parameter Kollagen I und III, Hyluronsäure und Hydroxyprolin als wichtigste Anteile dieser ECM. Dabei konnten wir keine signifikante Steigerung von Hyaluronsäure und Hydroxyprolin unter Arrhythmie feststellen. Kollagen I und III waren hingegen unter Arrhythmie sowohl nach 24 als auch nach 48 Stunden signifikant gesteigert. Arrhythmie führte zu einer Steigerung von Kollagen I nach 24 Stunden auf 317±70% und nach 48 Stunden auf 458±81%. Kollagen III war nach 24 Stunden unter Arrhythmie auf 218±61% und nach 48 Stunden auf 277±22% erhöht. Wir konnten somit eine Vermehrung der ECM auf Kollagenbasis unter Arrhythmie nachweisen. Alle aufgeführten Effekte waren signifikant mit p<0,05. Zusammenfassend lässt sich sagen, dass Arrhythmie zu einer profibrotischen Signaltransduktion führt. Durch eine erhöhte Expression von CTGF wird das strukturelle Remodelling entscheidend beeinflusst. Oxidativer Stress als Faktor, welcher CTGF beeinflusst, ist ebenfalls unter Arrhythmie erhöht. Diese Daten tragen zum zellulären Verständnis der Fibrogenese bei Vorhofflimmern bei.Atrial fibrillation is the most common arrhythmia. Atrial fibrillation is associated with electrical and structural remodelling in the atria. The most important characteristic of the structural remodelling is fibrosis. The pathogenesis of the profibrotic signal transduction is incompletely understood. Atrial fibrillation is a major reason for enhancement of profibrotic signal transduction. The detailed role of arrhythmia for these processes is incompletely understood. We developed a cell culture modell with neonatal rat cardiomyocytes to characterize the singular influence of arrhythmia on profibrotic signal transduction. We isolated neonatal rat cardiomyocytes and stimulated them for 24 or 48 hours in groups of rhythmic and arrhythmic stimulation, whereas both groups were stimulated with same frequency of 3Hz. After 24 hours of arrhythmic stimulation there was an increased protein expression of Connective Tissue Growth Factor (CTGF) up to 182±16%. After 48 hours there was even an increase of expression of 223±32%. In both groups there was no increase of expression after rhythmic stimulation. The 5´-AMP-aktivierte Kinase (AMPK) as an indicator for energy-guzzling metabolic processes was also increased after 24 and 48 hours of arrhythmic stimulation on 205±16% or 192±21%. Furthermore we showed under selective suppression of AMPK with Compound C a significant suppression of CTGF expression on 83±10%. Moreover we showed that arrhythmia leads to significant increase of expression of oxidative stress. There was a significant increase of reactive oxygen species (ROS) concentration on 131±18%. We could confirm these results with the opacification of 8-oH-Desoxyguanosin. In this opacification there was a potentiation of its expression up to 285±57%. In contrast to that there was an increase in mRNA concentration of catalase on 119±6%. Moreover concentration of superoxiddismutase was significantly increased. Nrf2 as a transcriptional factor was not increased in our study. As a linking between oxidative stress and fibrosis we showed that there was an increase in sST2 due to arrhythmia which is the reason for the suppression of the antifibrotic effects of IL-33 and ST2L. We investigated collagen I and III, hyaluronic acid and hydroxyprolin as the most important amount of ECM. There was no significant increase of hyaluronic acid and hydroxyprolin after arrhythmia. Collagen I and III however were significantly increased after 24 or 48 hours of arrhythmia. Arrhythmia was the reason of the increase of collagen I on 317±70% after 24 hours and 458±81% after 48 hours. Collagen III was increased after 24 hours of arrhythmia on 218±61% and on 277±22% after 48 hours. In conclusion we could show a proliferation of ECM due to collagen increase after arrhythmia. All mentioned effects were significant wih p<0,05. In summary, arrhythmia plays a essential role in profibrotic signal transduction as part of atrial fibrillation. Due to increased expression of CTGF structural remodelling is crucially influenced. Oxidative stress as an influencer of CTGF is also increased. This profibrotic signal transduction identifies arrhythmia as an important factor for the proliferation of ECM as a characteristic of fibrosis

Management of hyperkalaemia in acute kidney injury in a heart failure patient with patiromer

Aims: One prevalent comorbidity of chronic heart failure (CHF) is chronic kidney disease(CKD). Hyperkalemia is associated with both CHF and CKD, which often leads to withdrawal of heart failure medications in clinical praxis. Methods and results: A patient is presented who suffered from acute kidney injury with pre‐existing CKD as heart failure comorbidity and a history of hyperkalemia. Conclusions: This case shows that potassium levels remained stable in acute kidney injury under ongoing heart failure medications, including an MRA, with the use of the potassium binder patiromer

Time to benefit of heart rate reduction with ivabradine in patients with heart failure and reduced ejection fraction

Aims In the SHIFT (Systolic Heart failure treatment with the If inhibitor ivabradine Trial, ISRCTN70429960) study, ivabradine reduced cardiovascular death or heart failure (HF) hospitalizations in patients with HF and reduced ejection fraction (HFrEF) in sinus rhythm and with a heart rate (HR) ≥70 bpm. In this study, we sought to determine the clinical significance of the time durations of HR reduction and the significant treatment effect on outcomes among patients with HFrEF. Methods and results The time to statistically significant reduction of the primary outcome (HF hospitalization and cardiovascular death) and its components, all-cause death, and HF death, were assessed in a post-hoc analysis of the SHIFT trial in the overall population (HR ≥70 bpm) and at HR ≥75 bpm, representing the approved label in many countries. Compared to placebo, the primary outcome and HF hospitalizations were significantly reduced at 102 days, while there was no effect on cardiovascular death, all-cause death, and HF death at HR ≥70 bpm. In the population with a baseline HR ≥75 bpm, a reduction of the primary outcome occurred after 67 days, HF hospitalization after 78 days, cardiovascular death after 169 days, death from HF after 157 days and all-cause death after 169 days. Conclusion Treatment with ivabradine should not be deferred in patients in sinus rhythm with a HR of ≥70 bpm to reduce the primary outcome and HF hospitalizations, in particular in patients with HR ≥75 bpm. At HR ≥75 bpm, the time to risk reduction was shorter for reduction of hospitalization and mortality outcomes in patients with HFrEF after initiation of guideline-directed medication, including beta-blockers at maximally tolerated doses

Timely and individualized heart failure management: need for implementation into the new guidelines

Due to remarkable improvements in heart failure (HF) management over the last 30 years, a significant reduction in mortality and hospitalization rates in HF patients with reduced ejection fraction (HFrEF) has been observed. Currently, the optimization of guideline-directed chronic HF therapy remains the mainstay to further improve outcomes for patients with HFrEF to reduce mortality and HF hospitalization. This includes established device therapies, such as implantable defibrillators and cardiac resynchronization therapies, which improved patients' symptoms and prognosis. Over the last 10 years, new HF drugs have merged targeting various pathways, such as those that simultaneously suppress the renin–angiotensin–aldosterone system and the breakdown of endogenous natriuretic peptides (e.g., sacubitril/valsartan), and those that inhibit the If channel and, thus, reduce heart rate (e.g., ivabradine). Furthermore, the treatment of patient comorbidities (e.g., iron deficiency) has shown to improve functional capacity and to reduce hospitalization rates, when added to standard therapy. More recently, other potential treatment mechanisms have been explored, such as the sodium/glucose co-transporter inhibitors, the guanylate cyclase stimulators and the cardiac myosin activators. In this review, we summarize the novel developments in HFrEF pharmacological and device therapy and discuss their implementation strategies into practice to further improve outcomes

Heart failure outcomes according to heart rate and effects of empagliflozin in patients of the EMPEROR-Preserved trial

Aims Empagliflozin reduces cardiovascular death (CVD) or heart failure hospitalization (HHF) in patients with heart failure and preserved ejection fraction (HFpEF). Treatment effects and safety in relation to resting heart rate (RHR) have not been studied. Methods and results The interplay of RHR and empagliflozin effects in EMPEROR-Preserved was evaluated. We grouped patients (n = 5988) according to their baseline RHR (75 bpm [n = 1736]) and explored the influence of RHR on CVD or HHF (primary outcome) and its components in sinus rhythm or atrial fibrillation/flutter (AF) and adverse events. We studied the efficacy of empagliflozin across the RHR spectrum. Compared to placebo, empagliflozin did not change heart rate over time. The primary outcome (p for trend = 0.0004) and its components CVD (p trend = 0.0002), first HHF (p for trend = 0.0099) and all-cause death (p <  0.0001) increased with RHR only in sinus rhythm but not AF. The risk increase with RHR was similar in patients with heart failure and mildly reduced ejection fraction (left ventricular ejection fraction [LVEF] 40–49%) and HFpEF (LVEF ≥50%). Baseline RHR had no influence on the effect of empagliflozin on the primary outcomes (p for trend = 0.20), first HHF (p for trend = 0.49). There were no clinically relevant differences in adverse events between empagliflozin and placebo across the RHR groups. Conclusion Resting heart rate associates with outcomes only in sinus rhythm but not in AF. Empagliflozin reduced outcomes over the entire RHR spectrum without increase of adverse events

Time to benefit of heart rate reduction with ivabradine in patients with heart failure and reduced ejection fraction

Aims: In the SHIFT (Systolic Heart failure treatment with the If inhibitor ivabradine Trial, ISRCTN70429960) study, ivabradine reduced cardiovascular death or heart failure (HF) hospitalizations in patients with heart failure and reduced ejection fraction (HFrEF) in sinus rhythm and with a heart rate (HR) ≥70 bpm. In this study, we sought to determine the clinical significance of the time durations of heart rate reduction and the significant treatment effect on outcomes among patients with HFrEF. Methods and results: The time to statistically significant reduction of the primary outcome (HF hospitalization and cardiovascular death) and its components, all-cause death, and HF death, were assessed in a post-hoc analysis of the SHIFT trial in the overall population (HR ≥70 bpm) and at HR ≥75 bpm, representing the approved label in many countries. Compared to placebo, the primary outcome and HF hospitalizations were significantly reduced at 102 days, while there was no effect on cardiovascular death, all-cause death, and HF death at HR ≥70 bpm. In the population with a baseline HR ≥75 bpm, a reduction of the primary outcome occurred after 67 days, HF hospitalization after 78 days, cardiovascular death after 169 days, death from HF after 157 days and all-cause death after 169 days. Conclusion: Treatment with ivabradine should not be deferred in patients in sinus rhythm with a HR of ≥70 bpm to reduce the primary outcome and HF hospitalizations, in particular in patients with HR ≥75 bpm. At HR ≥75 bpm, the time to risk reduction was shorter for reduction of hospitalization and mortality outcomes in patients with HFrEF after initiation of guideline-directed medication, including beta blockers at maximally tolerated doses

Circadian Rhythm and Sleep Disruption: Causes, Metabolic Consequences and Countermeasures.

Circadian (∼ 24 hour) timing systems pervade all kingdoms of life, and temporally optimize behaviour and physiology in humans. Relatively recent changes to our environments, such as the introduction of artificial lighting, can disorganize the circadian system, from the level of the molecular clocks that regulate the timing of cellular activities to the level of synchronization between our daily cycles of behaviour and the solar day. Sleep/wake cycles are intertwined with the circadian system, and global trends indicate that these too are increasingly subject to disruption. A large proportion of the world's population is at increased risk of environmentally-driven circadian rhythm and sleep disruption, and a minority of individuals are also genetically predisposed to circadian misalignment and sleep disorders. The consequences of disruption to the circadian system and sleep are profound and include myriad metabolic ramifications, some of which may be compounded by adverse effects on dietary choices. If not addressed, the deleterious effects of such disruption will continue to cause widespread health problems; therefore, implementation of the numerous behavioural and pharmaceutical interventions that can help restore circadian system alignment and enhance sleep will be important

Radical surgery versus organ preservation via short-course radiotherapy followed by transanal endoscopic microsurgery for early-stage rectal cancer (TREC): a randomised, open-label feasibility study

Background: Radical surgery via total mesorectal excision might not be the optimal first-line treatment for early-stage rectal cancer. An organ-preserving strategy with selective total mesorectal excision could reduce the adverse effects of treatment without substantially compromising oncological outcomes. We investigated the feasibility of recruiting patients to a randomised trial comparing an organ-preserving strategy with total mesorectal excision. Methods: TREC was a randomised, open-label feasibility study done at 21 tertiary referral centres in the UK. Eligible participants were aged 18 years or older with rectal adenocarcinoma, staged T2 or lower, with a maximum diameter of 30 mm or less; patients with lymph node involvement or metastases were excluded. Patients were randomly allocated (1:1) by use of a computer-based randomisation service to undergo organ preservation with short-course radiotherapy followed by transanal endoscopic microsurgery after 8–10 weeks, or total mesorectal excision. Where the transanal endoscopic microsurgery specimen showed histopathological features associated with an increased risk of local recurrence, patients were considered for planned early conversion to total mesorectal excision. A non-randomised prospective registry captured patients for whom randomisation was considered inappropriate, because of a strong clinical indication for one treatment group. The primary endpoint was cumulative randomisation at 12, 18, and 24 months. Secondary outcomes evaluated safety, efficacy, and health-related quality of life assessed with the European Organisation for Research and Treatment of Cancer (EORTC) QLQ C30 and CR29 in the intention-to-treat population. This trial is registered with the ISRCTN Registry, ISRCTN14422743. Findings: Between Feb 22, 2012, and Dec 19, 2014, 55 patients were randomly assigned at 15 sites; 27 to organ preservation and 28 to radical surgery. Cumulatively, 18 patients had been randomly assigned at 12 months, 31 at 18 months, and 39 at 24 months. No patients died within 30 days of initial treatment, but one patient randomly assigned to organ preservation died within 6 months following conversion to total mesorectal excision with anastomotic leakage. Eight (30%) of 27 patients randomly assigned to organ preservation were converted to total mesorectal excision. Serious adverse events were reported in four (15%) of 27 patients randomly assigned to organ preservation versus 11 (39%) of 28 randomly assigned to total mesorectal excision (p=0·04, χ2 test). Serious adverse events associated with organ preservation were most commonly due to rectal bleeding or pain following transanal endoscopic microsurgery (reported in three cases). Radical total mesorectal excision was associated with medical and surgical complications including anastomotic leakage (two patients), kidney injury (two patients), cardiac arrest (one patient), and pneumonia (two patients). Histopathological features that would be considered to be associated with increased risk of tumour recurrence if observed after transanal endoscopic microsurgery alone were present in 16 (59%) of 27 patients randomly assigned to organ preservation, versus 24 (86%) of 28 randomly assigned to total mesorectal excision (p=0·03, χ2 test). Eight (30%) of 27 patients assigned to organ preservation achieved a complete response to radiotherapy. Patients who were randomly assigned to organ preservation showed improvements in patient-reported bowel toxicities and quality of life and function scores in multiple items compared to those who were randomly assigned to total mesorectal excision, which were sustained over 36 months’ follow-up. The non-randomised registry comprised 61 patients who underwent organ preservation and seven who underwent radical surgery. Non-randomised patients who underwent organ preservation were older than randomised patients and more likely to have life-limiting comorbidities. Serious adverse events occurred in ten (16%) of 61 non-randomised patients who underwent organ preservation versus one (14%) of seven who underwent total mesorectal excision. 24 (39%) of 61 non-randomised patients who underwent organ preservation had high-risk histopathological features, while 25 (41%) of 61 achieved a complete response. Overall, organ preservation was achieved in 19 (70%) of 27 randomised patients and 56 (92%) of 61 non-randomised patients. Interpretation: Short-course radiotherapy followed by transanal endoscopic microsurgery achieves high levels of organ preservation, with relatively low morbidity and indications of improved quality of life. These data support the use of organ preservation for patients considered unsuitable for primary total mesorectal excision due to the short-term risks associated with this surgery, and support further evaluation of short-course radiotherapy to achieve organ preservation in patients considered fit for total mesorectal excision. Larger randomised studies, such as the ongoing STAR-TREC study, are needed to more precisely determine oncological outcomes following different organ preservation treatment schedules. Funding: Cancer Research UK

Neues zur Diagnostik und Therapie der Herzinsuffizienz

The incidence and prevalence of heart failure are increasing worldwide. Despite numerous scientific and clinical innovations the mortality and morbidity rates in heart failure patients remain high, so that guideline-conform diagnostics and treatment are of decisive importance. Cardiac decompensation is one of the leading reasons for hospital admissions in Germany. Thus, the treatment of patients with heart failure represents a substantial challenge for the German healthcare system. This article highlights the latest scientific knowledge on acute and chronic heart failure from the years 2018-2020

Update on diagnostics and treatment of heart failure

Inzidenz und Prävalenz der Herzinsuffizienz steigen weltweit. Trotz zahlreicher wissenschaftlicher und klinischer Innovationen ist sie weiterhin mit einer hohen Morbidität und Mortalität behaftet, sodass eine leitliniengerechte Diagnostik und Therapie von entscheidender Bedeutung sind. Die kardiale Dekompensation zählt zu den häufigsten Aufnahmegründen in deutschen Krankenhäusern. Somit stellt die Behandlung herzinsuffizienter Patienten eine erhebliche Herausforderung für das deutsche Gesundheitssystem dar. Dieser Artikel fasst die neuesten wissenschaftlichen Erkenntnisse zur akuten und chronischen Herzinsuffizienz der Jahre 2018 bis 2020 zusammen.The incidence and prevalence of heart failure are increasing worldwide. Despite numerous scientific and clinical innovations the mortality and morbidity rates in heart failure patients remain high, so that guideline-conform diagnostics and treatment are of decisive importance. Cardiac decompensation is one of the leading reasons for hospital admissions in Germany. Thus, the treatment of patients with heart failure represents a substantial challenge for the German healthcare system. This article highlights the latest scientific knowledge on acute and chronic heart failure from the years 2018–2020