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Little is known about the physical and mental health among police students. Based on data on Swedish police students’ physical fitness (N = 1736) and mental health (N = 407), the results show that: (a) there are gender differences; (b) the physical fitness changes during police education; in general, the students get stronger but less flexible, and the aerobic endurance increases for women but decreases for men; and (c) students’ self-reported physical activity and mental health affect their perceived police ability differently in re- lation to gender. Consequently, this study questions if the Swedish police education is preparing the students adequately for their future profession.

Background Long-chain acyl-carnitines (ACs) are potential arrhythmogenic metabolites. Their role in atrial fibrillation (AF) remains incompletely understood. Using a systems medicine approach, we assessed the contribution of C18:1AC to AF by analysing its in vitro effects on cardiac electrophysiology and metabolism, and translated our findings into the human setting. Methods and results Human iPSC-derived engineered heart tissue was exposed to C18:1AC. A biphasic effect on contractile force was observed: short exposure enhanced contractile force, but elicited spontaneous contractions and impaired Ca2+ handling. Continuous exposure provoked an impairment of contractile force. In human atrial mitochondria from AF individuals, C18:1AC inhibited respiration. In a population-based cohort as well as a cohort of patients, high C18:1AC serum concentrations were associated with the incidence and prevalence of AF. Conclusion Our data provide evidence for an arrhythmogenic potential of the metabolite C18:1AC. The metabolite interferes with mitochondrial metabolism, thereby contributing to contractile dysfunction and shows predictive potential as novel circulating biomarker for risk of AF., Background: Long-chain acyl-carnitines (ACs) are potential arrhythmogenic metabolites. Their role in atrial fibrillation (AF) remains incompletely understood. Using a systems medicine approach, we assessed the contribution of C18:1AC to AF by analysing its in vitro effects on cardiac electrophysiology and metabolism, and translated our findings into the human setting. Methods and results: Human iPSC-derived engineered heart tissue was exposed to C18:1AC. A biphasic effect on contractile force was observed: short exposure enhanced contractile force, but elicited spontaneous contractions and impaired Ca2+ handling. Continuous exposure provoked an impairment of contractile force. In human atrial mitochondria from AF individuals, C18:1AC inhibited respiration. In a population-based cohort as well as a cohort of patients, high C18:1AC serum concentrations were associated with the incidence and prevalence of AF. Conclusion: Our data provide evidence for an arrhythmogenic potential of the metabolite C18:1AC. The metabolite interferes with mitochondrial metabolism, thereby contributing to contractile dysfunction and shows predictive potential as novel circulating biomarker for risk of AF.

Little is known about the physical and mental health among police students. Based on data on Swedish police students’ physical fitness (N = 1736) and mental health (N = 407), the results show that: (a) there are gender differences; (b) the physical fitness changes during police education; in general, the students get stronger but less flexible, and the aerobic endurance increases for women but decreases for men; and (c) students’ self-reported physical activity and mental health affect their perceived police ability differently in re- lation to gender. Consequently, this study questions if the Swedish police education is preparing the students adequately for their future profession.

Little is known about the physical and mental health among police students. Based on data on Swedish police students’ physical fitness (N = 1736) and mental health (N = 407), the results show that: (a) there are gender differences; (b) the physical fitness changes during police education; in general, the students get stronger but less flexible, and the aerobic endurance increases for women but decreases for men; and (c) students’ self-reported physical activity and mental health affect their perceived police ability differently in re- lation to gender. Consequently, this study questions if the Swedish police education is preparing the students adequately for their future profession.

Background Long-chain acyl-carnitines (ACs) are potential arrhythmogenic metabolites. Their role in atrial fibrillation (AF) remains incompletely understood. Using a systems medicine approach, we assessed the contribution of C18:1AC to AF by analysing its in vitro effects on cardiac electrophysiology and metabolism, and translated our findings into the human setting. Methods and results Human iPSC-derived engineered heart tissue was exposed to C18:1AC. A biphasic effect on contractile force was observed: short exposure enhanced contractile force, but elicited spontaneous contractions and impaired Ca2+ handling. Continuous exposure provoked an impairment of contractile force. In human atrial mitochondria from AF individuals, C18:1AC inhibited respiration. In a population-based cohort as well as a cohort of patients, high C18:1AC serum concentrations were associated with the incidence and prevalence of AF. Conclusion Our data provide evidence for an arrhythmogenic potential of the metabolite C18:1AC. The metabolite interferes with mitochondrial metabolism, thereby contributing to contractile dysfunction and shows predictive potential as novel circulating biomarker for risk of AF., Background: Long-chain acyl-carnitines (ACs) are potential arrhythmogenic metabolites. Their role in atrial fibrillation (AF) remains incompletely understood. Using a systems medicine approach, we assessed the contribution of C18:1AC to AF by analysing its in vitro effects on cardiac electrophysiology and metabolism, and translated our findings into the human setting. Methods and results: Human iPSC-derived engineered heart tissue was exposed to C18:1AC. A biphasic effect on contractile force was observed: short exposure enhanced contractile force, but elicited spontaneous contractions and impaired Ca2+ handling. Continuous exposure provoked an impairment of contractile force. In human atrial mitochondria from AF individuals, C18:1AC inhibited respiration. In a population-based cohort as well as a cohort of patients, high C18:1AC serum concentrations were associated with the incidence and prevalence of AF. Conclusion: Our data provide evidence for an arrhythmogenic potential of the metabolite C18:1AC. The metabolite interferes with mitochondrial metabolism, thereby contributing to contractile dysfunction and shows predictive potential as novel circulating biomarker for risk of AF.

The primary idea is to develop a new feed additive as an important climate initiative for organic cattle producers to reduce the enteric methane production in dairy cows with 30%. This is expected to be achieved by adding plant extracts from organically grown willow and hemp, plants with a high content of polyphenols such as tannins and flavonoids that inhibit methanogenic microorganisms.

Little is known about the physical and mental health among police students. Based on data on Swedish police students’ physical fitness (N = 1736) and mental health (N = 407), the results show that: (a) there are gender differences; (b) the physical fitness changes during police education; in general, the students get stronger but less flexible, and the aerobic endurance increases for women but decreases for men; and (c) students’ self-reported physical activity and mental health affect their perceived police ability differently in relation to gender. Consequently, this study questions if the Swedish police education is preparing the students adequately for their future profession.

Little is known about the physical and mental health among police students. Based on data on Swedish police students’ physical fitness (N = 1736) and mental health (N = 407), the results show that: (a) there are gender differences; (b) the physical fitness changes during police education; in general, the students get stronger but less flexible, and the aerobic endurance increases for women but decreases for men; and (c) students’ self-reported physical activity and mental health affect their perceived police ability differently in re- lation to gender. Consequently, this study questions if the Swedish police education is preparing the students adequately for their future profession.

Little is known about the physical and mental health among police students. Based on data on Swedish police students’ physical fitness (N = 1736) and mental health (N = 407), the results show that: (a) there are gender differences; (b) the physical fitness changes during police education; in general, the students get stronger but less flexible, and the aerobic endurance increases for women but decreases for men; and (c) students’ self-reported physical activity and mental health affect their perceived police ability differently in relation to gender. Consequently, this study questions if the Swedish police education is preparing the students adequately for their future profession.

Little is known about the physical and mental health among police students. Based on data on Swedish police students’ physical fitness (N = 1736) and mental health (N = 407), the results show that: (a) there are gender differences; (b) the physical fitness changes during police education; in general, the students get stronger but less flexible, and the aerobic endurance increases for women but decreases for men; and (c) students’ self-reported physical activity and mental health affect their perceived police ability differently in re- lation to gender. Consequently, this study questions if the Swedish police education is preparing the students adequately for their future profession.

Køer bøvser hver dag ca. 600 liter metan op i forbindelse med drøvtygning • En mindre mængde metan tabes som tarmgas og gasser fra gødning • På verdensplan står husdyrproduktion for 14-15 pct. af den totale drivhusgasemission • Metan er 28 gange stærkere som drivhusgas end CO2 • Metan står for ca. 35 pct. af emissionen i landbruget målt i CO2-ækvivalenter.

Køer bøvser hver dag ca. 600 liter metan op i forbindelse med drøvtygning • En mindre mængde metan tabes som tarmgas og gasser fra gødning • På verdensplan står husdyrproduktion for 14-15 pct. af den totale drivhusgasemission • Metan er 28 gange stærkere som drivhusgas end CO2 • Metan står for ca. 35 pct. af emissionen i landbruget målt i CO2-ækvivalenter.

Køer bøvser hver dag ca. 600 liter metan op i forbindelse med drøvtygning • En mindre mængde metan tabes som tarmgas og gasser fra gødning • På verdensplan står husdyrproduktion for 14-15 pct. af den totale drivhusgasemission • Metan er 28 gange stærkere som drivhusgas end CO2 • Metan står for ca. 35 pct. af emissionen i landbruget målt i CO2-ækvivalenter.

Køer bøvser hver dag ca. 600 liter metan op i forbindelse med drøvtygning • En mindre mængde metan tabes som tarmgas og gasser fra gødning • På verdensplan står husdyrproduktion for 14-15 pct. af den totale drivhusgasemission • Metan er 28 gange stærkere som drivhusgas end CO2 • Metan står for ca. 35 pct. af emissionen i landbruget målt i CO2-ækvivalenter.

Køer bøvser hver dag ca. 600 liter metan op i forbindelse med drøvtygning • En mindre mængde metan tabes som tarmgas og gasser fra gødning • På verdensplan står husdyrproduktion for 14-15 pct. af den totale drivhusgasemission • Metan er 28 gange stærkere som drivhusgas end CO2 • Metan står for ca. 35 pct. af emissionen i landbruget målt i CO2-ækvivalenter.

The physiological importance of NCX in human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) is not well characterized but may depend on the relative strength of the current, compared to adult cardiomyocytes, and on the exact spatial arrangement of proteins involved in Ca2+ extrusion. Here, we determined NCX currents and its contribution to action potential and force in hiPSC-CMs cultured in engineered heart tissue (EHT). The results were compared with data from rat and human left ventricular tissue. The NCX currents in hiPSC-CMs were larger than in ventricular cardiomyocytes isolated from human left ventricles (1.3 +/- 0.2 pA/pF and 3.2 +/- 0.2 pA/pF for human ventricle and EHT, respectively, p < 0.05). SEA0400 (10 mu M) markedly shortened the APD(90) in EHT (by 26.6 +/- 5%, p < 0.05) and, to a lesser extent, in rat ventricular tissue (by 10.7 +/- 1.6%, p < 0.05). Shortening in human left ventricular preparations was small and not different from time-matched controls (TMCs; p > 0.05). Force was increased by the NCX block in rat ventricle (by 31 +/- 5.4%, p < 0.05) and EHT (by 20.8 +/- 3.9%, p < 0.05), but not in human left ventricular preparations. In conclusion, hiPSC-CMs possess NCX currents not smaller than human left ventricular tissue. Robust NCX block-induced APD shortening and inotropy makes EHT an attractive pharmacological model.

The physiological importance of NCX in human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) is not well characterized but may depend on the relative strength of the current, compared to adult cardiomyocytes, and on the exact spatial arrangement of proteins involved in Ca2+ extrusion. Here, we determined NCX currents and its contribution to action potential and force in hiPSC-CMs cultured in engineered heart tissue (EHT). The results were compared with data from rat and human left ventricular tissue. The NCX currents in hiPSC-CMs were larger than in ventricular cardiomyocytes isolated from human left ventricles (1.3 +/- 0.2 pA/pF and 3.2 +/- 0.2 pA/pF for human ventricle and EHT, respectively, p < 0.05). SEA0400 (10 mu M) markedly shortened the APD(90) in EHT (by 26.6 +/- 5%, p < 0.05) and, to a lesser extent, in rat ventricular tissue (by 10.7 +/- 1.6%, p < 0.05). Shortening in human left ventricular preparations was small and not different from time-matched controls (TMCs; p > 0.05). Force was increased by the NCX block in rat ventricle (by 31 +/- 5.4%, p < 0.05) and EHT (by 20.8 +/- 3.9%, p < 0.05), but not in human left ventricular preparations. In conclusion, hiPSC-CMs possess NCX currents not smaller than human left ventricular tissue. Robust NCX block-induced APD shortening and inotropy makes EHT an attractive pharmacological model.

Aims Patients with cardiovascular comorbidities have a significantly increased risk for a critical course of COVID-19. As the SARS-CoV2 virus enters cells via the angiotensin-converting enzyme receptor II (ACE2), drugs which interact with the renin angiotensin aldosterone system (RAAS) were suspected to influence disease severity. Methods and results We analyzed 1946 consecutive patients with cardiovascular comorbidities or hypertension enrolled in one of the largest European COVID-19 registries, the Lean European Open Survey on SARS-CoV-2 (LEOSS) registry. Here, we show that angiotensin II receptor blocker intake is associated with decreased mortality in patients with COVID-19 [OR 0.75 (95% CI 0,59-0.96; p = 0.013)]. This effect was mainly driven by patients, who presented in an early phase of COVID-19 at baseline [OR 0,64 (95% CI 0,43-0,96; p = 0.029)]. Kaplan-Meier analysis revealed a significantly lower incidence of death in patients on an angiotensin receptor blocker (ARB) (n = 33/318;10,4%) compared to patients using an angiotensin-converting enzyme inhibitor (ACEi) (n = 60/348;17,2%) or patients who received neither an ACE-inhibitor nor an ARB at baseline in the uncomplicated phase (n = 90/466; 19,3%; p<0.034). Patients taking an ARB were significantly less frequently reaching the mortality predicting threshold for leukocytes (p<0.001), neutrophils (p = 0.002) and the inflammatory markers CRP (p = 0.021), procalcitonin (p = 0.001) and IL-6 (p = 0.049). ACE2 expression levels in human lung samples were not altered in patients taking RAAS modulators. Conclusion These data suggest a beneficial effect of ARBs on disease severity in patients with cardiovascular comorbidities and COVID-19, which is linked to dampened systemic inflammatory activity.

Fosfor, med den kemiske betegnelse P, er et meget vigtigt grundstof, som indgår i alt liv på jorden. Det er derfor vigtigt, at husdyrfoder indeholder den rette mængde P fra fodermidlerne, eller at dyrene får tildelt P via mineralblanding. Indholdet skal desuden være afstemt i forhold til andre mineraler – især calcium, da disse to mineraler bl.a. indgår i knogledannelse. Calcium indgår også i æggeskaller og ny viden tyder på, at ekstra calcium som ”hønens natmad” er en del af løsningen på fosforoverskud i marken hos ægproducenter. På længere sigt skal landbruget dog arbejde hen imod recirkulering af fosfor, så erhvervet undgår afhængighed af import, samt meget svingende kvalitet og priser på fosfat fra miner i lande som Marokko og Rusland.

Fosfor, med den kemiske betegnelse P, er et meget vigtigt grundstof, som indgår i alt liv på jorden. Det er derfor vigtigt, at husdyrfoder indeholder den rette mængde P fra fodermidlerne, eller at dyrene får tildelt P via mineralblanding. Indholdet skal desuden være afstemt i forhold til andre mineraler – især calcium, da disse to mineraler bl.a. indgår i knogledannelse. Calcium indgår også i æggeskaller og ny viden tyder på, at ekstra calcium som ”hønens natmad” er en del af løsningen på fosforoverskud i marken hos ægproducenter. På længere sigt skal landbruget dog arbejde hen imod recirkulering af fosfor, så erhvervet undgår afhængighed af import, samt meget svingende kvalitet og priser på fosfat fra miner i lande som Marokko og Rusland.

Fosfor, med den kemiske betegnelse P, er et meget vigtigt grundstof, som indgår i alt liv på jorden. Det er derfor vigtigt, at husdyrfoder indeholder den rette mængde P fra fodermidlerne, eller at dyrene får tildelt P via mineralblanding. Indholdet skal desuden være afstemt i forhold til andre mineraler – især calcium, da disse to mineraler bl.a. indgår i knogledannelse. Calcium indgår også i æggeskaller og ny viden tyder på, at ekstra calcium som ”hønens natmad” er en del af løsningen på fosforoverskud i marken hos ægproducenter. På længere sigt skal landbruget dog arbejde hen imod recirkulering af fosfor, så erhvervet undgår afhængighed af import, samt meget svingende kvalitet og priser på fosfat fra miner i lande som Marokko og Rusland.

Fosfor, med den kemiske betegnelse P, er et meget vigtigt grundstof, som indgår i alt liv på jorden. Det er derfor vigtigt, at husdyrfoder indeholder den rette mængde P fra fodermidlerne, eller at dyrene får tildelt P via mineralblanding. Indholdet skal desuden være afstemt i forhold til andre mineraler – især calcium, da disse to mineraler bl.a. indgår i knogledannelse. Calcium indgår også i æggeskaller og ny viden tyder på, at ekstra calcium som ”hønens natmad” er en del af løsningen på fosforoverskud i marken hos ægproducenter. På længere sigt skal landbruget dog arbejde hen imod recirkulering af fosfor, så erhvervet undgår afhængighed af import, samt meget svingende kvalitet og priser på fosfat fra miner i lande som Marokko og Rusland.

Fosfor, med den kemiske betegnelse P, er et meget vigtigt grundstof, som indgår i alt liv på jorden. Det er derfor vigtigt, at husdyrfoder indeholder den rette mængde P fra fodermidlerne, eller at dyrene får tildelt P via mineralblanding. Indholdet skal desuden være afstemt i forhold til andre mineraler – især calcium, da disse to mineraler bl.a. indgår i knogledannelse. Calcium indgår også i æggeskaller og ny viden tyder på, at ekstra calcium som ”hønens natmad” er en del af løsningen på fosforoverskud i marken hos ægproducenter. På længere sigt skal landbruget dog arbejde hen imod recirkulering af fosfor, så erhvervet undgår afhængighed af import, samt meget svingende kvalitet og priser på fosfat fra miner i lande som Marokko og Rusland.

Fosfor, med den kemiske betegnelse P, er et meget vigtigt grundstof, som indgår i alt liv på jorden. Det er derfor vigtigt, at husdyrfoder indeholder den rette mængde P fra fodermidlerne, eller at dyrene får tildelt P via mineralblanding. Indholdet skal desuden være afstemt i forhold til andre mineraler – især calcium, da disse to mineraler bl.a. indgår i knogledannelse. Calcium indgår også i æggeskaller og ny viden tyder på, at ekstra calcium som ”hønens natmad” er en del af løsningen på fosforoverskud i marken hos ægproducenter. På længere sigt skal landbruget dog arbejde hen imod recirkulering af fosfor, så erhvervet undgår afhængighed af import, samt meget svingende kvalitet og priser på fosfat fra miner i lande som Marokko og Rusland.

Aims Patients with cardiovascular comorbidities have a significantly increased risk for a critical course of COVID-19. As the SARS-CoV2 virus enters cells via the angiotensin-converting enzyme receptor II (ACE2), drugs which interact with the renin angiotensin aldosterone system (RAAS) were suspected to influence disease severity. Methods and results We analyzed 1946 consecutive patients with cardiovascular comorbidities or hypertension enrolled in one of the largest European COVID-19 registries, the Lean European Open Survey on SARS-CoV-2 (LEOSS) registry. Here, we show that angiotensin II receptor blocker intake is associated with decreased mortality in patients with COVID-19 [OR 0.75 (95% CI 0,59-0.96; p = 0.013)]. This effect was mainly driven by patients, who presented in an early phase of COVID-19 at baseline [OR 0,64 (95% CI 0,43-0,96; p = 0.029)]. Kaplan-Meier analysis revealed a significantly lower incidence of death in patients on an angiotensin receptor blocker (ARB) (n = 33/318;10,4%) compared to patients using an angiotensin-converting enzyme inhibitor (ACEi) (n = 60/348;17,2%) or patients who received neither an ACE-inhibitor nor an ARB at baseline in the uncomplicated phase (n = 90/466; 19,3%; p<0.034). Patients taking an ARB were significantly less frequently reaching the mortality predicting threshold for leukocytes (p<0.001), neutrophils (p = 0.002) and the inflammatory markers CRP (p = 0.021), procalcitonin (p = 0.001) and IL-6 (p = 0.049). ACE2 expression levels in human lung samples were not altered in patients taking RAAS modulators. Conclusion These data suggest a beneficial effect of ARBs on disease severity in patients with cardiovascular comorbidities and COVID-19, which is linked to dampened systemic inflammatory activity.

Aims: Patients with cardiovascular comorbidities have a significantly increased risk for a critical course of COVID-19. As the SARS-CoV2 virus enters cells via the angiotensin-converting enzyme receptor II (ACE2), drugs which interact with the renin angiotensin aldosterone system (RAAS) were suspected to influence disease severity. Methods and results: We analyzed 1946 consecutive patients with cardiovascular comorbidities or hypertension enrolled in one of the largest European COVID-19 registries, the Lean European Open Survey on SARS-CoV-2 (LEOSS) registry. Here, we show that angiotensin II receptor blocker intake is associated with decreased mortality in patients with COVID-19 [OR 0.75 (95% CI 0,59–0.96; p = 0.013)]. This effect was mainly driven by patients, who presented in an early phase of COVID-19 at baseline [OR 0,64 (95% CI 0,43–0,96; p = 0.029)]. Kaplan-Meier analysis revealed a significantly lower incidence of death in patients on an angiotensin receptor blocker (ARB) (n = 33/318;10,4%) compared to patients using an angiotensin-converting enzyme inhibitor (ACEi) (n = 60/348;17,2%) or patients who received neither an ACE-inhibitor nor an ARB at baseline in the uncomplicated phase (n = 90/466; 19,3%; p<0.034). Patients taking an ARB were significantly less frequently reaching the mortality predicting threshold for leukocytes (p<0.001), neutrophils (p = 0.002) and the inflammatory markers CRP (p = 0.021), procalcitonin (p = 0.001) and IL-6 (p = 0.049). ACE2 expression levels in human lung samples were not altered in patients taking RAAS modulators. Conclusion: These data suggest a beneficial effect of ARBs on disease severity in patients with cardiovascular comorbidities and COVID-19, which is linked to dampened systemic inflammatory activity.

Rationale: There are several methods to measure cardiomyocyte (CM) and muscle contraction but these require customized hardware, expensive apparatus and advanced informatics or can only be used in single experimental models. Consequently, data and techniques have been difficult to reproduce across models and laboratories, analysis is time consuming and only specialist researchers can quantify data. Objective: Here we describe and validate an automated, open source software tool (MUSCLEMOTION) adaptable for use with standard laboratory- and clinical imaging equipment that enables quantitative analysis of normal cardiac contraction, disease phenotypes and pharmacological responses. Methods and Results: MUSCLEMOTION allowed rapid and easy measurement of movement from high-speed movies in: (i) 1-dimensional in vitro models such as isolated adult and human pluripotent stem cell-derived CMs (hPSC-CMs); (ii) 2-dimensional in vitro models, such as beating CM monolayers or small clusters of hPSC-CMs; (iii) 3-dimensional multicellular in vitro or in vivo contractile tissues such as cardiac "organoids", engineered heart tissues (EHT), zebrafish- and human hearts. MUSCLEMOTION was effective under different recording conditions (bright field microscopy with simultaneous patch clamp recording, phase contrast microscopy and traction force microscopy). Outcomes were virtually identical to the current gold standards for contraction measurement such as optical flow, pole deflection, edge-detection systems or manual analyses. Finally, we used the algorithm to quantify contraction in in vitro and in vivo arrhythmia models and to measure pharmacological responses. Conclusions: Using a single open source method for processing video recordings, we obtained reliable pharmacological data and measures of cardiac disease phenotype in experimental cell-, animal- and human models.

Rationale: There are several methods to measure cardiomyocyte (CM) and muscle contraction but these require customized hardware, expensive apparatus and advanced informatics or can only be used in single experimental models. Consequently, data and techniques have been difficult to reproduce across models and laboratories, analysis is time consuming and only specialist researchers can quantify data. Objective: Here we describe and validate an automated, open source software tool (MUSCLEMOTION) adaptable for use with standard laboratory- and clinical imaging equipment that enables quantitative analysis of normal cardiac contraction, disease phenotypes and pharmacological responses. Methods and Results: MUSCLEMOTION allowed rapid and easy measurement of movement from high-speed movies in: (i) 1-dimensional in vitro models such as isolated adult and human pluripotent stem cell-derived CMs (hPSC-CMs); (ii) 2-dimensional in vitro models, such as beating CM monolayers or small clusters of hPSC-CMs; (iii) 3-dimensional multicellular in vitro or in vivo contractile tissues such as cardiac "organoids", engineered heart tissues (EHT), zebrafish- and human hearts. MUSCLEMOTION was effective under different recording conditions (bright field microscopy with simultaneous patch clamp recording, phase contrast microscopy and traction force microscopy). Outcomes were virtually identical to the current gold standards for contraction measurement such as optical flow, pole deflection, edge-detection systems or manual analyses. Finally, we used the algorithm to quantify contraction in in vitro and in vivo arrhythmia models and to measure pharmacological responses. Conclusions: Using a single open source method for processing video recordings, we obtained reliable pharmacological data and measures of cardiac disease phenotype in experimental cell-, animal- and human models.

Introduction Left ventricular dysfunction is a frequent and potentially severe side effect of many tyrosine kinase inhibitors (TKI). The mode of toxicity is not identified, but may include impairment of mitochondrial or sarcomeric function, autophagy or angiogenesis, either as an on-target or off-target mechanism. Methods and Results We studied concentration-response curves and time courses for nine TKIs in three-dimensional, force generating engineered heart tissue (EHT) from neonatal rat heart cells. We detected a concentration-and time-dependent decline in contractile force for gefitinib, lapatinib, sunitinib, imatinib, sorafenib, vandetanib and lestaurtinib and no decline in contractile force for erlotinib and dasatinib after 96 hours of incubation. The decline in contractile force was associated with an impairment of autophagy (LC3 Western blot) and appearance of autophagolysosomes (transmission electron microscopy). Conclusion This study demonstrates the feasibility to study TKI-mediated force effects in EHTs and identifies an association between a decline in contractility and inhibition of autophagic flux.

Analyzing contractile force, the most important and best understood function of cardiomyocytes in vivo is not established in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM). This study describes the generation of 3D, strip-format, force-generating engineered heart tissues (EHT) from hiPSC-CM and their physiological and pharmacological properties. CM were differentiated from hiPSC by a growth factor-based three-stage protocol. EHTs were generated and analyzed histologically and functionally. HiPSC-CM in EHTs showed well-developed sarcomeric organization and alignment, and frequent mitochondria. Systematic contractility analysis (26 concentration-response curves) reveals that EHTs replicated canonical response to physiological and pharmacological regulators of inotropy, membrane-and calcium-clock mediators of pacemaking, modulators of ion-channel currents, and proarrhythmic compounds with unprecedented precision. The analysis demonstrates a high degree of similarity between hiPSC-CM in EHT format and native human heart tissue, indicating that human EHTs are useful for preclinical drug testing and disease modeling.

Introduction Left ventricular dysfunction is a frequent and potentially severe side effect of many tyrosine kinase inhibitors (TKI). The mode of toxicity is not identified, but may include impairment of mitochondrial or sarcomeric function, autophagy or angiogenesis, either as an on-target or off-target mechanism. Methods and Results We studied concentration-response curves and time courses for nine TKIs in three-dimensional, force generating engineered heart tissue (EHT) from neonatal rat heart cells. We detected a concentration-and time-dependent decline in contractile force for gefitinib, lapatinib, sunitinib, imatinib, sorafenib, vandetanib and lestaurtinib and no decline in contractile force for erlotinib and dasatinib after 96 hours of incubation. The decline in contractile force was associated with an impairment of autophagy (LC3 Western blot) and appearance of autophagolysosomes (transmission electron microscopy). Conclusion This study demonstrates the feasibility to study TKI-mediated force effects in EHTs and identifies an association between a decline in contractility and inhibition of autophagic flux.

Analyzing contractile force, the most important and best understood function of cardiomyocytes in vivo is not established in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM). This study describes the generation of 3D, strip-format, force-generating engineered heart tissues (EHT) from hiPSC-CM and their physiological and pharmacological properties. CM were differentiated from hiPSC by a growth factor-based three-stage protocol. EHTs were generated and analyzed histologically and functionally. HiPSC-CM in EHTs showed well-developed sarcomeric organization and alignment, and frequent mitochondria. Systematic contractility analysis (26 concentration-response curves) reveals that EHTs replicated canonical response to physiological and pharmacological regulators of inotropy, membrane-and calcium-clock mediators of pacemaking, modulators of ion-channel currents, and proarrhythmic compounds with unprecedented precision. The analysis demonstrates a high degree of similarity between hiPSC-CM in EHT format and native human heart tissue, indicating that human EHTs are useful for preclinical drug testing and disease modeling.

UnlabelledDifferent tissue-engineering approaches have been developed to induce and promote cardiac regeneration; however, the impact of the immune system and its responses to the various scaffold components of the engineered grafts remains unclear. Fibrin-based engineered heart tissue (EHT) was generated from neonatal Lewis (Lew) rat heart cells and transplanted onto the left ventricular surface of three different rat strains: syngeneic Lew, allogeneic Brown Norway, and immunodeficient Rowett Nude rats. Interferon spot frequency assay results showed similar degrees of systemic immune activation in the syngeneic and allogeneic groups, whereas no systemic immune response was detectable in the immunodeficient group (p < .001 vs. syngeneic and allogeneic). Histological analysis revealed much higher local infiltration of CD3- and CD68-positive cells in syngeneic and allogeneic rats than in immunodeficient animals. Enzyme-linked immunospot and immunofluorescence experiments revealed matrix-directed TH1-based rejection in syngeneic recipients without collateral impairment of heart cell survival. Bioluminescence imaging was used for in vivo longitudinal monitoring of transplanted luciferase-positive EHT constructs. Survival was documented in syngeneic and immunodeficient recipients for a period of up to 110 days after transplant, whereas in the allogeneic setting, graft survival was limited to only 14 ± 1 days. EHT strategies using autologous cells are promising approaches for cardiac repair applications. Although fibrin-based scaffold components elicited an immune response in our studies, syngeneic cells carried in the EHT were relatively unaffected.SignificanceAn initial insight into immunological consequences after transplantation of engineered heart tissue was gained through this study. Most important, this study was able to demonstrate cell survival despite rejection of matrix components. Generation of syngeneic human engineered heart tissue, possibly using human i

Hypertrophic cardiomyopathy (HCM) is characterized by asymmetric left ventricular hypertrophy, diastolic dysfunction and myocardial disarray. HCM is caused by mutations in sarcomeric genes, but in 40 of patients, the mutation is not yet identified. We hypothesized that FHL1, encoding four-and-a-half-LIM domains 1, could be another disease gene since it has been shown to cause distinct myopathies, sometimes associated with cardiomyopathy. We evaluated 121 HCM patients, devoid of a mutation in known disease genes. We identified three novel variants in FHL1 (c.134delA/K45Sfs, c.459CA/C153X and c.827GC/C276S). Whereas the c.459CA variant was associated with muscle weakness in some patients, the c.134delA and c.827GC variants were associated with isolated HCM. Gene transfer of the latter variants in C2C12 myoblasts and cardiac myocytes revealed reduced levels of FHL1 mutant proteins, which could be rescued by proteasome inhibition. Contractility measurements after adeno-associated virus transduction in rat-engineered heart tissue (EHT) showed: (i) higher and lower forces of contraction with K45Sfs and C276S, respectively, and (ii) prolonged contraction and relaxation with both mutants. All mutants except one activated the fetal hypertrophic gene program in EHT. In conclusion, this study provides evidence for FHL1 to be a novel gene for isolated HCM. These data, together with previous findings of proteasome impairment in HCM, suggest that FHL1 mutant proteins may act as poison peptides, leading to hypertrophy, diastolic dysfunction and/or altered contractility, all features of HCM.

The reductions in mortality and morbidity being achieved among cancer patients with current therapies represent a major achievement. However, given their mechanisms of action, many anti-cancer agents may have significant potential for cardiovascular side effects, including the induction of heart failure. The magnitude of this problem remains unclear and is not readily apparent from current clinical trials of emerging targeted agents, which generally under-represent older patients and those with significant co-morbidities. The risk of adverse events may also increase when novel agents, which frequently modulate survival pathways, are used in combination with each other or with other conventional cytotoxic chemotherapeutics. The extent to which survival and growth pathways in the tumour cell (which we seek to inhibit) coincide with those in cardiovascular cells (which we seek to preserve) is an open question but one that will become ever more important with the development of new cancer therapies that target intracellular signalling pathways. It remains unclear whether potential cardiovascular problems can be predicted from analyses of such basic signalling mechanisms and what pre-clinical evaluation should be undertaken. The screening of patients, optimization of therapeutic schemes, monitoring of cardiovascular function during treatment, and the management of cardiovascular side effects are likely to become increasingly important in cancer patients. This paper summarizes the deliberations of a cross-disciplinary workshop organized by the Heart Failure Association of the European Society of Cardiology (held in Brussels in May 2009), which brought together clinicians working in cardiology and oncology and those involved in basic, translational, and pharmaceutical science.

The reductions in mortality and morbidity being achieved among cancer patients with current therapies represent a major achievement. However, given their mechanisms of action, many anti-cancer agents may have significant potential for cardiovascular side effects, including the induction of heart failure. The magnitude of this problem remains unclear and is not readily apparent from current clinical trials of emerging targeted agents, which generally under-represent older patients and those with significant co-morbidities. The risk of adverse events may also increase when novel agents, which frequently modulate survival pathways, are used in combination with each other or with other conventional cytotoxic chemotherapeutics. The extent to which survival and growth pathways in the tumour cell (which we seek to inhibit) coincide with those in cardiovascular cells (which we seek to preserve) is an open question but one that will become ever more important with the development of new cancer therapies that target intracellular signalling pathways. It remains unclear whether potential cardiovascular problems can be predicted from analyses of such basic signalling mechanisms and what pre-clinical evaluation should be undertaken. The screening of patients, optimization of therapeutic schemes, monitoring of cardiovascular function during treatment, and the management of cardiovascular side effects are likely to become increasingly important in cancer patients. This paper summarizes the deliberations of a cross-disciplinary workshop organized by the Heart Failure Association of the European Society of Cardiology (held in Brussels in May 2009), which brought together clinicians working in cardiology and oncology and those involved in basic, translational, and pharmaceutical science., Journal Article, Research Support, Non-U.S. Gov't, Review, FLWIN, SCOPUS: ar.j, info:eu-repo/semantics/published

The reductions in mortality and morbidity being achieved among cancer patients with current therapies represent a major achievement. However, given their mechanisms of action, many anti-cancer agents may have significant potential for cardiovascular side effects, including the induction of heart failure. The magnitude of this problem remains unclear and is not readily apparent from current clinical trials of emerging targeted agents, which generally under-represent older patients and those with significant co-morbidities. The risk of adverse events may also increase when novel agents, which frequently modulate survival pathways, are used in combination with each other or with other conventional cytotoxic chemotherapeutics. The extent to which survival and growth pathways in the tumour cell (which we seek to inhibit) coincide with those in cardiovascular cells (which we seek to preserve) is an open question but one that will become ever more important with the development of new cancer therapies that target intracellular signalling pathways. It remains unclear whether potential cardiovascular problems can be predicted from analyses of such basic signalling mechanisms and what pre-clinical evaluation should be undertaken. The screening of patients, optimization of therapeutic schemes, monitoring of cardiovascular function during treatment, and the management of cardiovascular side effects are likely to become increasingly important in cancer patients. This paper summarizes the deliberations of a cross-disciplinary workshop organized by the Heart Failure Association of the European Society of Cardiology (held in Brussels in May 2009), which brought together clinicians working in cardiology and oncology and those involved in basic, translational, and pharmaceutical science., Journal Article, Research Support, Non-U.S. Gov't, Review, FLWIN, SCOPUS: ar.j, info:eu-repo/semantics/published

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