Non-interventional follow-up versus fluid bolus in RESPONSE to oliguria in hemodynamically stable critically ill patients : a randomized controlled pilot trial

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Varied Responses to a High m.3243A>G Mutation Load and Respiratory Chain Dysfunction in Patient-Derived Cardiomyocytes

The m.3243A>G mutation in mitochondrial tRNA-Leu(UUR) is one of the most common pathogenic mitochondrial DNA mutations in humans. The clinical manifestations are highly heterogenous and the causes for the drastic clinical variability are unknown. Approximately one third of patients suffer from cardiac disease, which often increases mortality. Why only some patients develop cardiomyopathy is unknown. Here, we studied the molecular effects of a high m.3243A>G mutation load on cardiomyocyte functionality, using cells derived from induced pluripotent stem cells (iPSC-CM) of two different m.3243A>G patients, only one of them suffering from severe cardiomyopathy. While high mutation load impaired mitochondrial respiration in both patients’ iPSC-CMs, the downstream consequences varied. mtDNA mutant cells from a patient with no clinical heart disease showed increased glucose metabolism and retained cellular ATP levels, whereas cells from the cardiac disease patient showed reduced ATP levels. In this patient, the mutations also affected intracellular calcium signaling, while this was not true in the other patient’s cells. Our results reflect the clinical variability in mitochondrial disease patients and show that iPSC-CMs retain tissue specific features seen in patients

Varied Responses to a High m.3243A>G Mutation Load and Respiratory Chain Dysfunction in Patient-Derived Cardiomyocytes

The m.3243A>G mutation in mitochondrial tRNA-Leu(UUR) is one of the most common pathogenic mitochondrial DNA mutations in humans. The clinical manifestations are highly heterogenous and the causes for the drastic clinical variability are unknown. Approximately one third of patients suffer from cardiac disease, which often increases mortality. Why only some patients develop cardiomyopathy is unknown. Here, we studied the molecular effects of a high m.3243A>G mutation load on cardiomyocyte functionality, using cells derived from induced pluripotent stem cells (iPSC-CM) of two different m.3243A>G patients, only one of them suffering from severe cardiomyopathy. While high mutation load impaired mitochondrial respiration in both patients’ iPSC-CMs, the downstream consequences varied. mtDNA mutant cells from a patient with no clinical heart disease showed increased glucose metabolism and retained cellular ATP levels, whereas cells from the cardiac disease patient showed reduced ATP levels. In this patient, the mutations also affected intracellular calcium signaling, while this was not true in the other patient’s cells. Our results reflect the clinical variability in mitochondrial disease patients and show that iPSC-CMs retain tissue specific features seen in patients

Peak flow measurements in patients with severe aortic stenosis : a prospective comparative study between cardiovascular magnetic resonance 2D and 4D flow and transthoracic echocardiography

Background Aortic valve stenosis (AS) is the most prevalent valvular disease in the developed countries. Four-dimensional (4D) flow cardiovascular magnetic resonance (CMR) is an emerging imaging technique, which has been suggested to improve the evaluation of AS severity compared to two-dimensional (2D) flow and transthoracic echocardiography (TTE). We investigated the reliability of CMR 2D flow and 4D flow techniques in measuring aortic transvalvular peak systolic flow in patients with severe AS. Methods We prospectively recruited 90 patients referred for aortic valve replacement due to severe AS (73.3 +/- 11.3 years, aortic valve area 0.7 +/- 0.1 cm(2), and 54/36 tricuspid/bicuspid), and 10 non-valvular disease controls. All the patients underwent echocardiography and 2D flow and 4D flow CMR. Peak flow velocity measurements were compared using Wilcoxon signed rank sum test and Bland-Altman analysis. Results 4D flow underestimated peak flow velocity in the AS group when compared with TTE (bias - 1.1 m/s, limits of agreement +/- 1.4 m/s) and 2D flow (bias - 1.2 m/s, limits of agreement +/- 1.6 m/s). The differences between values obtained by TTE (median 4.3 m/s, range 2.7-6.1 m/s) and 2D flow (median 4.5 m/s, range 2.9-6.5 m/s) compared to 4D flow (median 3.1 m/s, range 1.7-5.1 m/s) were significant (p < 0.001). The difference between 2D flow and TTE were insignificant (bias 0.07 m/s, limits of agreement +/- 1.5 m/s). In non-valvular disease controls, peak flow velocity was measured higher by 4D flow than 2D flow (1.4 m/s, 1.1-1.7 m/s and 1.3 m/s, 1.1-1.5 m/s, respectively; bias 0.2 m/s, limits of agreement +/- 0.16 m/s). Conclusions CMR 4D flow significantly underestimates systolic peak flow velocity in patients with severe AS. 2D flow, in turn, estimated the AS velocity accurately, with measured peak flow velocities comparable to TTE.Peer reviewe

Noninterventional follow-up vs fluid bolus in RESPONSE to oliguria-The RESPONSE trial protocol and statistical analysis plan

Background Oliguria is a frequent trigger for administering a fluid bolus, but the effect of fluid bolus in improving urine output is inadequately demonstrated. Here, we summarize the protocol and detailed statistical analysis plan of the randomized, controlled RESPONSE trial comparing follow-up as the experimental group and a 500 mL crystalloid fluid bolus as the control group for oliguria in critically ill oliguric patients. Methods Our trial is an investigator-initiated, randomized, controlled, pilot trial conducted in three ICUs in two centers. We aim to randomize 1:1 altogether 130 hemodynamically stable oliguric patients either to a 2-hour follow-up without interventions or to receive a crystalloid bolus of 500 mL over 30 minutes. The primary outcome is the change in individual urine output during the 2-hour period compared to 2 hours preceding randomization. Doubling of the urine output is considered clinically significant. Additionally, we record the duration of oliguria, physiological and biochemical variables, adverse events, and the incidences of acute kidney injury and renal replacement therapy. Conclusions Oliguria is a frequent trigger for potentially harmful fluid loading. Therefore, the RESPONSE trial will give information of the potential effect of fluid bolus on oliguria in critically ill patients. Trial registration clinical.trials.gov, NCT02860572.Peer reviewe

Discovery of Triterpenoids as Reversible Inhibitors of α/β hydrolase Domain Containing 12 (ABHD12)

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Varied Responses to a High m.3243A&gt;G Mutation Load and Respiratory Chain Dysfunction in Patient-Derived Cardiomyocytes

The m.3243A&gt;G mutation in mitochondrial tRNA-Leu(UUR) is one of the most common pathogenic mitochondrial DNA mutations in humans. The clinical manifestations are highly heterogenous and the causes for the drastic clinical variability are unknown. Approximately one third of patients suffer from cardiac disease, which often increases mortality. Why only some patients develop cardiomyopathy is unknown. Here, we studied the molecular effects of a high m.3243A&gt;G mutation load on cardiomyocyte functionality, using cells derived from induced pluripotent stem cells (iPSC-CM) of two different m.3243A&gt;G patients, only one of them suffering from severe cardiomyopathy. While high mutation load impaired mitochondrial respiration in both patients&rsquo; iPSC-CMs, the downstream consequences varied. mtDNA mutant cells from a patient with no clinical heart disease showed increased glucose metabolism and retained cellular ATP levels, whereas cells from the cardiac disease patient showed reduced ATP levels. In this patient, the mutations also affected intracellular calcium signaling, while this was not true in the other patient&rsquo;s cells. Our results reflect the clinical variability in mitochondrial disease patients and show that iPSC-CMs retain tissue specific features seen in patients

Cardiac magnetic resonance -detected myocardial injury is not associated with long-term symptoms in patients hospitalized due to COVID-19

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DSP c.6310delA p.(Thr2104Glnfs*12) associates with arrhythmogenic cardiomyopathy, increased trabeculation, curly hair, and palmoplantar keratoderma

BackgroundPathogenic variants in DSP associate with cardiac and cutaneous manifestations including arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy, curly or wavy hair, and palmoplantar keratoderma (PPK). Episodes of myocardial inflammation associated with DSP cardiomyopathy might be confused in clinical work with myocarditis of other etiologies such as viral. Cardiac magnetic resonance imaging (CMR) may help in differential diagnosis.Methods and resultsThis study comprised 49 Finnish patients: 34 participants from families with suspected DSP cardiomyopathy (9 index patients and 25 family members) and 15 patients with myocarditis. All 34 participants underwent genetic testing and cardiac evaluation, and 29 of them also underwent CMR. Participants with the DSP variant, numbering 22, were dermatologically examined. The 15 patients with myocarditis underwent CMR and were evaluated during their hospitalization.A heterozygous truncating DSP c.6310delA p.(Thr2104Glnfs*12) variant was confirmed in 29 participants. Only participants with the DSP variant had pacemakers and life-threatening ventricular arrhythmias. Of the participants with the DSP variant, 24% fulfilled cardiomyopathy criteria, and the median age at diagnosis was 53. Upon CMR, myocardial edema was found to be more common in patients with myocarditis. Both groups had a substantial percentage of late gadolinium enhancement (LGE). A ring-like LGE and increased trabeculation were observed only in participants with the DSP variant. All the studied participants with the DSP variant had PPK and curly or wavy hair. Hyperkeratosis developed before the age of 20 in most patients.ConclusionsThe DSP c.6310delA p.(Thr2104Glnfs*12) variant associates with curly hair, PPK, and arrhythmogenic cardiomyopathy with increased trabeculation. Cutaneous symptoms developing in childhood and adolescence might help recognize these patients at an earlier stage. CMR, together with dermatologic characteristics, may help in diagnosis.Peer reviewe