Cirrhotic cardiomyopathy: review of pathophysiology and treatment

Cirrhotic cardiomyopathy is a cardiac condition observed in patients with cirrhotic regardless of the etiologies. It is characterized by the impaired systolic response to physical stress, diastolic dysfunction, and electrophysiological abnormalities, especially QT interval prolongation. Its pathophysiology and clinical significance has been a focus of various researchers for the past decades. The impairment of β-adrenergic receptor, the increase in endogenous cannabinoids, the presence of cardiosuppressants such as nitric oxide and inflammatory cytokines are the proposed mechanisms of systolic dysfunction. The activation of cardiac renin-angiotensin system and salt retention play the role in the development of cardiac hypertrophy and impaired diastolic function. QT interval prolongation, which is observed in 40–50 % of cirrhotic patients, occurs as a result of the derangement in membrane fluidity and ion channel defect. The increased recognition of this disease will prevent the complications of overt heart failure after procedures such as transjugular intrahepatic portosystemic shunt (TIPS) and liver transplantation. Better understandings of the pathogenesis and pathology of cirrhotic cardiomyopathy is crucial in developing more accurate diagnostic tools and specific treatments of this condition.     

Proteomic analysis of hemoglobin H-constant spring (Hb H-CS) erythroblasts

Hemoglobin H disease (Hb H) arises through the loss or dysfunction of three of the four alpha globin genes through the co-inheritance of either gross gene deletions or an abnormal hemoglobin which causes a non-deletional loss of α-globin expression. This study sought to investigate erythropoiesis in Hb H-Constant Spring (Hb H-CS) disease, a common form of Hb H disease in Southeast Asia, caused by the inheritance of the Constant Spring variant hemoglobin together with deletion of two of the alpha globin genes. In comparison to normal erythroblasts, Hb H-CS erythroblasts showed reduced cell expansion although no difference in differentiation was observed. Proteomic analysis revealed the increased expression of both chaperone and chaperonin proteins as well as down regulation of proteins regulating apoptosis. Both chaperone and chaperonin mediated folding require ATP, and evidence of increase energy demand was seen in the form of increased expression of enzymes involved in purine biosynthesis and increased levels of reactive oxygen species. A significant increase in apoptosis was seen in Hb H-CS erythroblasts, and the results from the proteomic analysis suggest that this arises at least in part from the consequences of increased folding requirements in the Hb H-CS erythroblast.     

Coinheritance of the different copy numbers of α-globin gene modifies severity of β-thalassemia/Hb E disease

β-Thalassemia/Hb E patients show a range of clinical severities, from nearly asymptomatic to transfusion-dependent thalassemia major. This study investigated the clinical heterogeneity and hematologic parameters obtained in the large cohort of 925 Thai β⁰-thalassemia/Hb E patients. Coinheritance of α-thalassemia with β⁰-thalassemia/Hb E produces a milder clinical phenotype in contrast to an interaction of α-globin gene triplication in severe thalassemia. The mean steady-state Hb was also higher, whereas the mean corpuscular volume and the percentage of Hb F were markedly lower in the former group. This finding demonstrates that the genetic combination leading to the more/less degree of α- to non-α-globin chains imbalance is indeed the cause of the severe/mild thalassemia phenotype.     

Modifiable Factors and Colon Cancer Risk in Thai Population

To demonstrate the possible impact of modifiable factors on colon cancer development in Thai population, we conducted this case-control study from June 2016 until June 2017. The study was conducted in 11 Thai provincial hospitals. The hospitals in this study were selected by stratification by regions. Patients included 504 ones who were newly diagnosed with colon cancer within 1 month. In the control group, 997 health individuals were enrolled. Both case and control were adjusted by age. The results of this study showed that age and socioeconomic factors were associated with colon cancer risk. In addition, it was found that family history of colon cancer had very high association with colon cancer risk. Behavioral factors, including smoking, inadequate physical exercise, and salty food consumption were associated with colon cancer. We detected no association between obesity, alcohol consumption, and colon cancer. The results suggested that colon cancer might have higher association with genetic factors than behavioral factors among Thai patients. Based on the results of this study, stop smoking and promote adequate physical activity are suggested to reduce the incidence of colon cancrr among Thai patients.     

Calibration of myocardial T2 and T1 against iron concentration

Background

The assessment of myocardial iron using T2* cardiovascular magnetic resonance (CMR) has been validated and calibrated, and is in clinical use. However, there is very limited data assessing the relaxation parameters T1 and T2 for measurement of human myocardial iron.

Methods

Twelve hearts were examined from transfusion-dependent patients: 11 with end-stage heart failure, either following death (n = 7) or cardiac transplantation (n = 4), and 1 heart from a patient who died from a stroke with no cardiac iron loading. Ex-vivo R1 and R2 measurements (R1 = 1/T1 and R2 = 1/T2) at 1.5 Tesla were compared with myocardial iron concentration measured using inductively coupled plasma atomic emission spectroscopy.

Results

From a single myocardial slice in formalin which was repeatedly examined, a modest decrease in T2 was observed with time, from mean (±SD) 23.7 ± 0.93 ms at baseline (13 days after death and formalin fixation) to 18.5 ± 1.41 ms at day 566 (p < 0.001). Raw T2 values were therefore adjusted to correct for this fall over time. Myocardial R2 was correlated with iron concentration [Fe] (R² 0.566, p < 0.001), but the correlation was stronger between LnR2 and Ln[Fe] (R² 0.790, p < 0.001). The relation was [Fe] = 5081•(T2)^-2.22 between T2 (ms) and myocardial iron (mg/g dry weight). Analysis of T1 proved challenging with a dichotomous distribution of T1, with very short T1 (mean 72.3 ± 25.8 ms) that was independent of iron concentration in all hearts stored in formalin for greater than 12 months. In the remaining hearts stored for <10 weeks prior to scanning, LnR1 and iron concentration were correlated but with marked scatter (R² 0.517, p < 0.001). A linear relationship was present between T1 and T2 in the hearts stored for a short period (R² 0.657, p < 0.001).

Conclusion

Myocardial T2 correlates well with myocardial iron concentration, which raises the possibility that T2 may provide additive information to T2* for patients with myocardial siderosis. However, ex-vivo T1 measurements are less reliable due to the severe chemical effects of formalin on T1 shortening, and therefore T1 calibration may only be practical from in-vivo human studies.     

Enhanced activation of autophagy in β-thalassemia/Hb E erythroblasts during erythropoiesis

Erythropoiesis in β-thalassemia patients is ineffective, primarily because of death of the erythroid progenitor cells at the polychromatic normoblast stage. While it is known that autophagy plays a critical role during erythropoiesis by removing organelles from erythroid cells during terminal differentiation, its role in erythroid cells whose function is impaired remains to be explored. To investigate this, CD34+ erythroid progenitor cells from normal controls and β-thalassemia/Hb E patients were isolated from peripheral blood and cultured under conditions driving differentiation into an erythroid lineage, and levels of autophagy and apoptosis were analyzed both directly and after biochemical manipulation with l-asparagine. A significantly higher level of autophagy was seen in β-thalassemia/Hb E erythroblasts as compared to normal control erythroblasts during erythropoiesis. Interestingly, this activation was mediated in part by the presence of high levels of Ca²⁺ as modulation of Ca²⁺ levels significantly reduced the level of autophagy in these cells. Inhibition of autophagic flux in normal erythroblasts significantly increased apoptosis in normal erythroblasts, but not in thalassemic erythroblasts, although sensitivity to autophagic flux inhibition was restored by reduction of Ca²⁺ levels. These results suggest that high levels of autophagy in β-thalassemia/HbE erythroblasts may contribute to the increased levels of apoptosis that lead to ineffective erythropoiesis in β-thalassemia/Hb E erythroblasts.     

Ethanol metabolism by HeLa cells transduced with human alcohol dehydrogenase isoenzymes: control of the pathway by acetaldehyde concentration

Background: Human class I alcohol dehydrogenase 2 isoenzymes (encoded by the ADH1B locus) have large differences in kinetic properties; however, individuals inheriting the alleles for the different isoenzymes exhibit only small differences in alcohol elimination rates. This suggests that other cellular factors must regulate the activity of the isoenzymes. Methods: The activity of the isoenzymes expressed from ADH1B*1, ADH1B*2, and ADH1B*3 cDNAs was examined in stably transduced HeLa cell lines, including lines which expressed human low K_m aldehyde dehydrogenase (ALDH2). The ability of the cells to metabolize ethanol was compared with that of HeLa cells expressing rat class I alcohol dehydrogenase (ADH) (HeLa‐rat ADH cells), rat hepatoma (H4IIEC3) cells, and rat hepatocytes. Results: The isoenzymes had similar protein half‐lives in the HeLa cells. Rat hepatocytes, H4IIEC3 cells, and HeLa‐rat ADH cells oxidized ethanol much faster than the cells expressing the ADH1B isoenzymes. This was not explained by high cellular NADH levels or endogenous inhibitors; but rather because the activity of the β1 and β2 ADHs was constrained by the accumulation of acetaldehyde, as shown by the increased rate of ethanol oxidation by cell lines expressing β2 ADH plus ALDH2. Conclusion: The activity of the human β2 ADH isoenzyme is sensitive to inhibition by acetaldehyde, which likely limits its activity in vivo. This study emphasizes the importance of maintaining a low steady‐state acetaldehyde concentration in hepatocytes during ethanol metabolism.     

Increased oxidative metabolism is associated with erythroid precursor expansion in β0-thalassaemia/Hb E disease

Erythropoiesis in β0-thalassaemia/Hb E patients, the most common variant form of β-thalassaemia in Southeast Asia, is characterized by accelerated differentiation and over-expansion of erythroid precursor cells. The mechanism driving this accelerated expansion and differentiation remain unknown. To address this issue a proteomic analysis was undertaken to firstly identify proteins differentially expressed during erythroblast differentiation and a second analysis was undertaken to identify proteins differentially expressed between β0-thalassaemia/Hb E erythroblasts and control erythroblasts. The majority of proteins identified as being differentially expressed between β0-thalassaemia/Hb E and control erythroblasts were constituents of the glycolysis/TCA pathway and levels of oxidative stress correlated with the degree of erythroid expansion. A model was constructed linking these observations with previous studies showing increased phosphorylation of ERK1/2 in thalassemic erythroblasts which predicted the increased activation of PKA, PKB and PKC which Western analysis confirmed. Inhibition of PKA or PKC reduced β0-thalassaemia/Hb E erythroblast differentiation and/or expansion. We propose that increased expansion and differentiation of β0-thalassaemia/Hb E erythroblasts occur as a result of feedback loops acting through increased oxidative metabolism.     

Comparison of Pharmacokinetics and Urinary Iron Excretion of Two Single Doses of Deferiprone in β-Thalassemia/Hemoglobin E Patients

Dose-related pharmacokinetics and urinary iron excretion (UIE) of an orally active iron chelator, deferiprone (L1), was investigated in 12 severe β-thalassemia/hemoglobin E patients. The patients received two single doses of 25 and 50 mg/kg with a 2-week washout period. Deferiprone was rapidly absorbed and reached maximum concentration (C(max)) within 1 h after administration. Pharmacokinetic parameters including C(max) and area under concentration time curve from time zero to infinity (AUC(0-∞)) as well as urinary excretion of non-conjugated and glucuronide-conjugated deferiprone (L1 and L1-G) increased proportionally with the dose of deferiprone. A constant ratio of AUC(0-∞) of L1-G to L1 and a percentage of urinary excretion of L1-G indicated that increasing the dosage does not influence deferiprone biotransformation. Longer terminal elimination half-lifeand higher volume of distribution of L1 were observed with the high dose and correlated with deferiprone-chelated iron in serum. Unexpectedly, UIE did not show a linear relationship with the increased dose of deferiprone. The correlation between UIE and creatinine clearance suggested the possibility of L1-iron complex redistribution in patients with renal impairment treated with high-dose deferiprone.