NBS1 lactylation is required for efficient DNA repair and chemotherapy resistance.

The Warburg effect is a hallmark of cancer that refers to the preference of cancer cells to metabolize glucose anaerobically rather than aerobically1,2. This results in substantial accumulation of lacate, the end product of anaerobic glycolysis, in cancer cells3. However, how cancer metabolism affects chemotherapy response and DNA repair in general remains incompletely understood. Here we report that lactate-driven lactylation of NBS1 promotes homologous recombination (HR)-mediated DNA repair. Lactylation of NBS1 at lysine 388 (K388) is essential for MRE11-RAD50-NBS1 (MRN) complex formation and the accumulation of HR repair proteins at the sites of DNA double-strand breaks. Furthermore, we identify TIP60 as the NBS1 lysine lactyltransferase and the 'writer' of NBS1 K388 lactylation, and HDAC3 as the NBS1 de-lactylase. High levels of NBS1 K388 lactylation predict poor patient outcome of neoadjuvant chemotherapy, and lactate reduction using either genetic depletion of lactate dehydrogenase A (LDHA) or stiripentol, a lactate dehydrogenase A inhibitor used clinically for anti-epileptic treatment, inhibited NBS1 K388 lactylation, decreased DNA repair efficacy and overcame resistance to chemotherapy. In summary, our work identifies NBS1 lactylation as a critical mechanism for genome stability that contributes to chemotherapy resistance and identifies inhibition of lactate production as a promising therapeutic cancer strategy.

Individualized prevention of proton pump inhibitor related adverse events by risk stratification.

Proton pump inhibitors (PPIs) are commonly used for gastric acid-related disorders, but their safety profile and risk stratification for high-burden diseases need further investigation. Analyzing over 2 million participants from five prospective cohorts from the US, the UK, and China, we found that PPI use correlated with increased risk of 15 leading global diseases, such as ischemic heart disease, diabetes, respiratory infections, and chronic kidney disease. These associations showed dose-response relationships and consistency across different PPI types. PPI-related absolute risks increased with baseline risks, with approximately 82% of cases occurring in those at the upper 40% of the baseline predicted risk, and only 11.5% of cases occurring in individuals at the lower 50% of the baseline risk. While statistical association does not necessarily imply causation, its potential safety concerns suggest that personalized use of PPIs through risk stratification might guide appropriate decision-making for patients, clinicians, and the public.

Co-designing a culturally-sensitive theory-driven advance care planning game with Chinese older adults and healthcare providers.

BACKGROUND: Advance care planning can be challenging because discussing end-of-life care often has negative connotations. Gamification is a novel approach to encourage advance care planning conversations in Western culture. AIM: To co-design a game with multiple stakeholders to promote advance care planning in Chinese communities. DESIGN: A two-phase design guided by the Medical Research Council framework for developing complex interventions was adopted between May 2019 and August 2020. In phase I, a game prototype was developed based on literature review, expert consultation and end-user consultation. In Phase II, the game prototype was tested among end-users and refined according to their feedback and expertise of a multi-disciplinary team through an iterative process. SETTING/PARTICIPANTS: Experts in the field of aged care, palliative care, life education and game development and Chinese community-dwelling adults aged 60 years or older. RESULTS: A board game called 'The Five Tastes Found in a Grocery Store' was developed. The game design was shaped by Bandura's Self-efficacy theory and feedback from experts and end-users. The participants generally found the gaming experience enjoyable and appreciated the opportunity to discuss end-of-life care openly. CONCLUSIONS: This study is the first to develop an evidence-informed, theory-based, culturally sensitive game for promoting advance care planning in the Chinese community using a co-design approach.

A serious game for engaging older adults in end-of-life care discussion: A mixed method study.

OBJECTIVE: To examine the acceptability of a board game newly developed through a co-design process for promoting end-of-life care discussion among Chinese older adults. METHODS: A multi-centre mixed method study, including a one group pre-test post-test study and focus group interviews, was conducted. Thirty older adults participated in a one-hour game session in a small group format. Acceptability was assessed by attrition rate and satisfaction with the game. Participants' experiences with the game were explored qualitatively. Within-subject changes in self-efficacy and readiness for advance care planning (ACP) behaviours were also examined. RESULTS: The players generally had positive experiences with the game, giving a low attrition rate. A significantly higher level of self-efficacy in sharing end-of-life care preferences with surrogates was reported after the game session (p = 0.008). There was a slight increase in the proportion of players indicated that they would complete ACP behaviours in the coming months immediately after the intervention. CONCLUSION: A serious game is acceptable by Chinese older adults to raise discussions regarding end-of-life matters. PRACTICE IMPLICATIONS: A game can be an ice-breaking tool to increase self-efficacy towards communicating end-of-life care preferences with surrogates, but follow-up support is needed to facilitate the uptake of ACP behaviours.

Corrigendum: Age-specific reference values for low psoas muscle index at the L3 vertebra level in healthy populations: A multicenter study.

[This corrects the article DOI: 10.3389/fnut.2022.1033831.].

Assessing Visceral Obesity and Abdominal Adipose Tissue Distribution in Healthy Populations Based on Computed Tomography: A Large Multicenter Cross-Sectional Study.

Objective: Abdominal adipose is closely related to many endocrine and metabolic diseases. The aim of this study was to analyze the distribution of abdominal adipose tissue in a healthy population in northern China determined by abdominal computed tomography (CT). Methods: Data for this study were obtained from a multicenter, retrospective, cross-sectional study that collected abdominal CT scans of 1787 healthy individuals from 4 representative cities in northern China. Areas of visceral adipose tissue (VATA) and subcutaneous adipose tissue (SATA) were obtained by measuring CT images at the level of the 3rd lumbar vertebra. Visceral adipose tissue index (VATI) and subcutaneous adipose index (SATI) were obtained by normalizing the square of height to analyze the distribution of the above indexes and visceral obesity among different body mass index (BMI), gender and age. Results: The mean age of this healthy population was 45.3 ± 15.2 years and the mean BMI was 23.5 ± 3.2 kg/m2, with 902 men and 885 women. Compared with women, men had a significantly higher median VATA (120.9 vs. 67.2 cm2), VATI (39.1 vs. 25.6 cm2/m2) and a significantly higher percentage of visceral adiposity (VATA ≥ 100 cm2) (60.8 vs. 30.4%), while women had significantly higher SATA (116.9 vs. 146.7 cm2) and SATI (38.8 vs. 55.8 cm2/m2) than men. Whether men or women, VATI was positively correlated with age. Interestingly, SATI was weakly positively correlated with age in women, while SATI was weakly negatively correlated with age in men. In persons with a normal BMI, the proportion of visceral adiposity increases with age, whereas in men with a normal BMI, the proportion of visceral adiposity decreases after the age of 60 years but remains >50%. Conclusions: The distribution of abdominal visceral and subcutaneous adipose tissue parameters measured by CT differed among gender, age, and BMI. Even men and women with normal BMI have a high proportion of visceral obesity.

Defining reference values for low skeletal muscle index at the L3 vertebra level based on computed tomography in healthy adults: A multicentre study.

BACKGROUND & AIMS: Skeletal muscle mass loss is an important aspect of malnutrition and is closely related to adverse clinical outcomes. Computed tomography (CT) is the gold standard for analysing muscle mass, and the skeletal muscle index at the third lumbar vertebra (L3-SMI), measured using CT, is an important indicator to evaluate total skeletal tissue. The aims of this study were to establish reference values for low L3-SMI in Northern China, and to investigate the correlation between L3-SMI and age, and the correlation between L3-SMI and body mass index (BMI). METHODS: This was a multicentre, retrospective, cross-sectional study. A search of abdominal CT imaging reports, using specific keywords, was conducted in four representative cities in northern China, from January 2016 to March 2021. Transverse CT images at the level of the third lumbar vertebra (L3) were identified, exported from the Radiology Information System, and measured using the analysis software SliceOmatic. Statistical analyses were performed using SPSS 24.0, and significance level was set at p < 0.05. Mean, standard deviations (SD) and percentiles (p5, p10, p25, p50, p75, p90, p95) were used to describe the distribution of L3-SMI in the study population. Low skeletal muscle index was defined as a 5% percentile, or two standard deviations below the mean value of younger healthy individuals (age 20-39 years). RESULTS: The study included 1787 healthy individuals, with a median age of 45 (25) years (range 20-88 years), and a median BMI of 23.1 (4.1) kg/m2 (range 18.5-38.7 kg/m2). Among them, 700 healthy individuals (39.1%) were aged 20-39 years. L3-SMI had a negative linear correlation with age, and a positive linear correlation with BMI. The L3-SMI reference values used to define low skeletal muscle mass loss in the Northern Chinese population, using the 5% percentile, were 40.2 cm2/m2 in men, and 31.6 cm2/m2 in women. Using the mean minus two standard deviations protocol, the reference values were 37.9 cm2/m2 and 28.6 cm2/m2 in men and women, respectively. CONCLUSIONS: This study analysed the human body composition of 1787 healthy people in four cities in northern China, using CT, and established diagnostic thresholds of skeletal muscle mass depletion based on 700 younger healthy adults, using the 5% percentile and mean-2SD methods. These reference values can be used to diagnose malnutrition in patients and may aide clinicians in predicting prognosis and improving nutritional therapy. Further research is warranted to determine the prognostic role of reference values against clinical outcomes in different disease populations.

Age-specific reference values for low psoas muscle index at the L3 vertebra level in healthy populations: A multicenter study.

Background and aims: The progressive and generalized loss of skeletal muscle mass, strength and physical function is defined as sarcopenia. Sarcopenia is closely related to the prognosis of patients. Accurate diagnosis and adequate management of sarcopenia are crucial. The psoas muscle mass index taken at the third lumbar vertebra (L3-PMI, cm2/m2) is one of the established methods for evaluating skeletal muscle mass. However, the cutoff values of L3-PMI for diagnosis of sarcopenia are not yet to be clarified in Asian populations. We attempted to establish reference values for low L3-PMI that would be suitable for defining sarcopenia in the Northern Chinese population. Methods: This was a retrospective, multicenter cross-sectional study. A search of abdominal CT imaging reports was conducted in four representative cities in northern China. Transverse CT images were measured using the analysis software Slice-O-Matic. Low psoas muscle index was defined as the 5th percentile or mean-2SD of the study group. Results: 1,787 healthy individuals in the study were grouped by age. The sex and number of people in each group were similar. L3-PMI had a negative linear correlation with age, and a strong correlation with the skeletal muscle index taken at the third lumbar vertebrae (L3-SMI, cm2/m2). The L3-PMI reference values in males were 5.41 cm2/m2 for 20-29 years, 4.71 cm2/m2 for 30-39 years, 4.65 cm2/m2 for 40-49 years, 4.10 cm2/m2 for 50-59 years and 3.68 cm2/m2 for over 60 years by using 5th percentile threshold. Similarly, the reference values in females were 3.32, 3.40, 3.18, 2.91, and 2.62 cm2/m2. When using mean-2SD as the reference, the values for each age group were 4.57, 4.16, 4.03, 3.37, and 2.87 cm2/m2 for males and 2.79, 2.70, 2.50, 2.30, and 2.26 cm2/m2 for females, respectively. Conclusion: We defined the reference values of age-specific low skeletal muscle mass when simply evaluated by L3-PMI. Further studies about the association of sarcopenia using these reference values with certain clinical outcomes or diseases are needed.

Metabolic syndrome and its component traits present gender-specific association with liver cancer risk: a prospective cohort study.

BACKGROUND & AIMS: Little is known on the gender-specific effect and potential role of non-linear associations between metabolic syndrome (MetS) components and liver cancer risk. We evaluated these associations based on the UK Biobank cohort. METHODS: We included 474,929 individuals without previous cancer based on the UK Biobank cohort. Gender-specific hazard ratios (HRs) and 95% confidence interval (CIs) were calculated by Cox proportional hazards regression, adjusting for potential confounders. Non-linear associations for individual MetS components were assessed by the restricted cubic spline method. RESULTS: Over a median follow-up of 6.6 years, we observed 276 cases of liver cancer (175 men, 101 women). MetS [HR 1.48, 95% CI 1.27-1.72] and central obesity [HR 1.65, 95% CI 1.18-2.31] were associated with higher risk of liver cancer in men but not in women. Participants with hyperglycaemia has higher risk of liver cancer. High waist circumference and blood glucose were dose-dependently associated with increased liver cancer risk in both genders. For high density lipoprotein (HDL) cholesterol (both genders) and blood pressure (women), U-shaped associations were observed. Low HDL cholesterol (< 1.35 mmol/L) in men and high HDL cholesterol in women (> 1.52 mmol/L) were associated with increased liver cancer risk. CONCLUSIONS: MetS components showed gender-specific linear or U- shaped associations with the risk of liver cancer. Our study might provide evidence for individualized management of MetS for preventing liver cancer.

Association of body composition with risk of overall and site-specific cancers: A population-based prospective cohort study.

Although excess adiposity has been linked with various cancers, association between body composition and some cancers remains unclear, like lung and prostate cancers. We investigated associations of body composition with risk of overall cancer and major site-specific cancers in a prospective cohort of 454 079 cancer-free participants from UK-Biobank. Body composition was measured with bioimpedance analysis. We evaluated hazard ratio (HR) and 95% confidence interval (CI) with multivariate Cox linear and nonlinear models in men and women separately. We identified 27 794 cancers over 7.6 years of follow-up. Multivariable adjusted models including fat-free mass (FFM) and fat mass (FM) showed that FFM was positively associated with overall cancer risk in men and women (HR 1.03, 95% CI 1.01-1.04 and 1.07, 1.04-1.10, respectively); while the association between FM and overall cancer disappeared after adjusting for FFM. FFM was associated with higher risks of obesity-related cancers combined, stomach (women only), malignant melanoma, postmenopausal breast, corpus uteri, prostate, kidney (men only), and blood cancers and lower risk of lung cancer. FM was associated with higher risks of obesity-related cancers combined, esophageal, colon, lung (men only), postmenopausal breast (at the lower end of FM range), and corpus uteri cancers and lower risks of rectal, malignant melanoma (women only), prostate and blood cancers. FFM and FM seemed to have different effects on cancer risk, and the effects varied substantially by cancer type, in both direction and size. Higher FM/FFM ratio was also associated with some cancers risk, and might be a useful predictor of cancer risk.

Body composition and risk of gastric cancer: A population-based prospective cohort study.

The recognition of adiposity as a risk factor for gastric cancer is mainly based on traditional anthropometric indices, such as body mass index, which are unable to discriminate between lean and fat mass. We undertook this study to examine body composition and subsequent risk of gastric cancer. This is a prospective analysis of participants free of cancer from the UK Biobank. We measured baseline body composition with electrical bioimpedance analysis and confirmed cancer diagnosis through linkage to cancer and death registries. We evaluated hazard ratios (HRs) and confidence interval (CIs) with COX models adjusting for potential confounders. We documented 326 cases of cancer from 474,929 participants over a median follow-up of 6.6 years. Both male (HR 1.70, 95% CI 1.01 to 2.89) and female participants (HR 2.47, 95% CI 1.15 to 5.32) in the highest quartile of whole body fat-free mass were associated with increased risk of gastric cancer as compared with those in the lowest quartile.Whole body fat mass was associated with a decreased risk of gastric cancer (HR per 5-unit increase 0.86, 95% CI 0.74 to 0.99) in females, but not in males. We concluded that fat-free mass and fat mass may have different effects on gastric cancer risk. This study provided evidence for individualized weight management for the prevention of gastric cancer.

DNA damage contributes to transcriptional and immunological dysregulation of testicular cells during Chlamydia infection.

Chlamydia is the most commonly reported sexually transmitted bacterial infection, with 127 million notifications worldwide each year. Both males and females are susceptible to the pathological impacts on fertility that Chlamydia infections can induce. However, male chlamydial infections, particularly within the upper reproductive tract, including the testis, are not well characterized. In this study, using mouse testicular cell lines, we examined the impact of infection on testicular cell lineage transcriptomes and potential mechanisms for this impact. The somatic cell lineages exhibited significantly fragmented genomes during infection. Likely resulting from this, each of the Leydig, Sertoli and germ cell lineages experienced extensive transcriptional dysregulation, leading to significant changes in cellular biological pathways, including interferon and germ-Sertoli cell signalling. The cell lineages, as well as isolated spermatozoa from infected mice, also contained globally hypomethylated DNA. Cumulatively, the DNA damage and epigenetic-mediated transcriptional dysregulation observed within testicular cells during chlamydial infection could result in the production of spermatozoa with abnormal epigenomes, resulting in previously observed subfertility in infected animals and congenital defects in their offspring.

An overview of exposure to ethanol-containing substances and ethanol intoxication in children based on three illustrated cases.

Alcohol addiction and intoxication are major health problems worldwide. Acute alcohol intoxication is well reported in adults and adolescents but less frequently reported in children of younger ages. We report three anonymized cases of pediatric ethanol exposure and illustrate the different mechanisms of intoxication. In all cases, a focused history is the key to prompt diagnosis and timely management. Physicians should be aware of this potential poison in children presented with acute confusional or encephalopathic state. In contrast, neonates with ethanol intoxication may present with nonspecific gastrointestinal symptomatology. Urgent exclusion of sepsis, electrolyte imbalance, drug intoxication, and surgical abdominal condition is critical. Using these illustrated cases, we performed a narrative literature review on issues of exposure to ethanol-containing substances and ethanol intoxication in children. In conclusion, a high level of suspicion and interrogation on ethanol or substance use are essential particularly in the lactating mother for an accurate and timely diagnosis of ethanol intoxication to be made.

Pathological Roles of Interleukin-22 in the Development of Recurrent Hepatitis C after Liver Transplantation.

OBJECTIVE: The aim of this study was to longitudinally evaluate and analyze the role of interleukin-22-producing CD4 positive cells (IL-22) in the pathogenesis of Hepatitis C Virus recurrence after Orthotopic Liver Transplantation (HCV-OLT). METHODS: 15 HCV-OLT, 15 age- and gender- matched non-HCV post-OLT (OLT) and 15 hepatitis C virus infected (HCV) patients were enrolled into our study from the liver transplantation and research center at Beijing 302 Hospital. We determined the frequencies of IL-22 using flow cytometry and expression of IL-22 mRNA using PCR in peripheral blood and liver tissue. We also divided HCV-OLT patients into rapid fibrosis progression (RFP) and slow fibrosis progression (SFP), examined IL-22 cells and analyzed the correlations between IL-22 frequencies and liver injury, fibrosis and clinical parameters. Moreover, we investigated the role of IL-22 in Human Hepatic Stellate Cells (HSCs). RESULTS: The levels of serum IL-22, frequencies of IL-22 producing cells in peripheral blood mononuclear cells, and expression of IL-22 mRNA and protein in the liver in the HCV-OLT group were significantly higher than that in the HCV and OLT groups. Furthermore, eight (53.3%) patients developed RFP after two years; another three patients were diagnosed liver cirrhosis. The frequencies of IL-22 were much higher in RFP compared with SFP, while no significant difference existed between OLT and SFP. Intrahepatic IL-22 positive cells were located in fibrotic areas and significantly correlated with α-smooth muscle actin (α-SMA) and fibrosis staging scores, not with grading scores and HCRVNA. In vitro, IL-22 administration prevented HSCs apoptosis, promoted HSCs proliferation and activation, up-regulated the expression of HSC-sourced growth factors including α-SMA, TGF-ß and TIMP-1, and increased the production of liver fibrosis markers including laminin, hyaluronic acid and collagen type IV. CONCLUSION: Peripheral and intrahepatic IL-22 is up-regulated and plays a pathological role in exacerbating liver fibrosis by activating HSCs in HCV-OLT patients, which may predict RFP and serve as an attractive target for anti-fibrotic therapy.

Durability of Hepatitis B e Antigen Seroconversion in Chronic Hepatitis B Patients Treated with Entecavir or Tenofovir.

INTRODUCTION: Loss of HBeAg and development of anti-HBe (seroconversion) is seen as a milestone and endpoint in the treatment of HBeAg-positive patients with chronic hepatitis B (CHB). Among patients treated with nucleos(t)ide analogs (NA), recurrent viremia is common after discontinuation of therapy. Entecavir (ETV) and tenofovir (TDF) are highly potent NA. The durability of virological response and HBeAg seroconversion in patients treated with these agents is not well studied. METHODS: We retrospectively studied the outcomes of 54 HBeAg-positive CHB patients who were treated with either ETV (n = 30) or TDF (23) or both (n = 1) that achieved virological response and underwent seroconversion and consolidation therapy before cessation of treatment. RESULTS: Only 4 (7%) patients had sustained virological, serological, and biochemical remission. Thirteen patients (24%) continued to have HBV DNA levels below 2000 IU/mL and normal alanine aminotransferase activity (ALT). Thirty-seven patients (69%) developed HBV DNA >2000 IU/mL, with 20 having elevated ALT. Among these 37 patients, 23 (62%) remained HBeAg negative/anti-HBe positive, 12 (32%) became HBeAg positive, and 2 (5%) were HBeAg and anti-HBe negative. Duration of consolidation therapy did not correlate with low versus high level of virological relapse. CONCLUSIONS: Durability of HBeAg seroconversion associated with ETV or TDF was not superior to that reported in patients treated with less potent NA. Our results, aggregated with others, suggest HBeAg seroconversion should not be considered as a treatment endpoint for most HBeAg-positive patients treated with NA. Future updates of treatment guidelines should reconsider HBeAg seroconversion as an endpoint to therapy.

Torsional mechanics of the left ventricle in patients after surgical repair of tetralogy of Fallot.

BACKGROUND: This study aimed to test the hypothesis that alteration of left ventricular (LV) torsional mechanics occurs in patients after repair of tetralogy of Fallot (TOF) and is associated with right ventricular (RV) volume overload and changes in LV configuration. METHODS AND RESULTS: Fifty-five TOF patients aged 19.0 ± 8.1 years and 27 age-matched healthy controls were studied. The LV and RV volumes were measured using 3-dimensional echocardiography while LV geometry was quantified by the diastolic eccentricity index (EI). The LV peak systolic torsion and systolic twisting and diastolic untwisting velocities were determined by speckle tracking. Compared with controls, patients had significantly greater RV end-systolic (P < 0.001) and diastolic (P < 0.001) volumes and LV diastolic EI (P < 0.001). In contrast, LV peak apical rotation (P < 0.001), systolic torsion (P = 0.004), systolic twisting velocity (P = 0.001), and diastolic untwisting velocity (P = 0.001) were lower in patients than in controls. For the whole cohort, RV EDV and LV diastolic EI correlated negatively with peak systolic torsion, systolic twisting velocity, and diastolic untwisting velocity (all P ≤ 0.001). Systolic torsion correlated strongly with diastolic untwisting velocity (r = 0.72, P < 0.001), while systolic twisting velocity correlated with LV ejection fraction (r = 0.3, P = 0.005). CONCLUSIONS: LV torsional mechanics is impaired and is negatively related to RV volume overload and LV eccentricity in patients after TOF repair.

Meta-analysis of pulmonary valve replacement after operative repair of tetralogy of fallot.

The present meta-analysis aimed to determine the outcomes and effect on right ventricular (RV) function of surgical pulmonary valve replacement (PVR) in patients after repair of tetralogy of Fallot. The reported outcomes of surgical PVR in children and adults after tetralogy of Fallot repair were from relatively small observational studies. The PubMed database was searched from its inception to April 2009. Observational studies reporting on the following outcomes measures after surgical PVR were reviewed: early and late all-cause mortalities, the redo-PVR rate, and changes in the indexed RV volumes, ejection fraction, and QRS duration after PVR. Of the 305 citations screened, 15 met the criteria and were analyzed. The pooled early mortality rate (n = 595) was 2.1% (95% confidence interval [CI] 1.1% to 4.0%). The late mortality rate was 0.5%/patient-year (95% CI 0.2% to 0.8%/patient-year), and the redo-PVR rate was 1.9%/patient-year (95% CI 1.3% to 2.5%/patient-year). Data on RV volumes and ejection fractions were available from 5 studies (n = 141). The pooled mean difference in the indexed RV end-diastolic and end-systolic volume was -63 ml/m(2) (95% CI -55 to -72) and -37 ml/m(2) (95% CI -30 to -45), respectively. No significant changes in the pooled mean difference of the RV ejection fraction (95% CI -1% to 3%) or QRS duration (95% CI -10 to 1 ms) were observed. In conclusion, surgical PVR in patients after tetralogy of Fallot repair has been associated with low early and late mortality and significant decreases in RV volumes but no changes in the RV ejection fraction or QRS duration.

Impact of right ventricular dilation on left ventricular myocardial deformation in patients after surgical repair of tetralogy of fallot.

Left ventricular (LV) dysfunction is 1 of the major determinants of late adverse clinical outcomes in patients after surgical repair of tetralogy of Fallot (TOF). The aim of this study was to test the hypothesis that LV myocardial deformation is impaired in patients after TOF repair and related to right ventricular (RV) dilation and exercise capacity. Longitudinal, radial, and circumferential LV myocardial deformation was determined using speckle-tracking echocardiography in 23 postoperative patients with TOF and compared to that of 23 age-matched controls. Relations between LV strain and strain rate (SR) and RV volumes and exercise parameters were determined in patients. Compared to controls, patients had reduced global LV longitudinal, radial, and circumferential strain (all p values <0.05). Patients with significantly increased RV end-systolic volume (>2 SDs higher than normal; n = 17) had reduced global LV circumferential strain (p = 0.048) and SR (p = 0.038), but similar longitudinal and radial speckle-tracking echocardiographic parameters, compared to those without (n = 6). RV end-systolic volume was correlated inversely with global LV circumferential strain and SR (r = -0.58, p = 0.004, and r = -0.58, p = 0.005, respectively), while RV end-diastolic volume was correlated only with global LV circumferential strain (r = -0.43, p = 0.047). In patients, the LV ejection fraction was correlated with global LV circumferential strain (r = 0.54, p = 0.01) and SR (r = 0.66, p = 0.001) but not with longitudinal or radial speckle-tracking echocardiographic parameters. Using multivariate analysis, global LV circumferential SR (beta = 0.66, p = 0.001) and male gender (beta = 0.46, p = 0.012) were identified as independent predictors of peak oxygen consumption. In conclusion, the negative impact of RV dilation on LV function relates to its influence on LV circumferential strain and SR in patients after TOF repair.

Impact of right ventricular volume overload on three-dimensional global left ventricular mechanical dyssynchrony after surgical repair of tetralogy of Fallot.

This study aimed to test the hypothesis that right ventricular (RV) volume overload may result in left ventricular (LV) systolic dysfunction through induction of LV systolic dyssynchrony after tetralogy of Fallot (TOF) repair. Sixty patients with TOF repair were studied at 14.3 +/- 7.2 years after TOF repair. Real-time 3-dimensional echocardiographic data sets were acquired for measurement of LV and RV volumes and derivation of ejection fractions and pulmonary regurgitant volume. The LV systolic dyssynchrony index (SDI) was derived from the dispersion of time to minimum regional volume using a 16-segment model. The results were compared with those of 29 healthy controls. LV SDI was significantly higher in patients than controls (7.4% +/- 2.0% vs 3.0% +/- 0.9%, p <0.001). The prevalence of LV mechanical dyssynchrony (SDI >4.7%) in patients was 93% (95% confidence interval 87% to 100%). The time to minimum regional volume was significantly longer in all of the 6 basal segments and the midposterior segment (all p <0.05) in patients than controls. Multivariate analysis identified RV end-diastolic volume (beta = 0.58, p <0.001), LV ejection fraction (beta = -0.38, p <0.001), and LV end-diastolic volume (beta = 0.26, p = 0.002) as significant correlates of LV SDI. In conclusion, in patients after TOF repair, RV volume overload has a negative effect on LV systolic function through induction of global LV mechanical dyssynchrony.