Non-alcoholic fatty liver disease and risk of incident cardiovascular disease: A meta-analysis

Non-alcoholic fatty liver disease and risk of fatal and non-fatal cardiovascular events: an updated systematic review and meta-analysis

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Since sex is a significant modifier of cardiovascular disease (CVD) and metabolic dysfunction-associated steatotic liver disease (MASLD), we performed a meta-analysis to estimate the sex-specific risk of fatal and non-fatal CVD events in adults with MASLD. We searched four major electronic databases from inception to November 2024 to identify observational cohort studies examining sex-specific associations between MASLD and the risk of fatal and/or non-fatal CVD events. The diagnosis of MASLD and its severity were assessed using serum biomarkers/scores, International Classification of Diseases codes, imaging or histology. Thirty-six cohort studies with aggregate data on ~18.5 million individuals were included (~25% with MASLD; 48% women; mean age of 50.2 years). During a median follow-up of 6.9 years (IQR 5.0-12.3), approximately 515 000 fatal and/or non-fatal CVD events occurred (42% in women). MASLD was associated with a higher risk of fatal or non-fatal CVD events in women (pooled hazard ratio [HR] 1.59, 95% confidence interval [CI] 1.44-1.75; I2 = 96.10%) than in men (pooled HR 1.37, 95% CI 1.27-1.48; I2 = 96.26%) (p-value for sex difference = 0.018). The severity of MASLD (variably assessed) further increased the magnitude of this risk, especially in women (pooled HR 2.40, 95% CI 1.73-3.32; I2 = 57.29%). Sensitivity analyses did not modify these findings. The funnel plot and Egger's test showed no significant publication bias. Women with MASLD are at higher risk of incident fatal and non-fatal CVD events compared with men, especially as the severity of MASLD increases. These findings emphasize the necessity for sex-specific CVD risk assessment and management strategies.

Nonalcoholic Fatty Liver Disease and Cardiovascular Disease Risk

A consensus of experts has proposed to replace the term nonalcoholic fatty liver disease (NAFLD), whose global prevalence is 25%, with metabolic dysfunction-associated fatty liver disease (MAFLD), to describe more appropriately the liver disease related to metabolic derangements. MAFLD is closely intertwined with type 2 diabetes, obesity, dyslipidaemia, all linked to a rise in the risk of cardiovascular disease (CVDs). Since controversy still stands on whether or not NAFLD/MAFLD raises the odds of CVD, the present review aims to evaluate the impact of NAFLD/MAFLD aetiologies on CV health and the potential correction by dietary and drug approaches. Epidemiological studies indicate that NAFLD raises risk of fatal or non-fatal CVD events. NAFLD patients have a higher prevalence of arterial plaques and stiffness, coronary calcification, and endothelial dysfunction. Although genetic and environmental factors strongly contribute to NAFLD pathogenesis, a Mendelian randomization analysis indicated that the PNPLA3 genetic variant leading to NAFLD may not be causally associated with CVD risk. Among other genetic variants related to NAFLD, TM6SF2 appears to be protective, whereas MBOAT7 may favour venous thromboembolism. NAFLD is correlated to a higher CVD risk which may be ameliorated by dietary interventions. This is not surprising, since new criteria defining MAFLD include other metabolic risk abnormalities fuelling development of serious adverse extrahepatic outcomes, for example CVD. The present lack of a targeted pharmacological approach makes the identification of patients with liver disease at higher CVD risk (eg diabetes, hypertension, obesity or high levels of C-reactive protein) of major clinical interest.

The impact of changes in leisure time physical activity (LTPA) is not well-documented, especially when considering occupational physical activity (OPA). This study examines the effects of LTPA changes in workers with varying physical activity demands. Part of the OPERA study, we tracked morbidities for over 20 years (P1, from 1993 to 2014) and mortality for over 8 years (P2, from 2014 to 2021-2022) with 599 participants. They were categorized into four LTPA groups ("sedentary," "started," "quit," "active") and two OPA groups ("office workers" and "occupationally physically active"). Maintaining regular LTPA was associated with lower incidence of hypertension, diabetes and metabolic syndrome (p-values 0.007, < 0.001 and <0.001 respectively). Non-fatal cardiovascular disease (CVD) events were more common (p = 0.006, HR 1.99, CI95% 1.22-3.26) in the "quit" group during P1, especially among "occupationally physically active" (p < 0.001, HR 2.29, CI95% 1.23-4.29). During P2, fatal CVD events were associated with being in the "sedentary" group (p = 0.042, HR 2.67, CI95% 1.04-7.03). This association was particularly evident among "office workers," where belonging to the "sedentary" and "quit" groups was associated with a higher risk of fatal CVD events (p = 0.017, HR 5.45, CI95%1.36-21.91, and p = 0.025, HR 4.55, CI95% 1.21-17.19, respectively). Furthermore, total mortality was associated with being in the "sedentary" or "quit" groups (p = 0.029, HR 3.69, CI95% 1.14-11.93, and p = 0.009, HR 4.61, CI95%1.47-14.49, respectively). Stopping LTPA in middle age was associated to higher risk for non-fatal CVD events in "occupationally physically active" individuals. Fatal CVD events were associated with a sedentary lifestyle in whole study population. Among "office workers," both a sedentary lifestyle and stopping regular LTPA were associated with higher risks of fatal CVD events and all-cause mortality.

Performance of WHO updated cardiovascular disease risk prediction charts in a low-resource setting – Findings from a community-based survey in Puducherry, India

The aim of this study is to determine the effectiveness of non-pharmacological interventions for prevention of cardiovascular disease (CVD) events and mortality in healthy adults or those at high risk of CVD. An umbrella review about primary prevention of non-pharmacological interventions was undertaken in key databases as PubMed Health, Effective Health Care Program AHRQ, McMaster University and the Cochrane Plus until July 2017. The primary outcomes were the relative risk of fatal and non-fatal CVD events, and mortality. Secondary outcomes were adverse events. Twenty-four reviews were included of which thirteen reported outcomes of interest. Four of these found a pooled statistically significant risk reduction: dietary supplements of vitamin D, increased consumption of omega 3 fatty acids, Qigong, and counselling or education to modify more than one cardiovascular risk factor. Seven studies reported adverse events but minor or insignificant with respect to the control group. Four non-pharmacological interventions have been shown to provide a statistically significant reduction in risk of CVD events or overall mortality, with minor adverse events if any. Further research should aim for higher methodological quality and longer follow-up of interventions to establish if these interventions, alone or in combination, translate into definite long-term health benefits.

Parathyroid hormone and cardiovascular disease events: A systematic review and meta-analysis of prospective studies

PurposeObstructive sleep apnea (OSA) is suggested to predispose to cardiovascular disease (CVD) events. It is uncertain whether compliance to continuous positive airway pressure (CPAP) treatment could attenuate the risk. We explored this issue in long-term CPAP users and untreated controls.MethodsRetrospective observational cohort of CPAP-treated and control patients were pairwise matched for gender, age, and apnea–hypopnea index (AHI). The study end point was a composite of nonfatal and fatal CVD events. Cox regression model was used to determine the association between CPAP treatment and event-free survival.ResultsA total of 2060 patients (75.8% male, mean age 56.0 ± 10.5 years), of which 76.4% had moderate–severe OSA, were included. In the CPAP-treated group (N = 1030), the median use of CPAP was 6.4 h/day during a median follow-up of 8.7 years. The control group (N = 1030) was followed for a median of 6.2 years after the CPAP treatment had ended. The study end point occurred in 14.4% (N = 148) of the CPAP-treated and in 18.8% (N = 194) of the control patients (p = 0.006). Using the Cox regression model adjusted for gender, age, AHI, body mass index, and history of CVD, hypertension, type 2 diabetes, and chronic obstructive pulmonary disease at baseline, a beneficial association between CPAP treatment and CVD risk was observed (hazard ratio 0.64, confidence interval 95% 0.5–0.8, p < 0.001).ConclusionsCPAP treatment was associated with a decreased risk of nonfatal and fatal CVD events. Majority of the patients were compliant to CPAP. The association was demonstrated independent from common cardiovascular risk factors and AHI.

Electrocardiographic Changes Improve Risk Prediction in Asymptomatic Persons Age 65 Years or Above Without Cardiovascular Disease

Non-alcoholic fatty liver disease (NAFLD) has become one of the most common forms of chronic liver disease worldwide and its prevalence is expected to continue rising. NAFLD has traditionally been considered a consequence of metabolic syndrome (MetS). However, the link between NAFLD and MetS components, especially type 2 diabetes mellitus (T2DM), hypertension (HTN), and cardiovascular disease (CVD) is more complex than previously thought. Indeed, the adverse effects of NAFLD extend far beyond the liver, with a large body of clinical evidence now suggesting that NAFLD may precede and/or promote the development of T2DM, HTN and atherosclerosis/CVD. The risk of developing these cardiometabolic diseases parallels the underlying severity of NAFLD. Accumulating evidence suggests that the presence and severity of NAFLD is associated with an increased risk of incident T2DM and HTN. Moreover, long-term prospective studies indicate that the presence and severity of NAFLD independently predicts fatal and nonfatal CVD events. In this review, we critically discuss the rapidly expanding body of clinical evidence that supports the existence of a bi-directional relationship between NAFLD and various components of MetS, particularly T2DM and HTN, as well as the current knowledge regarding a strong association between NAFLD and CVD morbidity and mortality. Finally, we discuss the most updated putative biological mechanisms through which NAFLD may contribute to the development of HTN, T2DM and CVD.

Cardiovascular disease (CVD) is the number one cause of death for women, and major life events across midlife may contribute to CVD risk. The present study aimed to test whether greater exposure to major life events across nearly two decades of longitudinal follow-up would be associated with higher risk of clinical cardiovascular disease events. 3,222 middle-aged women from the multi-ethnic Study of Women’s Health Across the Nation reported and provided up to 15 years of major life events, non-fatal incident CVD events, traditional biobehavioral and sociodemographic factors, and death certificates. Cox proportional hazards models were used to test the association between average annual life events and incident fatal and nonfatal CVD events. Each additional major life event was associated with a 1.16-fold (95% CI: 1.08-1.23) increase in CVD events. CVD risk will be discussed considering evidence of racial/ethnic disparities in exposure to major life events.

How does the risk of cardiovascular disease (CVD) vary with type and age of menopause? Earlier surgical menopause (e.g. <45 years) poses additional increased risk of incident CVD events, compared to women with natural menopause at the same age, and HRT use reduced the risk of CVD in women with early surgical menopause. Earlier age at menopause has been linked to an increased risk of CVD mortality and all-cause mortality, but the extent that this risk of CVD varies by type of menopause and the role of postmenopausal HRT use in reducing this risk is unclear. Pooled individual-level data of 203767 postmenopausal women from 10 observational studies that contribute to the International collaboration for a Life course Approach to reproductive health and Chronic disease Events (InterLACE) consortium were included in the analysis. Postmenopausal women who had reported menopause (type and age of menopause) and information on non-fatal CVD events were included. Type of menopause (natural menopause and surgical menopause) and age at menopause (categorised as <35, 35-39, 40-44, 45-49, 50-54 and ≥55 years) were exposures of interest. Natural menopause was defined as absence of menstruation over a period of 12 months (no hysterectomy and/or oophorectomy) and surgical menopause as removal of both ovaries. The study outcome was the first non-fatal CVD (defined as either incident coronary heart disease (CHD) or stroke) event ascertained from hospital medical records or self-reported. We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% CI for non-fatal CVD events associated with natural menopause and surgical menopause. Compared with natural menopause, surgical menopause was associated with over 20% higher risk of CVD (HR 1.22, 95% CI 1.16-1.28). After the stratified analysis by age at menopause, a graded relationship for incident CVD was observed with lower age at menopause in both types of natural and surgical menopause. There was also a significant interaction between type of menopause and age at menopause (P < 0.001). Compared with natural menopause at 50-54 years, women with surgical menopause before 35 (2.55, 2.22-2.94) and 35-39 years (1.91, 1.71-2.14) had higher risk of CVD than those with natural menopause (1.59, 1.23-2.05 and 1.51, 1.33-1.72, respectively). Women who experienced surgical menopause at earlier age (<50 years) and took HRT had lower risk of incident CHD than those who were not users of HRT. Self-reported data on type and age of menopause, no information on indication for the surgery (e.g. endometriosis and fibroids) and the exclusion of fatal CVD events may bias our results. In clinical practice, women who experienced natural menopause or had surgical menopause at an earlier age need close monitoring and engagement for preventive health measures and early diagnosis of CVD. Our findings also suggested that timing of menopause should be considered as an important factor in risk assessment of CVD for women. The findings on CVD lend some support to the position that elective bilateral oophorectomy (surgical menopause) at hysterectomy for benign diseases should be discouraged based on an increased risk of CVD. InterLACE project is funded by the Australian National Health and Medical Research Council project grant (APP1027196). GDM is supported by Australian National Health and Medical Research Council Principal Research Fellowship (APP1121844). There are no competing interests.

BACKGROUNDThere are no consistent results between previous studies for an independent association between non-alcoholic fatty liver disease (NAFLD) and cardiovascular disease (CVD) events.AIMTo determine if there is an independent association between NAFLD and CVD events.METHODSIn the present study, valid outcome data of 4808 subjects were available for phase 2 of our cohort study. These subjects had been followed up for seven years from phase 1, beginning in 2009-2010 to phase 2 during 2016-2017. Simple and multiple Cox proportional models were used to determine the association between NAFLD in the primary phase of the cohort and subsequent fatal and non-fatal CVD events during follow-up.RESULTSThe incidence of non-fatal CVD events in males with NAFLD was significantly higher (P = 0.004) than in males without NAFLD. A positive association was demonstrated between NAFLD and non-fatal CVD events in males (Hazard ratio = 1.606; 95%CI: 1.166-2.212; P = 0.004) by the simple Cox proportional hazard model, but no independent association was detected between these in the multiple Cox models.CONCLUSIONNo independent association was detected between NAFLD and CVD. It is likely that diabetes mellitus and age may be the principle mediators in this regard.