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Mantovani et al. Hepatoma Res 2020;6:78 I http://dx.doi.org/10.20517/2394-5079.2020.75 Page 11 of 22

and non-fatal cardiovascular events; (2) alterations in cardiac structure and function; and (3) an increased
prevalence of microvascular complications [such as chronic kidney disease (CKD) and distal symmetric
polyneuropathy] [134] . Importantly, these associations were significant even after adjustment for many
established cardiovascular risk factors and diabetes-related confounders [134] .

Association between NAFLD and macrovascular complications
It is now established that the principal cause of mortality in patients with NAFLD is cardiovascular disease
(CVD), followed by extrahepatic cancers and liver-related complications [134] . In this regard, in a recent
meta-analysis of 45 studies for a total of nearly 8 million individuals who were followed from 4 to 13 years,
Younossi et al. [135] documented that the pooled CVD-specific mortality rate among NAFLD patients (with
or without diabetes mellitus) was approximately 4.8 per 1,000 person-years. Working with data from the
National Vital Statistics System multiple-cause mortality data (2007-2016), Paik et al. [136] further showed
that CVD is one of the main causes of death among USA patients with NAFLD. In a 2016 meta-analysis
of 16 observational studies, Targher et al. [137] showed that patients with NAFLD had a higher risk of fatal
and/or non-fatal CVD events when compared to patients with no NAFLD (random effects-odds ratio 1.64,
95% confidence interval 1.26-2.13) over a median period of nearly 7 years. In a 2020 nested cohort study
of nearly 4,000 USA patients, who underwent coronary computed tomography angiography as part of the
[138]
PROMISE (PROspective Multicenter Imaging Study for Evaluation of Chest Pain) study, Meyersohn et al.
showed that hepatic steatosis (on computed tomography) was associated with major adverse cardiovascular
events, even after controlling for established cardiovascular risk factors or extent of coronary artery disease
(hazard ratio 1.69, 95% confidence interval 1.16-2.48).

These findings can be broadly explained by the fact that NAFLD adversely affects cardiac structure and
function, leading to an increased risk of cardiomyopathy (e.g., left ventricular diastolic dysfunction
and hypertrophy), cardiac valvular calcification [e.g., aortic valve sclerosis (AVS) and mitral annulus
calcification (MAC)], and cardiac arrhythmias (mainly atrial fibrillation) [134] .

Restricting the discussion to the observational studies conducted in patients with T2DM [Table 2], the
Valpolicella Diabetes Heart Study in 2007 documented that T2DM patients with NAFLD (on ultrasound)
had an increased prevalence of coronary, cerebrovascular and peripheral vascular diseases as compared
with those with no NAFLD [123] . Interestingly, in a cross-sectional study enrolling 222 T2DM outpatients,
[45]
Mantovani et al. documented that NAFLD (on ultrasound) was independently associated with increased
risk of mild and/or moderate left ventricular diastolic dysfunction (evaluated by echocardiography). In
another cross-sectional study of nearly 120 elderly T2DM patients with hypertension, Mantovani et al. [139]
reported that NAFLD (on ultrasound) was associated with left ventricular hypertrophy (as detected by
echocardiography). In a cross-sectional study enrolling 19 adults with T2DM, 19 adults with NAFLD (on
1
proton magnetic resonance spectroscopy [ H-MRS]) and 19 healthy controls, Cassidy et al. [124] showed
that alterations in cardiac structure (evaluated by cardiac magnetic resonance) were mainly evident in
T2DM patients with NAFLD. Some studies using biopsy or Fibroscan® also observed a graded relationship
between functional and structural myocardial abnormalities and the severity of NAFLD in patients with
and without T2DM [134] .

Regarding the heart valve calcifications, studies have demonstrated an association between NAFLD and
risk of AVS and MAC in patients with and without T2DM [125,134] . For example, in an observational study
enrolling 247 consecutive T2DM outpatients, Mantovani et al. [125] reported that NAFLD (on ultrasound)
was independently associated with cardiac calcifications in both the aortic and mitral valves. These
findings are of clinical interest, as it is established that AVS and MAC are associated with all-cause and
cardiovascular mortality in T2DM patients [140] .