Reviews in Endocrine and Metabolic Disorders (2023) 24:901–919

https://doi.org/10.1007/s11154-023-09813-5

Obesity phenotypes and cardiovascular risk: From pathophysiology

to clinical management
Alberto Preda1 · Federico Carbone2,3 · Amedeo Tirandi2,3 · Fabrizio Montecucco2,3 · Luca Liberale2,3

Accepted: 31 May 2023 / Published online: 26 June 2023

© The Author(s) 2023

Abstract
Obesity epidemic reached the dimensions of a real global health crisis with more than one billion people worldwide living
with obesity. Multiple obesity-related mechanisms cause structural, functional, humoral, and hemodynamic alterations with
cardiovascular (CV) deleterious effects. A correct assessment of the cardiovascular risk in people with obesity is critical for
reducing mortality and preserving quality of life. The correct identification of the obesity status remains difficult as recent
evidence suggest that different phenotypes of obesity exist, each one associated with different degrees of CV risk. Diagno-
sis of obesity cannot depend only on anthropometric parameters but should include a precise assessment of the metabolic
status. Recently, the World Heart Federation and World Obesity Federation provided an action plan for management of
obesity-related CV risk and mortality, stressing for the instauration of comprehensive structured programs encompassing
multidisciplinary teams. In this review we aim at providing an updated summary regarding the different obesity phenotypes,
their specific effects on CV risk and differences in clinical management.

Keywords Obesity · Cardiovascular risk · Inflammation · Insulin resistance · Fat · Adipose tissue

1 Introduction to obesity and cardiovascular functional, humoral and hemodynamic alterations believed
risk to underpin the development of CVD including atherothrom-
bosis, atrial fibrillation (AF) and myocardial dysfunction
Over the last 30 years, the epidemic of overweight and [6–8]. Thus, a correct assessment of the cardiovascular (CV)
obesity has increased dramatically, reaching the dimension risk in people with obesity is critical for reducing mortality
of a real global health crisis [1]. According to the data of and preserving quality of life in this class of patients. How-
the World Health Organization, more than 1 billion people ever, the correct identification of the obesity status is still
worldwide are living with obesity (650 million adults, 340 tricky as recent evidence suggest that different phenotypes
million adolescents and 39 million children) accounting for of obesity exist, each one associated with different degree of
about 2.8 million deaths every year [2]. Adipocytes secrete CV risk [9, 10]. Body mass index (BMI) has been longtime
different hormones and peptides under several physiological indicated as golden standard to assess adipose depots and
and pathological conditions, known globally as adipokines the associated cardiovascular risk, but several limitations
and playing an important role in local and systemic regula- apply [8]. Considerable variations occur according with sex,
tion of energy homeostasis and inflammation [3–5]. Mul- age, and race/ethnicity. In the last decade, a shift toward a
tiple obesity-related mechanisms are cause of structural, qualitative approach led to rephrase the paradigm of obe-
sity into the concept of obesities [11]. With time, several
other anthropometric measures have made their way along-
* Fabrizio Montecucco side or replacing BMI: mainly waist circumference (WC)
fabrizio.montecucco@unige.it [12, 13] but also, waist-hip ratio (WHiR), waist to height
1
ratio (WHtR), bioimpedance, 3D scanning and dual energy
Vita-Salute San Raffaele University, Milan, Italy
x-ray absorptiometry (DEXA). Such a paradigm shift takes
2
IRCCS Ospedale Policlinico San Martino Genoa – Italian into great account qualitative differences in adiposity as
Cardiovascular Network, Genoa, Italy
associated with different degrees of metabolic and athero-
3
Department of Internal Medicine, University of Genoa, 6 genic derangements and different responses to weight loss,
viale Benedetto XV, 16132 Genoa, Italy

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902 Reviews in Endocrine and Metabolic Disorders (2023) 24:901–919

lifestyle modification or medications. Recently, the World impact the weight loss trajectory. On the other hand, unin-
Heart Federation (WHF) and World Obesity Federation tentional weight loss is often marked by relative reduction of
(WOF) provided an action plan for management of obesity- muscle mass and peripheral fat, rather than central fat [24].
related CV risk and mortality, stressing for the institution This phenomenon cannot be discriminate by the use of BMI
of comprehensive structured programs encompassing mul- [25]. The predictive role of WHR seems to be higher for CV
tidisciplinary teams [14]. In this review we aim at providing risk stratification in those patients [26, 27]. In a recent study,
an updated summary regarding the different obesity pheno- WHR and WC better correlate with the severity of CAD
types, their specific effects on CV risk and differences in in patients undergoing PCI while BMI only showed a low
clinical management. predictive value [28]. Markers of central fat should be con-
sidered better indicators of future risk in this context [29].

2 The journey from BMI to visceral adiposity 2.2 “Adiposopathy” and “diabesity”

and obesity phenotypes
Adipocyte hypertrophy in visceral adipose tissue and ectopic
2.1 The obesity paradox fat accumulation leads to cellular dysfunction, metabolic
abnormalities and endocrine disturbances [30]. Adipose
Historically, the increase in adiposity depots expressed by tissue dysfunction also known as “adiposopathy” is a root
BMI is linearly associated with growing CVD risk and mor- cause of some of the most common metabolic diseases
tality. Nevertheless, the first decade of this century saw the observed in clinical practice, including DM, hypertension
emergence of a mismatch between the awareness of excess and dyslipidemia [31]. While classically related to the vis-
body weight burden and its related metabolic consequences. ceral fat, growing evidence suggest a role for dysfunctional
The concept of ‘obesity paradox’ was born, and scientist stimulation of the subcutaneous adipose tissue in obesity
stayed in this swamp for a decade further [15]. In several [32]. Metabolic consequences of adiposopathy have been
studies patients with obesity have indeed shown a better traditionally clustered in the general term metabolic syn-
prognosis as compared with leaner ones [16]. Gruberg and drome (MetS) accounting for central obesity, hyperglyce-
co-workers firstly described this evidence in patients affected mia, hypertriglyceridemia, low levels of HDL and hyperten-
by coronary artery disease (CAD) undergoing percutaneous sion [33]. Shift toward visceral adipose tissue distribution,
coronary intervention (PCI) [17]. Subsequently, numerous ectopic fat deposition and inflammatory/adipokines dysregu-
other conflicting data where published regarding the benefits lation are now considered the central tenets of adiposopa-
of weight reduction in some high-risk CV conditions—heart thy [34]. Hypertrophic adipocytes showed an unbalanced
failure (HF), atrial fibrillation (AF) or hypertension—as well adipokines production, promoting insulin resistance (IR),
as other non-CV conditions such as frailty, diabetes mel- inflammation, fatty liver, increased LDL-cholesterol, oxi-
litus (DM), end-stage renal disease and chronic obstructive dative stress, endothelial dysfunction and pro-thrombotic
pulmonary disease [18, 19]. Notably, in patients affected by state [35]. Among adipokines, leptin levels were shown to
chronic HF, those losing more weight over time also showed be directly proportional to obesity and body fat levels, while
higher mortality rate [20]. Numerous possible explanations its counter-hormone adiponectin resulted reduced [36].
to this phenomenon were provided. First, patients with This imbalance is thought to enhance atherogenesis, fibro-
obesity and CVD are on average younger and with better sis, hyperglycemia and inflammation [37, 38]. Chemerin, a
conserved systolic function than lean patients. Acute myo- newly characterized chemoattractant released by adipocytes,
cardial infarction (AMI) in patients with obesity has been is gaining more and more attention as a potential MetS bio-
found to be associated with less severe and complex CAD marker being related with adipogenesis, angiogenesis and
than in non-obese subjects [21]. Moreover, patients with glucose metabolism [39, 40]. In humans, chemerin posi-
obesity have higher levels of arterial pressure, thus they tively correlates with adiposity [41, 42], independently from
can be exposed to higher dosages of anti-ischemic and anti- WC or BMI [42], and strongly predicts MetS development
remodeling medications. Nevertheless, the higher survival [43]. Adipocyte hypertrophy also leads to ischemic dysfunc-
after AMI in this population was found to be independent of tion and hypoxia-related signaling. The surrounding micro-
their younger age and more intensive medication treatment environment then modifies its architecture. Inflammatory
[22]. Other clinical features may in part explain the reduc- cells from both innate and adaptive immunity infiltrate the
tion of hospitalization time, as well as short- and long-term dysfunctional adipose tissue and activate inflammatory path-
mortality [21, 23]. Different confounding factors (e.g. smok- ways that further sustain such pathophysiological processes.
ing, chronic illness, lung disease, cancer) as well as reverse Among the other, the upstream mediator osteopontin (OPN)
causality were also pointed out as possible explanations for seems also to be strongly associated with adiposopathy and
the OP. Indeed, the severity of the disease could strongly cardiometabolic consequences. Released by macrophage

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Reviews in Endocrine and Metabolic Disorders (2023) 24:901–919 903

Table 1  Summary of defining criteria of different obesity phenotypes

Underweight MHNW MUNW MHO MUO SO
Waist circumference normal normal Normal/high normal high High WC
BMI (kg/m2) <18.5 18.5 – 24.9 18.5 – 24.9 >25 >25 and/or
BMI>25
Visceral adipose tissue Low Low High fat mass Low High High fat mass
Lean mass – – – High – Low
Metabolic abnormalities – Absent Present Absent Present Present
Normal values are in green, pathological ones are in red, and the intermediate ones in orange. Waist circumference categorized as normal
(men < 102 cm and women < 88 cm) or high (men ≥ 102 cm and women ≥ 88 cm). Visceral adipose tissue and lean mass are a non-standardized
measure actually. Metabolic abnormalities refer to the metabolic syndrome defining criteria
BMI body mass index, MHNW metabolically healthy normal weight, MUNW metabolically unhealthy normal weight, MHO metabolically
healthy overweight/obese, MUO metabolically unhealthy overweight/obese, SO sarcopenic obese

within dysfunctional adipose tissue, OPN sustains adipo- four groups: i) metabolic unhealthy normal weight (MUNW),
cyte and metabolic dysregulation in both experimental and ii) metabolically healthy overweight/obese (MHO), iii)
clinical studies [44–46]. Lipolysis and insulin resistance metabolically unhealthy overweight/obese (MUO), and iv)
finally characterize such a dysfunctional microenvironment sarcopenic obesity (SO) (Table 1). MHO and MUO are the
and reach peripheral tissues (e.g., skeletal muscle and liver) most representative categories, including patients with a
[47, 48]. Especially within the skeletal muscle, decrease in BMI > 25 kg/m [2] but very different metabolic profile [52]
GLUT-4 translocation reduces glucose uptake and facili- (Table 2). Alterations in body fat distribution is the key factor
tates glycogenolysis [49]. In the liver, FFAs promote glu- characterizing those two phenotypes. MUO encompasses the
coneogenesis and lipogenesis further increasing insulin old features of MetS, which translates in a higher cardiometa-
levels. Again, within pancreas islets, FFAs exert lipotoxic bolic risk [53]. In addition to age and higher WC, reduced
effect on beta cells leading to reduced insulin secretion and subcutaneous fat and shift toward a visceral and dysfunc-
a failure of compensation [50]. Since adiposity and DM are tional/pro-inflammatory hypertrophic adipose tissue distri-
strictly related, the term “diabesity” was coined to describe bution characterize MUO. Impaired fat storage and ectopic
the superadded effects of DM and obesity on CV risk [51]. visceral fat deposition in liver and skeletal muscle further
characterize this prototypic phenotype of adiposopathy [54,
55]. Contrariwise, the healthier MHO phenotype is less
3 Obesity phenotypes common among European population, with a prevalence of
10–30% [56]. They are more often young, female, physically
Pitfalls in the characterization of body fat distribution active people with a better nutritional status [57]. Although
through the BMI and distinction of fat vs. lean tissue have a definition of MHO is not standardized yet [58], this group
provided a critical contribution to explain the non-unique would include people with high BMI and healthy metabolic
subdivision of obesity phenotypes among studies. Based on profile: preserved insulin sensitivity, favorable lipid profile
current knowledge, “obesities” may be categorized across and low plasma levels of pro-inflammatory cytokines [59].

Table 2  Over time development and controversies in definition of metabolically healthy/unhealthy overweight/obese

Wildman et al. [90] BioSHaRE-EU Healthy Obese Project [56] Lavie et al. [91]
Less strict Stricter

IFG/IGT/T2DM FPG > 126 mg/dL FPG > 110 mg/dL FPG > 100 mg/dL
BP ≥ 130/85 mmHg BP > 140/90 mmHg BP > 130/85 mmHg BP > 130/85 mmHg
TAG > 150 mg/dL
HDL < 40 (W) or < 35 (M) mg/dL
WC > 88 cm (W), > 102 cm (M)
HOMA-IR [92]
hsCRP
BMI > 25 or > 30 kg/m [2] None (MHO) or ≥ 1 (MUO) 0–1 (MHO) or ≥ 1 (MUO)

IFG impaired fasting glucose, IGT impaired glucose tolerance, T2DM type 2 diabetes mellitus, BP blood pressure, TAG​triglycerides, HDL high-
density lipoprotein, WC waist circumference, BMI body mass index, CAD coronary artery disease, HOMA-IR homeostasis model assessment
for insulin resistance, hsCRP high-sensitivity C-reactive protein, MHO metabolically healthy overweight/obese, MUO metabolically unhealthy
overweight/obese

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Nevertheless, even the alleged lower CV risk associated tools for discriminating increased visceral adiposity and/
with MHO has been questioned [60]. Although CV risk did or unbalanced fat/lean mass ratio [69, 70]. Its prevalence
not differ from normal weight individuals, MHO had sig- is estimated in high as 67% [71]. MUNW may or not be
nificantly higher risk to develop MetS over time and then associated with changes in other anthropometric parameters,
increase by about 60% the chance of suffering major CV such as WC, WHiR, WHtR. The threshold of body fat mass
events in the MESA study [61, 62]. applied in MUNW diagnosis varies among different stud-
Similarly, a recent report from a UK biobank includ- ies, ranging from 19 to 32% for men and from 29 to 44%
ing > 380.000 people characterized MHO as at increased for women [72]. MUNW usually includes older and seden-
risk of HF (76%), respiratory diseases, all-cause mortal- tary individuals [73] with generally a very low amount of
ity, and atherosclerotic CVD (20%) as compared to normal gluteo-femoral fat mass compared with the visceral one [74].
weight/MHO individuals [63]. Despite a lower baseline CV Cardiometabolic risk associated with MUNW is high and
risk, MHO then develops atherosclerotic CVD risk factors high risk of CVD independently of elevated trunk fat mass
earlier than lean individuals. Moreover, overweight itself is as reported in lean women from Women’s Health Initiative
a non-negligible adverse factor that affects the natural his- Study [75]. MUO and MUNW phenotypes genetically dif-
tory of several comorbidities such as respiratory, renal, and fer: a variability in loci regulating food intake is reported
orthopedic ones [64, 65]. The MUNW group is another para- in MUO, whereas genetic characterization of MUNW has
digm of the prevalent qualitative – rather than quantitative highlighted a prevalence in genes regulating adipocyte dif-
– relevance of adiposity (Table 3). They share similar CV ferentiation, lipogenesis, and lipolysis (e.g. IRS1, GRB14,
risk factors [66] and metabolic alterations with traditionally PPARG, LYPLAL1) [76, 77].
patients with obesity, including chronic low-grade inflam- As additional phenotype, SO is characterized by low
mation [67, 68]. MUNW has the highest rate of underdi- skeletal muscle mass due to metabolic changes second-
agnoses among obesity phenotypes due to both the lack of ary to a sedentary lifestyle, adipose tissue derangements or
consensus definition and the limited access to diagnostic chronic comorbidities [78]. Loss of skeletal muscle mass

Table 3  Over time development and controversies in definition of metabolically unhealthy normal weight
Ruderman et al.93 Wildman et al.90 Combined models

Metabolic/biochemical MetS criteria94, 95

UA >8 mg/dL
IFG (110-125 mg/dL); IGT/T2DM HOMA-IR 93 IFG/IGT/T2DM
BP 125-140/85-90 mmHg;
BP ≥130/85 mmHg
BP >140/90 mmHg TyG
HDL<50 (W) or 35 (M) 96
TAG 100-150 mg/dL150 mg/dL
mg/dL
TAG >150 mg/dL
TAG >150 mg/dL
TAG>150+HDL <35 mg/dL
hsCRP
VAI
LAP 97
CMI
Anthropometric indexes/Adipose 99 98
tissue
WC >71, >76cm (W) and >86, >91cm WC >88 cm (W), >102 cm
(M) (M)
BMI 23-24.9 or 25-27 kg/m2 BMI<25 kg/m2100
Weight gain >4, 8 or 12 kg
WHtR
WHR
DXA101-103

Family history
Hypertension/CAD (under 60yrs)
T2DM/hyper-TAG

Predisposing factors
Low birth weight (<2.5 kg); inactivity
Polycystic ovaries

Ethnic group at high risk

Multivariable score BMI<25 kg/m2 + >2 metabolic/biochemical criteria

UA uric acid, IFG impaired fasting glucose, IGT impaired glucose tolerance, T2DM type 2 diabetes mellitus, BP blood pressure, TAG​ triglyc-
erides, HDL high-density lipoprotein, WC waist circumference, BMI body mass index, CAD coronary artery disease, HOMA-IR homeostasis
model assessment for insulin resistance, WHtR waist-to height ratio, WHR waist-to-hip-ratio, DXA dual-energy X-ray absorptiometry, LAP lipid
accumulation product; VAI visceral adiposity index, CMI cardiometabolic index, TyG triglycerides-glucose index [90, 93–103]

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and function generally occurs with ageing and is com- cellular senescence, mitochondrial dysfunction, impaired
monly paralleled by relative or absolute body fat gain, autophagy and dysbiosis [108]. Moreover, the impaired
favoring the potential development of SO. Adipose tissue crosstalk between adipocytes and the immune cells infil-
has indeed a negative impact on muscle mass both directly trating the adipose tissue as well as the degeneration of
through metabolic derangements (i.e. inflammation and self- and non-self-receptors is thought to contribute to the
IR) [79] and indirectly through increased prevalence of establishment of inflamm-aging itself [109]. Of interest,
obesity-related chronic diseases with a negative impact on the innate immune response activates after food ingestion
muscle metabolism (i.e., orthopedic disorders). Of interest, [110]. The so-called “postprandial inflammation” is part
the skeletal muscle is now increasingly considered as an of the adaptive response to meals and causes the release of
endocrine organ secreting a large number of factors, termed several pro-inflammatory mediators [111]. Therefore, the
myokines, that favour the metabolic dialogue between the excess nutrients intake characterizing obesity associates
muscle and other organs, including the adipose tissue [80]. with higher levels of inflammatory hormones (i.e. leptin)
Although diagnostic criteria are variable among studies, secreted by adipose tissue, leading to a metabolic repro-
SO is usually diagnosed when parameters of altered skel- gramming of immune cells, in particular macrophages,
etal muscle strength coexist with altered body composition, towards a pro-inflammatory phenotype. Such condition
in particular increased fat mass and reduced muscle mass – known as “metaflammation” – synergistically works with
[81]. Preclinical and clinical studies suggest the existence accelerated inflammaging to create a dysregulated energetic
of a biological connection between IR, obesity and sarco- environment, whose metabolic hallmarks are high levels
penia, mediated by the impaired function of the growth dif- of lipids, free fatty acids, glucose, and reactive oxygen
ferentiation factor myostatin [82]. Such mediator, histori- species (ROS). Prolonged mitogenic signal induced by
cally recognized among most important negative regulators chronic hyperinsulinemia leads dysfunctional hypertrophic
of muscle mass, recently gains notoriety due to its role on adipocytes to activate a post-mitotic cell cycle that initi-
glucose and fat metabolism including inhibition of insulin ate a senescent cell program. This process is associated to
signaling, lipid oxidation and energy expenditure [83]. In a pro-inflammatory secretome, which sustains and further
addition to myostatin, sarcopenia and sarcopenic obesity contributes to low-grade chronic inflammation [112]. Mac-
are associated with a dysregulation of other myokines with rophages and adipocytes demonstrate remarkable functional
important cardiometabolic functions, such as IL-6, FNDC5/ overlap, as both cell types secrete cytokines and can be acti-
irisin, fibroblast growth factor 21 or brain-derived neuro- vated by bacterial products (i.e. lipopolysaccharide) [113].
trophic factor, which play a critical role in skeletal muscle Furthermore, pre-adipocytes can transdifferentiate into
mass and function as well as metabolic homeostasis [84]. macrophages. Of interest, whereas inflammation-resolving
In SO, obesity and sarcopenia may therefore synergistically M2 macrophages dominate insulin-sensitive adipose tissue
enhance each another with a vicious cycle facilitating weight in the lean, pro-inflammatory M1 macrophages accumulate
gain and muscle loss through reduced mobility, dependency in parallel to adiposity in individuals with obesity, promot-
and disability [85]. As a consequence, such individuals show ing inflammation and IR. Indeed, M1/M2 ratio indirectly
higher rate of adverse health consequences including falls correlates with both tissue-specific and whole-body insu-
and fractures, decreased mobility [86], poor quality of life lin sensitivity [114]. Dysfunctional adipocytes induce M1
and hospitalization [87] as compared to patients with iso- phenotype shifting by altering several intracellular path-
lated obesity or sarcopenia. Furthermore, systematic reviews ways including IKK, JNK1, HIF and TLR signals against
and metanalysis report SO as a strongly predictor for all- IL-4- and IL-13-mediated phosphorylation of STAT6 and
cause mortality [88, 89]. expression of the lipid-sensing nuclear factors PPAR-γ and
PPAR-δ [115, 116] M1 macrophages produce IL-1β, IL-6,
TNFα and ROS further reducing insulin signaling in adipo-
4 How does obesity affect the heart? cytes. As a result, the number of M1 macrophages parallels
the expansion of adipose tissue, exacerbating inflammation
4.1 Inflamm‑aging and metaflammation and IR. Many of those mediators may be clustered in the
emerging concept of senescence-associated secretory pat-
The term “inflamm-aging” merges two words “inflamma- terns (SASP), increasingly considered leading driver of
tion” and “aging” to describe the chronic, sterile, low-grade age-related disorders [117]. Among different molecules
inflammation characterizing elderly individuals and play- our research group has long time focused on the role of
ing fundamental roles in different age-dependent chronic OPN – above described as upstream mediators of adipo-
diseases or conditions [5, 104–107]. Increased body fat cyte dysfunction – is an interesting candidate bridge with
composition and IR strongly associates with aging through cardiometabolic risk [118, 119]. Finally, gut microbiota
several cellular and molecular mechanisms including also plays central roles in energetic homeostasis, as it can

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release inflammatory and anti-inflammatory products con- its common association with conditions affecting the car-
tributing to metaflammation [120]. Patients with obesity diac interstitium (such as hypertension and DM). Effects
present a characteristically overgrowth of Firmicutes phyla of the activation of the renin–angiotensin–aldosterone
(i.e. Lactobacillus and Faecalibacterium) and Escherichia system (RAAS) is consistently noted in the fibrotic myo-
coli against Bacteroidetes [121]. Such “obese microbiota” cardium of these patients. Several cellular pathways are
showed higher ability to extract calories from the diet [122] involved in the fibrogenic program [133]. The link between
as well as being associated with increased gut permeabil- an overactive TGF-β cascade and cardiac fibrosis is well-
ity, leading to increased absorption of bacterial endotox- established and mediated through effects involving Smad
ins [123]. The gut microbiota produces a wide variety of signaling [134, 135]. TGF- β stimulates different other
metabolites because of the anaerobic fermentation of undi- GFs (i.e. epidermal GF, insulin-like GF-1, growth differ-
gested food [124]. Short-chain fatty acids (SCFAs) includ- entiation factor-11 and CTGF) involved in the inhibition of
ing acetate, propionate and butyrate are main metabolites myofibroblast apoptosis leading to a vicious circle of sus-
of gut microbiota providing important anti-inflammatory tained and progressive fibrotic response [136]. The altered
effects. Studies showed that a reduction in the levels of adipokine balance also play a role in cardiac fibrosis and
SCFAs generate intestinal inflammation and foam cell for- dysfunction. Impaired leptin/adiponectin ratio was impli-
mation, contributing to gut barrier disruption and favoring cated in the pathogenesis of cardiac remodeling in obesity
bacterial translocation including mobilization of lipopoly- and metabolic dysfunction being a marker of inflammation
saccharides (LPS), trimethylamine N-oxide (TMAO) and [137]. Elevated circulating leptin levels were associated
phenylacetyl glutamine (PAGIn) which, in general circula- with left ventricular hypertrophy and fibrosis [138, 139].
tion, induce systemic inflammation, macrophage activation On the contrary, adiponectin exerts anti-fibrotic and anti-
and favor atherosclerosis [125]. inflammatory effects on cardiac fibroblasts, presumably
mediated by PPAR-α activation [140, 141]. OPN has been
4.2 Cardiac fibrosis widely associated with cardiac remodeling in both experi-
mental and clinical studies [142, 143].
The strong association between obesity and CVD directly Although not listed among adipokines, neprilysin is
involves the heart, independent of the atherosclerotic largely expressed on the surface of mature adipocytes in peo-
process. Several stress factors are involved in substantial ple with obesity [144]. This molecule degrades endogenous
changes at molecular, cellular, and interstitial levels in natriuretic peptides increasing renal sodium reabsorption,
obese hearts including dysregulated activation of different aldosterone secretion from the adrenal gland, cardiac inflam-
neuro-hormonal systems, hyperinsulinemia and inflam- mation and fibrosis. In subjects with obesity and HFpEF
mation [126]. Cardiac cells respond to such an environ- soluble neprilysin levels and its inhibition decreased ven-
ment eliciting the hypertrophic growth response through tricular overload and improved LA overfilling [145].
secretion of cytokines, growth factors (GFs), vasoactive Matricellular proteins are upregulated in remodeled
peptides, and hormones [127]. Although considered an hearts and regulate inflammatory, fibrotic and angiogenic
adaptation mechanism, such response associates with cell responses [146]. Thrombospondins (TSP), tenascins, Cilp-1,
death, fibrosis, and microvascular dysfunction. Cardiac secreted protein acidic and rich in cysteine (SPARC), osteo-
fibrosis plays an important role in the pathogenesis of pontin and members of the CCN family are involved in a
heart disease in patients with obesity causing impaired variety of cardiac pathophysiologic conditions such as MI,
diastolic function, altered contraction, atrial and ventric- cardiac hypertrophy, aging, diabetic cardiomyopathy and
ular remodeling eventually leading to heart failure with valvular disease. TSP-1 is the best-characterized matricel-
preserved ejection fraction (HFpEF), atrial and ventricular lular protein in obesity, DM and MetS and it is potently
tachyarrhythmias and increased incidence of sudden death induced by hyperglycemia [147]. The role of TSP-1 in car-
[128]. Cardiac fibroblasts are the most abundant interstitial diac remodeling was largely explored in clinical and pre-
cells in myocardium and are responsible for the forma- clinical studies, confirming its regulatory effect in fibrotic
tion and preservation of the matrix network [129]. Cardiac response of injured myocardium, deposition of collagen
fibroblasts can influence cardiac function through direct and angiogenesis [148-150]. Accordingly, such mediator is
and indirect effects on cardiomyocytes [130]. While in increasingly seen as a potential target for novel drugs in this
young individuals, cardiac fibroblasts maintain quiescence context (Fig. 1).
exhibiting limited inflammatory or proliferative activity, in
aging hearts cardiomyocyte loss parallels the expansion of 4.3 Ectopic adipose tissue
the interstitium and increased collagen content due to acti-
vation of fibroblasts [131, 132]. Documentation of cardiac Obesity-related vascular dysfunction is not only character-
fibrosis in the isolated obesity is challenging considering ized by increased collagen deposition within the vascular

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• Dysmetabolism Cardiac fibrosis in

• MetS Hypertrophic Myofibroblasts in
• Hyperinsulinemia proliferation with
dysmetabolic subjects
cardiomyocyte
• Inflammation deposition of
• Hypertension ECM

Perimysial,
perivascular,
and endomysial
fibrosis

Causing:
- Cells death
- Fibrosis
Secretion of: - Microvascular dysfunction
- Cytokines
- Growth Factors Clinically:
- Vasoactive peptides - HFpEF
- Hormones - Arrhythmias
- Sudden death

Fig. 1  Cardiac fibrosis in dysmetabolic subjects. Patients with dysme- deaths, microvascular damages, and deposition of excessive extra-
tabolism are at higher risk of developing cardiac fibrosis. The long- cellular matrix. Consequently, patients frequently experience heart
term exposure to inflammatory, oxidative, and hyper-insulinemic failure, especially HFpEF, eventually arrhythmias, and even sudden
environment causes the secretion of several molecules that concur death. HFpEF, heart failure with preserved ejection fraction; TGF-β,
in causing cardiac fibrosis. Microscopically, this process causes cells transforming growth factor beta; TSP-1, tronbospondin-1

wall and progressive arterial thickening but also by perivas- role in physiological and pathological modulation of coro-
cular fat accumulation and inflammatory infiltrate [151]. nary homeostasis. EAT is located on the surface of the myo-
Perivascular adipose tissue (PVAT) is located around most cardium in direct contact with coronaries and accounts for
large blood vessels close to the vasculature and direct con- ≈5% to 20% of the heart weight [163]. Age, WC, ethnicity,
tact with the adventitia, providing mechanical protection and and cardiac mass are independent determinants of EAT vol-
regulation of blood vessel tone via paracrine and vasocrine ume [164]. Of interest, EAT volume is a known risk factor
pathways [152, 153]. PVAT’s phenotype is heterogeneous for CAD, HFpEF and AF [165]. Specifically, EAT thickness
and strongly location-dependent [154, 155]. In lean indi- has been correlated with the presence of high-risk/unstable
viduals, PVAT is mostly thermogenic brown and beige, coronary plaques [166] and coronary microvascular impair-
located in the cervical, supraclavicular, axillary, paraspi- ment [167, 168]. Similarly to PVAT, EAT releases factors
nal, renal and epicardial regions [156, 157]. Instead, the (i.e. adiponectin, leptin omentin-1, nitric oxide, palmitic
abdominal aorta and mesenteric vasculature are surrounded acid methyl ester prostacyclin) and cytokines that affect
by white adipocytes, also found in visceral and subcutaneous both vascular and myocardial homeostasis through paracrine
adipose depots [158]. Functional PVAT secrets a number and vasocrine pathways [169]. Recent studies focused on the
of adipokines (i.e. adiponectin and angiotensin 1–7) with role of EAT-released exosomes, through which EAT carries
antithrombotic and vasodilating effect on the vasculature lipids, proteins, ribonucleic acids (RNAs), and microRNAs,
[159, 160]. Moreover, PVAT is populated with different facilitating intercellular signaling. According to these stud-
immune cells important for vascular homeostasis (i.e. regu- ies, EAT’s exosomes may be implicated in a number of CVD
latory T-cells) [161]. Obesity induces changes in the vasoac- such as MI, adverse cardiac remodeling and atrial fibrillation
tive factors in which the beneficial paracrine effect of PVAT (AF) and are currently investigated for their potential role in
is shifted to a pro-oxidant, pro-inflammatory, contractile and modulation of myocardium healing [170, 171].
trophic environment [162]. Furthermore, the dysfunctional Although not close to myocardial tissue, ectopic
PVAT promote endothelial dysfunction, atherogenesis, vas- fat accumulation in the liver, skeletal muscle, and kid-
cular IR, impaired relaxation, and vascular stiffness. Quite ney belong to the central tenets of adiposopathy [172].
different from PVAT, the interest to the epicardial one (EAT) Macrovesicular steatosis involving more than 5% of
has grown rapidly in the past decade after the discovery of its hepatocytes is considered the cut-off point triggering a

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multiple-hit cascade is mainly characterized by lipotox- 5 Obesity phenotypes and cardiovascular risk
icity, but would also include mitochondrial dysfunction,
endoplasmic reticulum stress, hypoxia. Those mechanisms Obesity phenotypes have been shown to impact on CV
would include cytokine unbalance, hypothalamic signal- diseases differently (Table 4 and Fig. 2). For coronary vas-
ing modifications and changes in microbiota. Although far cular and microvascular disease risk increases in MUO
from myocardial tissue, non-alcoholic fatty liver disease is proportional to the number of MetS defining criteria
has been associated with right ventricular dysfunction (hypertension, dyslipidemia, glucose intolerance and the
and right bundle branch block, AF and QTc prolonga- degree of WC) [175, 176]. Direct negative effects of ener-
tion [173]. Although less is known about other ectopic fat getic dysmetabolism related to MUO and NUNW on car-
depots, increasing data are describing those within skeletal diac structure are diverse and fall within the broad family
muscle. They are highly expressed in diabetic patients and of metabolic cardiomyopathies [177]. The hallmark of this
associated with cardiovascular risk and poor outcome after condition is the development of left ventricle hypertrophy
cardiovascular events [174]. Similarly, peri-renal fat has (LVH), independently related to the predominance of obe-
been demonstrated an index of sub-clinical atherosclerosis. sity, hypertension, and diabetes [178, 179]. The pathway

Table 4  Summary of studies linking cardiometabolic disease with different obesity phenotypes
MUNW MHO MUO SO

MetS – ↑ risk insulin resistance –

↑ risk hyper-TAG​
↑ risk low HDL
↑ risk hypertension
vs. normal weight lean [217]
Atherosclerosis ↑ vascular inflammation [203] ↑ peripheral microvascular ↑ peripheral ↑ arterial stiffness [223]
↑ PWV dysfunction (PMID: microvascular ↑ CACS [224]
↑ soft plaques [201] 28,275,071) dysfunction [222] vs. non-sarcopenic
↑ CACS 218vs. normal weight ↑ cIMT [219, 220] ↑ cIMT [220] ↑ cIMT [225]
lean ↑ CACS [218] ↑ CACS [218] vs. non-sarcopenic elderly
vs. normal weight lean vs. normal weight lean
↑ cIMT [221] ↑ cIMT [221]
vs. MUNW < 60y old vs. MUNW < 60y old
HF ↑ LVsD ↑ risk [199, 229, 230] ↑ risk [183] ↓ CRF [216, 234]
↑ LVdD [226, 227] vs. normal weight lean vs. normal weight lean vs. non-sarcopenic HFrEF
↑ risk [228] ↑ LVdD [231] post-menopausal
vs. normal weight lean vs. MUNW woman
↑ risk [183] ↑ risk [230] ↑ LVH [178, 179, 232,
vs. normal weight lean post- over time 233] vs. MHO
menopausal woman = risk than normal weight lean
↑ LVH [178] in post-menopausal woman
vs. MHO (PMID: 33775111)
AF ↑ risk [228] ↑ risk [186, 199, 229, 235] ↑ risk [186] ↑ risk [225]
vs. normal weight lean vs. normal weight lean vs. normal weight lean vs. non-sarcopenic elderly
↓ risk [236]
vs. MUO
CV events/mortality ↑ risk [204, 230, 237] vs. ↑ risk [199, 229, 237, 239, ↑ risk [204, 230, 242] ↑ risk [216, 243, 244]
normal weight lean 240] vs. normal weight lean vs. non-sarcopenic HF and
↑ risk [238] vs. normal weight lean elderly
vs. obese (MHO/MUO) ↑ risk [206, 241] ↑ risk [213]
vs. MUNW vs. non-sarcopenic after STEMI
↑ MI risk
vs. non-sarcopenic elderly

Waist circumference categorized as normal (men < 102 cm and women < 88 cm) or high (men ≥ 102 cm and women ≥ 88 cm). Visceral adipose
tissue and lean mass are non-standardized measures. Metabolic abnormalities refer to the metabolic syndrome defining criteria
BMI body mass index, MONW metabolically obese normal weight, NOW normal weight obese, MHO metabolically healthy obese, MO meta-
bolically obese, SO sarcopenic obese

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from LVH to overt HF is complex and still partially unex- and AF [199]. Similarly, in a nationwide analysis conducted
plored, despite LVH being clearly recognized as an inde- in South Korea, Lee et al. reported a non-increased risk of
pendent predictor of CV mortality [180], stroke, and renal ischemic stroke in MHO individuals [200].
outcomes [181]. Increased left ventricle stiffness and mass On the contrary, MUNW is historically defined as a “fat
impairs the relaxation phase of the cardiac cycle leading mass disease” due to its higher risk of developing MetS and
to diastolic dysfunction, potentially leading to HF with CVD despite normal weight [68]. Several large studies sug-
preserved ejection fraction (HFpEF) [182]. To be noted, gested the absence of correlation between normal weight and
HF with reduced ejection fraction (HFrEF) is reported unhealthy status in patients with CV events, pointing out the
less frequently in patients with MUO and MUNW, and possible role of other risk factors. MUNW individuals carry
mostly associates with acute CV events (e.g., acute MI) a higher incidence of subclinical atherosclerosis assessed by
[183]. Such negative structural and energetic remodeling coronary computed tomography angiography as compared
is—together with inflammation and neuro-hormonal acti- with healthy individuals [201]. Moreover, MUNW associ-
vation—a well-established substrate for arrhythmias [184]. ates with soft atherosclerotic plaques [202] and subclinical
In MUO, cardiac arrhythmias are frequent and precipi- vascular inflammation [203], known predictors of plaque
tated by several co-factors including hypoxia, hypercapnia, rupture and ischemic events. The characterization of CV risk
electrolyte imbalances due to diuretic therapy, CAD and in such patients is far from being yet compete. Few clinical
obstructive sleep apnea [185]. AF is the most common studies explored the incidence of CVD in this subgroup of
sustained cardiac arrhythmia diagnosed in individuals obesity, reporting an increased risk of myocardial infarction
with obesity being an important determinant of stroke, in Chines [204] and Mexican American [205] populations.
HF, MI, dementia, and death in such population [186]. Of interest, a single study evaluated the incidence of HF in
Of interest, positive correlations were found between the MUNW compared with MHO so far, reporting a twofold risk
cumulative metabolic affliction and the risk of incident over 6 years [206]. Regarding AF, MUNW carries twofold
AF [187]. Of paramount, DM and hypertension are well- increased risk as compared with healthy people or to MHO/
known independent risk factor of AF as well as criteria of MUO individuals [207].
the CHA2DS2-VASc-score [188]. As for the relationship Sarcopenia may promote atherogenesis due to relative
between elevated TG and the risk of AF, reports remain fat mass increase in response to loss of muscle mass and
controversial. While the Multi-Ethnic Study of Athero- replacement of myocytes by adipocytes. Hence, an even
sclerosis (MESA) and the Framingham Heart Study (FHS) greater effect on CVD is expected for such a derangement
reported an association between hypertriglyceridemia and with respect to obesity or sarcopenia alone [208]. Despite
AF [189], this was not confirmed by the Niigata Preventive evidence on the relationships between SO and cardiovascu-
Medicine Study and by post-hoc analysis from the ARIC lar risk factors, its association with CVD is far from being
study [187, 190]. Obesity has been identified as the most clarified [209]. Cross-sectional studies have often yielded
common nonischemic cause of SCD [191]. Indeed, its inconsistent results while prospective studies reported
association with SCD is well established [192] and every higher CV events in SO groups compared with the nor-
5-unit increment in BMI indeed confers a 16% higher risk mal body composition groups only when SO was defined
of SCD [193]. Cardiac fibrosis due to LVH, QRS fragmen- by using grip strength and WC criteria [86, 210]. In the
tation, QT prolongation, premature ventricular complexes, Cardiovascular Health Study, a large prospective study
autonomic imbalance and increased EAT [194, 195] may of community-dwelling older men and women, SO based
explain the greater risk of ventricular tachycardia/ven- on WC and muscle strength was associated with the high-
tricular fibrillation in such population [196]. est risk of CVD and HF over 8 years as compared with
Few studies explored and compared the different mecha- healthy subjects [211]. Few studies reported also higher
nisms involved in the development of CV disease (CVD) incidence of myocardial infarction and AF, particularly in
in MHO and MUNW with respect to MUO and metaboli- elderly [212]. Furthermore, patients with SO showed poor
cally healthy individuals. Several studies suggested MHO prognosis after STEMI, characterized by increased rate of
as a pre-MUO condition with an intermediate risk of CVD all-cause death, MI, ischemic stroke, hospitalization for HF
between MUO and the healthy phenotype [197, 198]. How- and unplanned revascularization [213]. The role of body
ever, this relationship may vary depending on the definition composition in the development and progression of HF has
of MHO, the lack of adjustment for some confounding fac- recently received intense scrutiny [214]. In fact, in addition
tors such as age, sex or a history of smoking, and the lack to cardiac dysfunction patients with HF also present abnor-
of separate analyses of the different subtypes of incident malities in body composition such as sarcopenia, SO and
CV events. Individuals with MHO do not appear to carry a cachexia [215] with direct negative impact on their quality
higher risk of MI, ischemic stroke, or CV death than healthy of life and survival. The FRAGILE-HF trial reported an
individuals. On the opposite, they show an increased risk HF high predictive role of SO in predicting mortality in adults

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Higher risk of:

• MI, ischemic stroke, or CV
death compared to MUO
• HF
• AF

Higher risk of:

• Dysmetabolism - MetS
• LVH
MHO • HFrEF
• CV mortality
• Stroke
• metabolic cardiomyopathy
• arrhythmias
• AF
• HF
• MI
• Deposition of EAT

Higher risk of:

A) “Inflammaging” = low, chronic

MUO inflammation associated with aging.
Consequently:
• Cellular senescence
• Mitochondrial dysfunction
• Altered autophagy
• Microbiota dysbiosis

B) “Metaflammation”
Because of ↑↑ nutrients intake =
↑ inflammatory hormones (i.e., leptin)
favouring pro-inflammatory macrophages,
resulting in:
• Sustained inflammation
• Insulin resistance
• ROS production with tissue damages

MUNW
Higher risk of:
• Dysmetabolism - MetS
• LVH
• HF
• CV mortality
• stroke
• metabolic cardiomyopathy
• Deposition of EAT

Higher risk of:

• CV diseases and HF
compared to MHNW
SO • All-cause death after ST-
elevation MI

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 Reviews in Endocrine and Metabolic Disorders (2023) 24:901–919 911

◂Fig. 2  Obesity phenotypes and cardiovascular risk. This figure sum- oxidation in patients with MHO to prevent MetS/DM [249].
marizes the close relationship between the different obesity phe- Suitable approaches include increased aerobic activity, Medi-
notypes and the CV risk. AF, atrial fibrillation; CV, cardiovascular;
EAT, epicardial adipose tissue; HF, heart failure; LVH, left ventricu-
terranean diet, and supplementation with catechins, capsai-
lar hypertrophy; MetS, metabolic syndrome; MHO, metabolically cin, or L-carnitin [250, 251]. Regarding SO, both dietary
healthy obese; MI, myocardial infarction; MUNW, metabolically interventions and regular exercise are reccomended [252].
unhealthy normal weight; MUO, metabolically unhealthy obese; Aerobic activity, resistance training and their combination
ROS, reactive oxygen species; SO, sarcopenic obese
increase muscle protein synthesis in older adults despite age-
related decreases in anabolic signaling [253]. Furthermore,
with HF [216]. However, the lack of universally recognized physical activity leads to the recruitment of muscle satellite
diagnostic criteria remained a non-negligible factor which cells located between myofibers and their surrounding basal
affects patient identification, reliable assessment of SO lamina [254] and downregulation of inflammatory biomarker
prevalence and outcomes. In 2022, the European Society for [255]. SO patients should be advised to follow a hypoca-
Clinical Nutrition and Metabolism (ESPEN) and the Euro- loric high-protein diet (1.2–1.4 g/kg body weight reference/
pean Association for the Study of Obesity (EASO) provided day) to preserve their muscle mass [256]. On the opposite,
the first consensus on SO definition, screening, diagnosis significant weight loss is not recommended for individuals
and staging [81]. Such consensus will help to uniform the with MUNW. These individuals have less fat mass than other
selection criteria of SO patients in future studies. phenotypes, therefore, therapeutic strategies should focus on
improving metabolic health and their effects on different adi-
pose tissue compartments and on lipid accumulation in the
6 Therapeutic management of obesity liver. As an example, the Mediterranean diet reduces the risk
phenotypes of CV events by about 30%, compared with a control diet,
despite having little effect on bodyweight [257]. Anti-obesity
Preliminary results suggest that the different obesity phe- drugs have historically faced multiple issues relating to study
notypes also have different responses to weight loss inter- design, premature termination due to safety issues or failure
ventions, including diets, medications, devices, and surgery to show CV benefit [258]. Furthermore, there is no evidence
[245]. Yet, by now no randomized controlled trials on obesity on obesity phenotype‐specific effects of such medications
treatment compared cardiometabolic outcomes among indi- to date. Metabolic/bariatric surgery remains the most effec-
viduals with different obesity phenotypes. However, numer- tive strategy to accomplish a significant (≥ 30%) and durable
ous studies support the need for a stratification effort in rela- (at ≥ 5 years) weight loss leading to reduced all-cause and
tion to the type of obesity. Weight reduction approaches are CV mortality and lower incidence of several CVD [259].
initially based on incremented on physical activity imple- However, this approach remains strictly recommended only
mentation and dietary strategies. In patients living with obe- for patients with complicated severe obesity.
sity, regular physical activity and aerobic exercise provide
a moderately reduction of risk factors for CAD, including
body fat and body mass, blood pressure, triglycerides, and 7 Conclusions
improved lipoprotein profile. Furthermore, physical activity
improved insulin sensitivity and endothelial function regard- Guidelines from major European and American Societies
less of weight loss. As a result, regular physical activity asso- highlight the importance of effective diagnosis and treatment
ciates with a sensible improvement of obesity-associated of obesity in preventing CVD in clinical practice [8, 260,
complications including CAd [246]. As for the diet, despite 261]. Obesity diagnosis may not be as simple as previously
the scientific soundness of energy restriction approaches, thought. Specifically, it cannot depend only on anthropomet-
the evidence shows only modest effects with high individual ric parameters but should include a precise assessment of the
differences and short duration. The Mediterranean dietary metabolic status. Under this point of view different pheno-
pattern has been widely recognized for its protective effects types of obesity have been proposed each one with specific
on obesity, CVD and DM in addition to decreasing all-cause effects on the CV system and with different responses to
mortality [247]. In MUO phenotype, weight loss is the cor- anti-obesity interventions. The current lack of standardized
nerstone of the clinical management. Body weight reduction definitions reflects on a general paucity of experimental
together with a low glycemic index diet have several ben- evidence impacting on the daily ability to provide person-
eficial effects on serum glucose, LDL and blood pressure alized prescriptions to patients living with obesity. Such a
improving CVD risk [248]. In patients with MHO weight complexity requires a multidisciplinary approach including
loss strategies should be recommended to preserve cardio- specialists in obesity medicine, internal medicine, cardiol-
metabolic risk profile and avoid MHO/MUO conversion. ogy, psychology, as well as dieticians, family doctors, and
Several studies highlighted the importance of improving fat bariatric surgeons. Accordingly, the therapeutic management

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of adiposopathy and its CV sequelae should be based on 8. Powell-Wiley TM, Poirier P, Burke LE, Despres JP, Gordon-
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