International Journal of Cardiology 291 (2019) 29–35

Contents lists available at ScienceDirect

International Journal of Cardiology

journal homepage: www.elsevier.com/locate/ijcard

Review

Microvascular complications in diabetes: A growing concern

for cardiologists
Angelo Avogaro ⁎, Gian Paolo Fadini
Department Medicine, Section of Diabetes and Metabolic Diseases, University of Padova, Italy

a r t i c l e i n f o a b s t r a c t

Article history: Randomized, cross-sectional, and prospective studies have demonstrated that microvascular complications in
Received 7 January 2019 patients with diabetes are not only the cause of blindness, renal failure and non-traumatic amputations, but
Received in revised form 6 February 2019 also powerful predictors of cardiovascular complications. Beside the metabolic theory, the pathophysiology of di-
Accepted 15 February 2019
abetic microvascular complications is determined by the interaction among several factors, including epigenetic
Available online 25 February 2019
modifications and the reduced release of progenitor cells by the bone marrow, that contribute simultaneously to
Keywords:
damage and impaired vascular protection against hyperglycemia. Identifying and preventing microvascular com-
Diabetes mellitus plications has the significant potential to reduce major adverse cardiovascular events. For these reasons, there
Microvascular complications may no longer be a rational to consider microangiopathy and macroangiopathy as entirely separate entities,
Coronary heart disease but they should most likely be viewed as a continuum of the widespread vascular damage determined by diabe-
Heart failure tes mellitus.
© 2019 Elsevier B.V. All rights reserved.

1. Introduction to underline that MICRO should be considered in the overall assessment

of treatment efficacy.
Microvascular complications (MICRO) are highly prevalent in pa- Contrary to cardiologists, after the results of the Diabetes Control
tients with diabetes: 38% of the patients with type 2 diabetes (T2D) and Complication Trial (DCCT) and the United Kingdom Diabetes Pro-
present any stage of chronic kidney disease (CKD) [1], almost 30% spective Study (UKPDS) on the role of a good metabolic control on
have retinopathy (DR) [2], and N30% have peripheral neuropathy (PN) MICRO [6,7], diabetologists mostly emphasized the MICRO and deflated
[3]. While the onset and the progression of macrovascular disease the MACRO. Thus, cardiologists and diabetologists perceive the two en-
(MACRO) are determined by the combined negative effects of several tities as separate, and not tightly linked, as it should be. An additional
risk factors, MICRO are mostly determined by hyperglycemia, but signif- relevant point is that MICRO are perceived as existing only in selected
icant roles are also provided by high blood pressure and hyperlipidemia organs such eyes, kidneys, and nerves. Rather, functional and structural
[4]. MICRO can lead to visual impairment, advanced CKD, and amputa- microvascular alterations have been recognized also in other organs
tions; cardiologists tend to underappreciate the clinical significance of such as the heart [8] where they can be viewed as an early event of
MICRO in people with diabetes, while they focus the attention mostly more widespread derangement of coronary circulation (Fig. 1). Note-
on MACRO, without linking the two conditions. The perception that worthy, there is an ample variation in the individual propensity to de-
the clinical importance of MACRO outweighs that of MICRO is wrongly velop MICRO: some patients with chronic metabolic decompensation
dictated by the design of typical cardiovascular outcome trials never develop either CKD or DR, while others display serious complica-
(CVOTs), wherein the primary end-point is composed by the composite tions despite an optimal metabolic control. In the DCCT, duration of di-
of cardiovascular death, non-fatal acute myocardial infarction, and non- abetes and HbA1c explained only about 11% of the variation in the risk
fatal stroke (3-point MACE). MICRO is almost exclusively included as of DR [9]. This may be probably ascribed to the existence of a genetic
secondary outcomes, mostly as renal end-points, frequently ignoring predisposition: relatives of patients with diabetes and DR have approx-
retinal complications, and completely neglecting neuropathy [5]. imately a 2- to 4-fold risk of developing DR compared with relatives of
While this standard has been generated by guidance for industries is- patients with diabetes but without DR. Heritability has been estimated
sued by the U.S. Food and Drug Administration (FDA), it is important to be almost 30% for DR and 52% for proliferative DR [10]. Also CKD
runs in families: the 25-year cumulative incidence of CKD was 25% in di-
⁎ Corresponding author at: Dipartimento di Medicina, Via Giustiniani 2, 35128 Padova,
abetic siblings of probands without CKD, the risk was 43% and 58% in
Italy. siblings of probands with diabetic nephropathy (DN) or end stage
E-mail address: angelo.avogaro@unipd.it (A. Avogaro). renal disease (ESRD) [11]. Thus, consistent data suggest a heritability

https://doi.org/10.1016/j.ijcard.2019.02.030
0167-5273/© 2019 Elsevier B.V. All rights reserved.
30 A. Avogaro, G.P. Fadini / International Journal of Cardiology 291 (2019) 29–35

Fig. 1. The widespread consequence of microvascular disease. DME: Diabetic Macular Edema; eGFR: estimated glomerular filtration rate; BBB: blood brain barrier; ESRD: end-stage renal
disease.

of microangiopathy: for more in depth knowledge on this issue we refer Epigenetic mechanisms, a set of reactions which regulate the activity
the readers to dedicated reviews [12,13]. of DNA without changes in the nucleotide sequence, such as DNA meth-
We believe that MICRO should be considered as a continuum of car- ylation, histone modifications, and the expression of microRNAs can in-
diovascular disease (CVD) in patients with diabetes, and their clinical fluence gene expression, and contribute to the onset of MICRO.
and prognostic impact on CVD thoroughly appreciated also by cardiolo- Hyperglycemia increases trimethyl-histone H4 lysine 20 (H4K20me3)
gists. This concept is underscored by the findings that having MICRO in- at retinal superoxide dismutase (sod)2, while reversal of hyperglycemia
creases by 18% the risk of a composite endpoint of cardiovascular death failed to prevent these alterations, suggesting that epigenetic changes
or heart failure hospitalization [14], and that having one or three MICRO not only are causative of DR but they may also explain the so called met-
increase the risk from 32% as compared to none to 99%, respectively abolic memory [19,20], a condition in which changes in microcircula-
[15]. tion due to hyperglycemia are relatively reversible if an early and
adequate control of blood glucose is achieved [21]. The epigenetic regu-
2. Pathophysiology of microangiopathy: old and novel insights lation of oxidative stress in endothelial cells has been further clarified by
Paneni and Cosentino, who showed effects of hyperglycemia through
In the recent years, several mechanisms have been identified to ex- the activation of p66shc, a mitochondrial adaptor protein, that is epige-
plain the pathogenesis of MICRO in patients with diabetes (Supplement netically regulated by the promoter CpG hypomethylation: this effect
Fig. 1). Unfortunately, in this article only selected mechanisms have maintains protein kinase (PKC) βII upregulation thus leading to
been taken into account, since a comprehensive review of the pathways glucose-induced ROS production and detrimental “metabolic memory”
promoting the development of diabetic complications is beyond the [22–24]. Epigenetic modifications were also shown in several genes
scope of the manuscript. Among these the so called “metabolic hypoth- coding for proteins mediating antioxidant [25,26], and pro-oxidant ef-
esis”, clarified by Brownlee and coworkers, who showed that high glu- fects in the retina [27], and kidney [28–33].
cose concentrations lead to a maladaptive production of reactive The renin-angiotensin system (RAAS) has been implicated in the
oxygen species (ROS) within endothelial cells [16]. The metabolic the- pathogenesis of MICRO: the use of angiotensin-converting enzyme
ory foresees an increased aldose reductase substrate conversion, In- (ACE) inhibitors, angiotensin type-1 receptor blockers (ARB), and
creased intracellular formation of the advanced glycation end- their combination may delay both the onset and the progression of
products methylglyoxal, activation of protein kinase C β, δ, and θ, in- CKD and DR [34,35]. The endoplasmic reticulum stress (ERS) induced
creased protein modification by O-acetylglucoseamine, an increased by misfolded proteins, and intracellular calcium perturbations, may
production of reactive oxygen species (ROS), and decreased concentra- play a role in the pathogenesis of MICRO [36]: unresolved ERS initiates
tion of anti-oxidant enzyme such as Decreased Nuclear Erythroid– signaling that promotes apoptosis. The break of this process protects
Related Factor 2 (Nrf2). from DN, improves permeability in the retina, and ameliorate peripheral
Low grade inflammation is a major factor leading to atherosclerosis: DN. Finally, diabetes compromises mechanisms of tissue repair. Our
this condition, mediated by the nod-like receptor family pyrin domain group have found that reduced number of circulating endothelial pro-
containing 3 (NLRP3) inflammasome, leads to increased levels of genitor cells (EPC) is associated with MICRO [37]. Low CD34+ EPC
citokines, and, subsequently, to cell death known as pyroptosis [17]: in- count correlate with the progression of CKD, DR, and PN even after cor-
terestingly, this pathway may also represent the common denominator rection for age, HbA1c, and duration of the disease [38]. It was experi-
between metabolic alterations and premature ageing [18]. mentally shown that autonomic neuropathy and loss of the circadian
 A. Avogaro, G.P. Fadini / International Journal of Cardiology 291 (2019) 29–35 31

rhythm leads to impair release of EPCs, to their blunted functionality, examination should be performed every 1–2 years. In the presence of
and to DR [39]. However, the reduced circulating EPC levels is mostly re- DME and/or severe non-proliferative diabetic retinopathy patients
lated to the presence of a so called “diabetic mobilopathy”, the incompe- must be immediately referred to an ophthalmologist.
tence of the bone marrow (BM) of patients with diabetes to efficiently Randomized controlled trials, cohort studies, retrospective studies,
respond to ischemic stimuli [40]. Different causes have been hypothe- and meta-analyses show that the presence of any retinopathy, and par-
sized to explain this condition, but an important role may be played ticularly proliferative retinopathy and DME confer an increased risk of
by resident macrophages in the BM. It has also been described a specific all-cause mortality, coronary heart disease (CHD) (Fig. 2), hospitaliza-
MICRO of the BM [41], which could further explain the low EPC count: tion for heart failure (hHF), stroke, and lower limb amputation both in
since low EPC also strongly associated with major adverse cardiovascu- type 1 and type 2 diabetes (Supplemental Table S1). The pathophysio-
lar events, this regenerative defect may represent the link between logical link between DR and CHD has been a matter of debate. On the
MICRO and MACRO in patients with diabetes [42]. As it can be appreci- one side, pathologic angiogenesis plays an important role in the devel-
ated, a consistent amount of detrimental mechanisms explain the path- opment of retinopathy, while defective vascularization is a key factor
ogenesis of MICRO in patients with diabetes. Notably, most of these in CHD. This dichotomous behaviour has been identified as the diabetic
mechanisms damage not only the endothelial cells in the microcircula- paradox [48]. DR may be simply a marker of a widespread continuum of
tion, but also the endothelial layer in the macrocirculation: therefore the the vascular disease induced by the diabetic state [49], or a representa-
glucose-mediated endothelial dysfunction may be indeed represent the tion of the same pathologic processes taking place in the cardiovascular
link between MICRO and MACRO in patients with diabetes. system. Kampschulte and colleagues, using ex vivo micro-CT scans,
demonstrated that pathological sprouting pattern, similar to that ob-
3. Retinopathy, macular edema and cardiovascular disease served in the retina, can also be observed in vasa vasorum of small ani-
mal models of atherosclerosis [50]. Pathologic angiogenesis also
Retinopathy is a common complication of diabetes: its onset and associates with inflammation and increased permeability, equivalent
progression are closely related to plasma glucose. A 1% increase in to those observed in DME [51]. In general, MICRO is associated with cor-
HbA1c is associated with N30% increase in retinopathy risk, with N20% onary plaque progression with a subsequent compromised structural
in its progression, and with almost 15% increase in blindness [43]. Re- integrity of microvascular endothelium, which may explain both a
cently, the concept of DR as a MICRO has evolved into the concept of broad spectrum of coronary syndromes and HF [52], and the leakage re-
neurovascular unit composed by several cellular phenotypes, including sponsible for intraplaque haemorrhage in coronary plaques [53]. Thus,
endothelial cells, pericytes, glial cells, microglia and neurons: diabetes we should emphasize the importance of the retina as a mirror of a
impairs all these components [44]. Diabetic macular edema (DME) is more widespread MICRO, and highlight the concept that MICRO is not
another sight-threatening complication of diabetes, and represents an confined only in the retina but it is frequently present within the cardio-
accumulation of fluid within the central portion of the retina, which vascular system.
arises as a consequence of failure of the blood-retinal barrier (BRB). Dif-
fuse edema is caused by extensive capillary leakage, whereas localized 3.1. Neuropathy and cardiovascular disease
edema is caused by focal leakage from grouped microaneurysms [45].
DME is classified as a distinct entity from DR because it can occur in iso- Diabetic neuropathy may occur in proximal or distal nerve fibers as
lation without other signs of microangiopathy in the retina. DME is mononeuritis or may affect the somatic or autonomic nervous system.
often associated with hard exudates and causes blurring and distortion Distal symmetric polyneuropathy affects up to one third of persons
of central vision. The Wisconsin Epidemiologic Study of Diabetic Reti- with type 1 or type 2 diabetes [54]. Decreased sensation confers a pre-
nopathy found that 20% of patients with type 1 diabetes and 25% of disposition to painless foot ulcers and subsequent amputations. The life-
those with type 2 diabetes will develop DME after 10 years of follow- time risk of a foot lesion, including an ulcer or gangrene, is 15 to 25%. A
up [46]. neuropathic foot ulcer per se increases the odd of having CHD by N3-fold
The 2019 Standards in Medical Care in Diabetes [47] state that adults [55]. Particularly in patients with long diabetes duration, autonomic
with type 1 diabetes should have a comprehensive eye examination neuropathy (AN), when it involves the cardiac function, independently
within 5 years after the onset of diabetes while patients with type 2 di- predicts risk of CV death and AMI. The ADA guidelines state that a
abetes should have a comprehensive eye examination at the time of the screening for diabetic neuropathy should be performed at diagnosis in
diabetes diagnosis. If there is no evidence of retinopathy, a follow-up patients with type 2 diabetes, and 5 years after the diagnosis of type 1

Fig. 2. The prediction of diabetic retinopathy on incident CHD (left panel) and HF (right panel) in cohort studies.
32 A. Avogaro, G.P. Fadini / International Journal of Cardiology 291 (2019) 29–35

diabetes, and at least annually thereafter [47]. Most importantly, symp- abnormalities, chronic inflammation, sodium overload, and uremic
toms and signs of autonomic neuropathy (AN) should be assessed in pa- toxins [69]. Nonetheless, the precise link between albuminuria and
tients with MICRO. As shown in Supplemental Table S2, when CVD has not been entirely clarified: therefore, it is unclear whether pro-
considering publications reporting outcomes, alterations of several tein loss in the urine is causative of vascular damage or simply a marker
measures of autonomic functions, such as orthostatic hypotension, of it. Some hypothesis have been proposed such as: 1. endothelial dys-
heart rare response (HRR) to adenosine, RR interval, heart rate variabil- function as common ground between CKD and CVD [70]; 2. reduced
ity were all linked to substantial increased mortality, AMI, and HF. levels of heparan sulfate, which exerts anti-thrombogenic effects and
The presence of AN disrupts the so called sympatho-vagal balance, decreases vessel permeability in the glycocalyx [71]; 3. Low grade in-
and predisposes to arrhythmias and sudden cardiac death [56]. To un- flammation being the common soil of CKD and CVD [72]. Whatever
derstand the mechanisms responsible for this condition, we assessed the mechanism(s), two important facts remain: first albuminuria is a
the mechanisms of exercise-induced left ventricular (LV) dysfunction powerful risk factor for MACE not only in patients with diabetes but
in asymptomatic patients with type 1 diabetes in the absence of hyper- also in non-diabetic individuals: a ACR N 30 mg/g confers a 41% higher
tensive or coronary artery disease [57]. Myocardial iodine-123 risk of hHF, and a ACR N300 mg/g an 88% higher risk [73]. Second, the
metaiodobenzylguanidine (MIBG) uptake, a method to assess adrener- relationship between albuminuria and CV disease extends below tradi-
gic cardiac innervation, was significantly blunted in patients with diabe- tional lower-limit thresholds of albuminuria: in the Framingham Off-
tes, with a strong linear correlation between left ventricular ejection spring Study without prevalent CV, hypertension, diabetes, or kidney
fraction (LVEF) at peak handgrip and myocardial MIBG uptake normal- disease, an albuminuria as low as 5.3 mg/g in men and 10.8 mg/g in
ized for LV mass. These findings have been confirmed by others [58]: in- women discriminated between incident CHD, HF, peripheral vascular
terestingly, in patients with diabetes and with HF showed lower cardiac disease, or death [74]. For these reasons, the 2019 ADA recommenda-
sympathetic activity than HF patients not having diabetes or than pa- tions state that, at least once a year, urinary albumin and eGFR in both
tients with diabetes and with a similar degree of autonomic dysfunction patients with type 1 and type 2 diabetes.
not having HF [59]. The underlying alteration of β-adrenoceptor (β-AR)
signaling in AN is a major factor for cardiac dysfunction in patients with 3.3. The case for treating microvascular complications
diabetes: this has been confirmed in animal studies showing a reduction
of left ventricular β-AR, and a parallel Gs (guanine nucleotide binding Both the 2019 Medical Care Guidelines and the 2018 Consensus Re-
protein stimulatory) reduction [60]. The clinical importance of these al- port by the ADA and the EASD [47,75] endorse specific therapeutic ap-
terations is magnified in response to insulin-induced hypoglycemia, proaches that should be followed not only by diabetologists but also
during which various degrees of heart block are observed, mediated by cardiologists, in patients with diabetes especially if they share pa-
through a maladaptive sympatho-adrenal activation of β1 adrenergic tients either with CVD or HF and MICRO. These approaches derived
receptors [61]. Overall, it is clinically relevant to rule out or confirm both from the old efficacy trials (treat to target) and by the recent
the presence of AN since this condition may aggravate the clinical out- CVOTs (treat to benefit). Needless to say that glucose control must be
look of patients with diabetes. Unfortunately, beside a good metabolic optimized to reduce the risk or slow the progression of MICRO. How-
control, there is no specific treatment for this complication nor robust ever, it is important not only to reduce glucose but how this is reduced:
results from the CVOTs that suggest that the innovative antidiabetic for patients with type 2 diabetes and CKD, we should consider the use of
drugs could modify the natural history of neuropathy. a sodium-glucose cotransporter 2 (SGLT2) inhibitor or glucagon-like
peptide-1 receptor agonist (GLP-1RA) that have been shown to signifi-
3.2. Diabetic kidney disease and cardiovascular disease cantly reduce the risk of CKD and CVD or both [76]. These drugs should
be prescribed according to renal function, and specific contraindica-
Diabetic kidney disease is a heterogeneous condition, such that in tions. However, it should be bear in mind that the use of GLP-1RA
patients with diabetes, various kidney diseases may coexist. The Na- yielded conflicting results in the Trial to Evaluate Cardiovascular and
tional Kidney Foundation Work Group for Diabetes affirmed that the Other Long-term Outcomes with Semaglutide in Subjects with Type 2
presence of retinopathy in patients with a urinary albumin/creatinine Diabetes (SUSTAIN-6), where the drug increased the risk for retinopa-
ratio (UACR) N300 mg/g strongly suggests a classic DN, while a reduced thy by 76% [77]. Yet, this relationship has not been replicated [78]. Fur-
estimated glomerular filtration rate (eGFR) and albuminuria ther studies will be necessary in order to precisely identify the role of
30–300 mg/g creatinine may suggest nondiabetic CKD [62,63]. The con- both SGLT2 inhibitors and GLP-1RA on all the components of the retinal
certed and negative actions of both hyperglycemia and inflammation neurovascular unit. The control of blood pressure with RAAS inhibitor
alter the fenestrated glomerular endothelium, leading to the loss of glo-
merular permeability and selectivity, followed by glomerular cell apo-
ptosis and a concomitant triggering of abnormal angiogenesis [64].
Maladaptive expression of angiogenetic factors, mainly vascular endo-
thelial growth factor (VEGF), causes further albuminuria. In classic DN,
mesangial expansion, glomerular basement membrane thickening,
and podocyte loss are observed: the latter being the best predictor of al-
buminuria and progression [65]. A crowd of RCT, observational, and ret-
rospective studies [66,67] have definitively confirmed that both DN and
CKD substantially increased the risk for CVD (Table S3). An additional
validation of both the existence of a cardio-renal syndrome, and the im-
portance of the kidney protection as a major drive of CV protection
comes from the 12 available CVOTs: in these trials it appears that a pos-
itive primary outcome may be associated to a positive renal outcome
(Fig. 3).
A reduced eGFR as an indicator of reduced function increased the
odd ratio for CV risk from 1.5 for a eGFR of 60–89 to an odd ratio of
10–50 for eGFR b15 [68].
There are several explanations linking CKD to adverse cardiovascular Fig. 3. Correlation between the percentage decrement in the risk of primary end-point and
outcomes, including dyslipidemia, anemia, calcium/phosphate the percentage decrement in renal end-point.
 A. Avogaro, G.P. Fadini / International Journal of Cardiology 291 (2019) 29–35 33

Fig. 4. The additive effect of traditional risk factor for CV disease, diabetes, microvascular complication, and events in the natural history of vascular disease in patients with diabetes.

and of blood lipids is equally important also for DR and DN. In the pres- Servier, Vifor Pharma, Jannsen, and Takeda. GPF received grant support,
ence of ongoing CVD, the coexistence of retinopathy is not a contraindi- lecture or advisory board fees from AstraZeneca, Boehringer-Ingelheim,
cation for the use of aspirin therapy. There have been some concerns on Eli Lilly, NovoNordisk, Sanofi, Genzyme, Abbott, Novartis, Merck Sharp &
the use of GLP-1RA in the presence of HF and DR, as well as the use of Dohme.
dipeptidyl peptidase (DPP-4) inhibitors in the presence of HF. Indeed
the use of saxagliptin [79] and liraglutide [80] as antidiabetic drugs Authors' contribution
should not be supported in patients with advanced HF, as semaglutide
in the presence of severe diabetic retinopathy [77], although the rela- Data collection and analysis: AA and GPF. Manuscript writing: AA
tionship between GLP-1RA and retinopathy has been thoroughly and GPF. All authors approved the final version of the manuscript.
questioned [81].
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