Main Findings
To our knowledge, this is the first study investigating the relationship between platelets morphology and central non-dipping pattern in the T1DM population. We found that MPV and PDW were significantly higher in central non-dippers compared to dippers among people with T1DM. MPV and PDW were independently positively associated with the presence of a central non-dipping pattern.
There are different methods to assess platelet reactivity, but many of them are complicated and high-priced [28]. The alternative is MPV, an indirect method of platelet activity measurement. It correlates with platelet aggregation markers, which are easy to perform and cost-effective [29]. Higher MPV correlates to a higher number of dense bodies per platelet, LDH activity, speed of ADP-induced aggregation, serotonin uptake, and release [30]. However, many other factors could influence MPV: genetic variants, race, ethnicity, age, sex, and lifestyle [31].
It is known that hypertension relates to a hypercoagulable state, resulting from increased platelet activity. Hypertensives have higher MPV and higher quantity of P-selectin and beta-thromboglobulin normotensives. These proteins take part in platelet activation [32]. Gang et al. in a prospective study with a 9-years follow-up proved that elevated MPV allows predicting the development of hypertension independently of other risk factors like age, gender, and SBP [33]. Prehypertension is also associated with higher MPV [34].
Chinese prospective study in a large group of 31751 people revealed that higher values of MPV were associated with a higher risk of stroke, cardiovascular disease, and coronary heart disease after six years of follow-up. Higher PDW was related to a higher risk of cardiovascular disease and coronary heart disease [9]. Higher MPV is also associated with a higher risk of restenosis after percutaneous transluminal coronary angioplasty [10].
Both non-dipping pattern and increased MPV are associated with elevated cardiovascular risk [5, 35]. However, the pathophysiology of the relationship between the non-dipping pattern and MPV is unknown. The non-dipping pattern is related to higher nighttime SBP and the same higher mean diurnal SBP. Increased BP may lead to endothelium damage which results in elevated shear stress, an imbalance between free radicals and antioxidants, platelet activation, and aggregation [36]. Another possible pathomechanism is the impairment of the autonomic nervous system – low parasympathetic and high sympathetic activity. Catecholamines may stimulate alpha-2 adrenoreceptors which induce platelet aggregation [37]. This theory also suggests that adrenaline causes the release of the large activated platelets sequestered in the spleen [38].
It is known that the presence of diabetes is associated with increased platelet activity. Shimodaira et al proved that MPV was positively, independently related to fasting plasma glucose among both individuals with prediabetes and healthy people with normal glucose levels [39]. In children with T1DM MPV was related to aortic intima-media thickness which is an early indicator of subclinical atherosclerosis [40]. Abdel-Moneim et al compared three groups of children: with established T1DM (duration: 0.66± 0.4 years), with newly-diagnosed T1DM (duration: 0.66±0.4 years), and healthy controls. MPV and PDW were significantly higher in children with T1DM than those in the control group [41]. Platelet number was lower in children with established T1DM than in children with the newly diagnosed disease and controls. MPV was related to HbA1C among people with T1DM as opposed to T2DM subjects [11]. Children with HbA1C ≤7.5% had significantly higher MPV and PDW than children with HbA1C below 7.5%. MPV was positively correlated with T1DM duration [12].
The relationship between platelets morphology and dipping pattern among T1DM subjects is uninvestigated. Our study is the first one and revealed the need for further research. Nevertheless, there are some works focused on dipping pattern in this population. Theilade et al investigated for the first time the central dipping among subjects with T1DM [42]. They proved that nocturnal central and brachial SBP fall decreased with diabetes duration and albuminuria. There was an association between HbA1C and non-dipping pattern [43]. However, Mamta et al observed no relationship between brachial non-dipping pattern and glucose variability in subjects with T1DM [44]. Another study showed that nephropathy (but not other diabetic complications) was independently associated with a brachial non-dipping pattern [45]. Spallone et al suggested the role of autonomic neuropathy in the development of nephropathy and non-dipping pattern in T1DM subjects, but further studies did not confirm that relationship [46, 47]. In our study, we did not observe such associations. The groups did not differ in long-term diabetic control (HbA1C, skin autofluorescence), presence of diabetic complications, and insulin resistance (eGDR). However, the central non-dipping pattern was independently, positively related to daily insulin intake. The whole study group was relatively young and had a low level of albumin to creatine ratio. It suggests that the non-dipping pattern may develop independently of glycemic control.
The prevalence of non-dipping pattern among people with T1DM is uninvestigated because few studies have been published on this topic. It was noted by Jaiswal et al. [44]. In their study, the prevalence of non-dipping pattern in 41 T1DM subjects was only 10%. A previous study by Stella et al showed that 27,8 % of 61 T1DM entities were non-dippers [45]. The prevalence was 40,3% for the brachial non-dipping pattern and 58.1% for the central non-dipping pattern in our study.
In the literature, several works describe the association between MPV and non-dipping pattern, but all of them are based only on brachial BP. MPV is thought to be higher in non-dippers than dippers among people with hypertension treated at least 6 months [14]. Inanc et al. demonstrated that non-dippers have higher MPV than dippers and normotensives [15]. Other studies confirmed the positive relationship between MPV and non-dipping patterns among hypertensives [16, 17, 48]. A similar finding was obtained among hypertensive children, people with uncontrolled hypertension, and prehypertensive non-smokers [18, 49]. Meric et al. observed that the mean platelet volume/ platelet count (MPV/PC) ratio was significantly higher in non-dippers than dippers and it could be used to predict non-dipping pattern with 95 sensitivity and 95 specificity [19]. In our study MPV was higher in central non-dippers than dippers. There were no significant differences in MPV based on the brachial dipping pattern. However, MPV was independently associated with a brachial non-dipping pattern in the multivariate regression model. We found no association between dipping pattern and MPV/PC ratio.
Previously described studies were performed in relatively small populations. On the contrary, Pusuroglu et al. found no difference in MPV between hypertensive dippers and non-dippers in the group of 840 participants [50]. However, MPV was significantly higher in hypertensives compared to normotensives. The non-dipping pattern was diagnosed only in hypertensives, so there was no information on how many subjects without hypertension were non-dippers. We included only subjects with T1DM and without diagnosed hypertension. In our study group, there was no difference in MPV between dippers and non-dippers based on peripheral BP, but MPV was significantly higher in central BP non-dippers than dippers. Further studies are needed to confirm if MPV is more strongly associated with central than brachial dipping.
In our study, we excluded people with alcoholism. However, non-dippers consumed significantly more standard units of alcohol per week than dippers. Even small amounts of alcohol may be associated with the non-dipping pattern but because of the cross-sectional character of our study, we cannot find any cause and effect relationships.
Strengths and practical implications
We proved for the first time the relationship between non-dipping pattern and MPV among people with T1DM. Moreover, this is the first study investigating not only the brachial but central non-dipping pattern and its association with platelets morphology. Several studies proved that brachial non-dippers have higher MPV than dippers. We also showed that PDW (which was not investigated earlier) is higher in people without appropriate nocturnal fall in BP.
Those results bring practical implications because people with non-dipping pattern and increased platelet activity have elevated cardiovascular risk. Thanks to 24-hour BP measurement, PDW, and MPV, it is possible to identify them. We know that in non-dippers increased platelet activity should be suspected. These people should be watchfully observed. Non-pharmacological treatment could be useful because 20-weeks lifestyle modification (decreased sodium intake, intensified physical activity, reduction of alcohol consumption, and DASH diet) may reduce MPV in prehypertensive subjects [51]. Aspirin and other antiplatelet drugs are not recommended in primary prevention among T1DM subjects with low or moderate cardiovascular risk [52]. According to the ASCEND study, aspirin brings more side effects than benefits, in primary cardiovascular prevention among people with diabetes [53]. However, this data is based mostly on subjects with type 2 diabetes mellitus and the topic remains controversial. People with diabetes with non-dipping pattern and increased platelet activity may have benefits from using antiplatelet drugs. Further studies are needed to establish proper treatment for T1DM subjects with a non-dipping pattern.
Limitations
Our study has some limitations. We did not measure cardiac autonomic neuropathy, which could influence on dipping pattern. However, studies did not confirm the relationship between non-dipping pattern and autonomic neuropathy [47]. We used MPV and PDW as indirect markers of platelet activity and we did not perform more complicated, direct methods of platelet activity assessment. Each participant had only one day of 24-hour BP measurement.