The major findings of our study were that with advent of diastolic dysfunction since 3 month, adiponectin expression and serum concentration decreased simultaneously and increased at 15 month though systolic dysfunction appeared at 18 month. We also demonstrated no distribution differences of adiponectin among visceral adipose tissues.
SHR is a well established hypertension model similar to human hypertension such as the occurrence of LV hypertrophy followed by a transition to heart failure. Therefore SHR has been regarded as a useful tool for studying the disease progression and mechanisms of LV hypertrophy and heart failure. Echocardiography is one of the most widely used as a non-invasive technique to provide quantitative measurements of ventricular structure and function in humans and experimental animals. High-frequency transducers (17.5 MHz) was used in our study, which greatly overcame the difficulties of a small weight of around ~1 g with 2 mm LV wall thickness in rats and a rapid heart rate of 300–400 bpm, providing high resolution images for morphometric and functional measurements[19, 20].
It is clear during the development of hypertension, alteration in LV geometry occurs as an early adaptation to increasing pressure and volume overload. In our study, during first 3 months, LVEDD, IVS and LVPW were increased whereas LVESD remain unchanged, indicating concentric hypertrophy. In the mean time cardiac function as assessed by echocardiography in terms of EF and FS was kept unchanged until 18 months. Meanwhile, diastolic dysfunction became overt from 6 month with decreased E/A ratio and E′/A′ ratio. However IVRT and DT values didn’t alter possibly due to high heart rate.
As a key functional abnormality in diastolic dysfunction and heart failure, abnormal diastolic filling pressure leads to a release of natriuretic peptides including NT-proBNP, which was released predominantly by the ventricles in response to stretch. NT-proBNP levels increased significantly according to the severity of overall diastolic dysfunction, ranging from impaired relaxation to pseudonormal filling and restrictive filling, however, the role of NT-proBNP in patients with diastolic heart failure is still under investigation[23, 24]. Although it has been found that NT-proBNP correlates with diastolic abnormalities in patients with reduced systolic function and in patients with advanced forms of isolated diastolic heart failure[26, 27], several Doppler echocardiographic studies found them not to be useful for the detection of mild diastolic dysfunction. The latter is associated with increased filling pressures at exertion only and will be missed by conventional Doppler echocardiography, which is performed at rest.
Documented data indicated that chronic inflammation is closely associated with the development of cardiovascular and cardiovascular-related disorders, such as hypertension, heart failure, etc. Adipokines secreted from adipose tissue, such as leptin and interleukin-6 (IL-6) showed significant contribution to the positive regulation of inflammatory.
It is reported that low levels of adiponectin was associated with a further progression of left ventricular hypertrophy in patients presenting with hypertension, left ventricular diastolic dysfunction and hypertrophy. Our data are in line with such reports describing an association between decreasing levels of adiponectin serum concentration and increasing hypertension. In current study we determined multiple biomarkers including NT-proBNP, IL-6 and adiponectin at multiple time points during transition period from hypertension to heart dysfunction. Reason for choosing a combination of biomarkers such as NT-proBNP, IL-6 and adiponectin is to cover different pathophysiological mechanisms such as cardiac stress, inflammation and adipocytokines. Our results have shown that, being different from NT-proBNP and IL-6 which keep increasing during progression of heart dysfunction, adiponectin was decreased from 3 month when diastolic dysfunction occurred and then increased at 15 month prior to advent of systolic dysfunction which was apparent at 18 month. Therefore adiponectin is the biomarker indicating onset rather than progression of heart dysfunction. In contrast, NT-proBNP and IL-6 are biomarkers not only for onset of heart dysfunction but also progression of heart dysfunction. Though our animal model is mainly hypertension induced heart dysfunction rather than heart failure, as is evidenced in other studies[29, 30], serum adiponectin level was elevated in chronic heart failure, our study also witnessed a trend.
Finally, adiponectin is produced exclusively by adipocytes and its concentrations were predominantly determined by visceral fat. However, up to now, difference in adiponectin gene expression in relation to various adipose tissue depots is still not fully elucidated. Our study demonstrated no difference in adiponectin distribution, at least among pericardial, perinephric and mesenteric adipose tissues. However, adiponectin expression and serum level decreased with cardiac diastolic dysfunction and increased prior to systolic dysfunction while not in line with systolic dysfunction. We speculated the reasons might be as follows: (1) with disease progression, renal and hepatic functions might be impaired, and the clearance of adiponectin might also decrease[34, 35], combined with relatively increased adiponectin expression, resulting in a prior serum elevation, which is partially consistent with our observations; (2) adiponectin is present in plasma in different isoforms: a large multimeric structure of high molecular weight and in a trimer and examer form, whereas the monomeric form is not found in peripheral circulation but only in the adipose tissue. Moreover, the lipolysis in adipose cells appears to be hormone-dependent, catecholamines and natriuretic peptides, besides insulin, exerting important effects. (3) Circulating adiponectin concentrations can be regulated by various hormonal, nutritional and pharmacological factors. In heart dysfunction there are increased levels of IL-6 and TNF-α, as evidenced in our study, which might lead to decrease in serum adiponectin levels and it is also reported adiponectin gene expression is reversibly downregulated by IL-6. The precise mechanism still needs further investigation.
In conclusion, we demonstrated that serum adiponectin level may be a useful biomarker during transition from hypertension to onset of cardiac dysfunction and adiponectin level is tempting to serve as a valuable indicator for early intervention. However, effectiveness and specificity are the two basic characteristics for a useful biomarker. The establishment of adiponectin as a valuable biomarker needs practical examination. Hence, whether and to what extent adiponectin could be used as a practical biomarker for cardiac function transition need more studies especially clinical data to support and prove and cautions should be take when making such conclusions.