Differential Role of Aldosterone and Transforming Growth Factor Beta-1 in Cardiac Remodeling.

Angiotensin II, a major culprit in cardiovascular disease, activates mediators that are also involved in pathological cardiac remodeling. In this context, we aimed at investigating the effects of two of them: aldosterone (Ald) and transforming growth factor beta-1 (TGF-ß1) in an in vivo model. Six-week-old male wild-type (WT) and TGF-ß1-overexpressing transgenic (TGF-ß1-TG) mice were infused with subhypertensive doses of Ald for 2 weeks and/or treated orally with eplerenone from postnatal day 21. Thehearts' ventricles were examined by morphometry, immunoblotting to assess the intracellular signaling pathways and RT qPCR to determine hypertrophy and fibrosis marker genes. The TGF-ß1-TG mice spontaneously developed cardiac hypertrophy and interstitial fibrosis and exhibited a higher baseline phosphorylation of p44/42 and p38 kinases, fibronectin and ANP mRNA expression. Ald induced a comparable increase in the ventricular-heart-weight-to-body-weight ratio and cardiomyocyte diameter in both strains, but a less pronounced increase in interstitial fibrosis in the transgenic compared to the WT mice (23.6% vs. 80.9%, p < 0.005). Ald increased the phosphorylation of p44/42 and p38 in the WT but not the TGF-ß1-TG mice. While the eplerenone-enriched chow partially prevented Ald-induced cardiac hypertrophy in both genotypes and interstitial fibrosis in the WT controls, it completely protected against additional fibrosis in transgenic mice. Ald appears to induce cardiac hypertrophy independently of TGF-ß1, while in the case of fibrosis, the downstream signaling pathways of these two factors probably converge.

Improvement of hypertension control and left-ventricular function after cure of primary hyperparathyroidism.

Introduction: Cardiovascular mortality is significantly higher in patients with primary hyperparathyroidism (PHPT) compared to the general population. The role of the renin-angiotensin-aldosterone system (RAAS) as a mediator of cardiovascular pathology in PHPT is unclear, as is the question whether successful parathyroidectomy (PTX) mitigates hypertension (HT), and left-ventricular (LV) dysfunction. Methods: In 45 consecutive, hypercalcemic PHPT patients (91% female, 20 normotensive, mean age 54.6 ± 14.6), laboratory examinations, and 24 h ambulatory blood pressure monitoring (ABPM) were performed before, one and six months after successful PTX, while transthoracic echocardiography (TTE) pre- and six months post-PTX. Results: Both in patients with normotension (NT) and HT, lower calcemia and parathyroid hormone (PTH) as well as higher phosphatemia were observed on follow-up, while B-type natriuretic peptide, aldosterone, plasma renin activity, and aldosterone-to-renin ratios were comparable. Six months post-PTX, only in patients with HT, median 24-hour SBP/DBP decreased by 12/6 mmHg, daytime SBP by 10, and nighttime DBP by 5 mmHg. Improvement in BP was observed in approximately 78% of patients with HT. Six months post-PTX, TTE revealed: 1) decrease in median LV mass index (by 2 g/m2) and end-diastolic dimension (by 3 mm) among patients with HT; 2) normalization of global longitudinal strain in 22% of patients (comparable between those with NT and HT); 3) a mean 12.7% reduction in left-atrium volume index among patients with HT, which underlay normalization of indeterminate diastolic function in 3 out of 6 patients with HT, who exhibited it at baseline (dysfunction persisted in 2). Conclusions: PTX was shown to significantly reduce BP, LV hypertrophy and diastolic dysfunction parameters in PHPT patients with HT, and improve systolic function in all PHPT patients.

Low catestatin as a risk factor for cardiovascular disease - assessment in patients with adrenal incidentalomas.

Background: Catestatin (Cts) is a peptide derived from proteolytic cleavage of chromogranin A, which exhibits cardioprotective and anti-inflammatory properties. Cts has been proposed as a potential biomarker for cardiovascular (CV) disease. Objectives: examining Cts in patients with incidentally discovered adrenocortical adenomas (AI), and its associations with CV risk factors and blood pressure (BP). Materials and methods: In this cross-sectional study, 64 AI patients without overt CV disease other than primary hypertension were recruited along with 24 age-, sex-, and body-mass-index (BMI)-matched controls with normal adrenal morphology. Laboratory, 24-h ambulatory BP monitoring, echocardiography, and common carotid artery sonography examinations were performed. Results: Unadjusted Cts was higher in AI patients (median 6.5, interquartile range: 4.9-37 ng/ml) versus controls (4.5 (3.5 - 28)), p=0.048, however, the difference was insignificant after adjusting for confounding variables. Cts was lower in subjects with metabolic syndrome than in those without it (5.2 (3.9- 6.9) vs. 25.7 (5.8-115) ng/ml, p<0.01), and in men compared to women (4.9 (4-7.4) ng/ml vs. 7 (4.8-100), p=0.015). AI patients in the lower half of Cts levels compared to those in the upper had a higher prevalence of hypertension (OR 0.15, 95% CI: 0.041-0.5, p<0.001) and metabolic syndrome (OR 0.15, 95% CI 0.041-0.5, p<0.001). In AI patients Cts correlated positively with high-density lipoprotein cholesterol (Spearman's r=0.31), negatively with BMI (r=-0.31), and 10-year atherosclerotic CV disease risk (r=-0.42). Conclusions: Our data indicate associations between CV risk factors and Cts. More clinical research is needed to apply serum Cts as a biomarker.

The role of selected adipokines in tumorigenesis and metabolic disorders in patients with adrenal tumors.

Recently, more and more attention has been directed to the role of adipose tissue and adipocytokines in the pathogenesis of metabolic and inflammatory disorders in humans. Excess fat tissue has also been associated with a higher risk of malignancies. Advances in the research on the role of adipokines in adrenal tumors may elucidate the relationship between various types of adipose tissue (visceral, subcutaneous, and periadrenal) and metabolic disorders observed in hormonally active adrenal tumors, as well as associations with adrenal cortex cancer. In patients with active or cured Cushing syndrome, increased leptin and resistin concentrations as well as release of pro-inflammatory cytokines can be associated with cardiovascular risk. Also, the renin-angiotensin-aldosterone system in patients with primary hyperaldosteronism may affect the metabolic activity of the adipose tissue. Elevated resistin concentrations in this group of patients are associated with morphological changes of the myocardium independently of the effects of the metabolic syndrome. Further, it has been suggested that hypoadiponectinemia comprises an additional factor in the pathogenesis of carbohydrate metabolism disorders and the risk of cardiovascular complications in pheochromocytoma patients. Understanding the mechanisms of action of adipokines may be important in developing prophylactic and therapeutic strategies in hormonally active and malignant tumors of the adrenal glands.

Autonomous Aldosterone Secretion in Patients with Adrenal Incidentaloma.

In recent years, research has emphasized the significance of mild clinical and biochemical presentations of primary aldosteronism (PA) that do not meet current diagnostic criteria of the syndrome. In this study, we assessed the prevalence of autonomous aldosterone (Ald) secretion (AAS), defined as a positive (>1.2 ng/dL/mIU/L) Ald-to-renin ratio (ADRR) combined with unsuppressed Ald (>4 ng/dL), and its associations with blood pressure (BP), cardiac function, and common carotid artery (CCA) intima-media thickness (IMT) in patients with incidentally discovered adrenal adenomas (AI), who were either normo- or hypertensive but had no other cardiovascular disease. Among 332 AI patients hospitalized between November 2018 and December 2019, 63 study participants were recruited (26 normo- and 37 hypertensive), who underwent hormonal examinations, 24 h ambulatory BP measurement, transthoracic echocardiography, and CCA IMT assessment without altering chronic medications. AAS was found in approximately 25% of subjects (seven normo- and nine hypertensive); urinary aldosterone excretion (UAldE) exceeded 10 ug/day in none of the subjects. The left ventricular mass index correlated positively with UAldE in non-diabetic patients (n = 50), and negatively with renin in those without beta blocker therapy (n = 38). The study shows that a pragmatic approach to hormonal assessment (no chronic therapy modification) may reveal patients with AAS. Screening for this subclinical PA presentation is probably more effective with a permissive ADRR than UAldE in such a setting.

Role of Catestatin in the Cardiovascular System and Metabolic Disorders.

Catestatin is a multifunctional peptide that is involved in the regulation of the cardiovascular and immune systems as well as metabolic homeostatis. It mitigates detrimental, excessive activity of the sympathetic nervous system by inhibiting catecholamine secretion. Based on in vitro and in vivo studies, catestatin was shown to reduce adipose tissue, inhibit inflammatory response, prevent macrophage-driven atherosclerosis, and regulate cytokine production and release. Clinical studies indicate that catestatin may influence the processes leading to hypertension, affect the course of coronary artery diseases and heart failure. This review presents up-to-date research on catestatin with a particular emphasis on cardiovascular diseases based on a literature search.

Autonomous Aldosterone Secretion as a Subclinical Form of Primary Aldosteronism: Pathogenesis and Clinical Significance.

In recent years, a substantial prevalence of primary aldosteronism (PA) has been demonstrated in both normotensive and mildly hypertensive cohorts. Consequently, a classic presentation of the syndrome, i. e. moderate-to-severe and resistant hypertension with concomitant hypokalemia, should be considered a tip-of-the-iceberg phenotype of a wide PA spectrum. Its entire range encompasses the non-classic clinical forms of mild hypertension and prehypertension but also several biochemical presentations, including patients who meet PA screening and confirmation test criteria, as well as those with either of them and those with other parameters indicating mineralocorticoid excess. In the current review, research insights on the pathogenetic background and clinical significance of autonomous aldosterone secretion (AAS) are presented, which is defined as a constellation of either: 1) normotension, normokalemia, a positive PA screening (high aldosterone-to-renin ratio) and/or confirmation test, or 2) hypertension, normokalemia and a positive PA screening but negative confirmation test. For this purpose, a literature search of the PubMed database was conducted. Advances in immunohistochemistry and genetic sequencing of isolated adrenal cells are provided as probable morphologic basis of the wide range of aldosterone secretion autonomy. Also, the role of corticotropin as an aldosterone secretagogue is discussed. To date, clinical studies depict consequences of subclinical PA phenotypes, such as increased mortality and risk of developing hypertension, impaired arterial and kidney function, association with metabolic syndrome and age, as well as osteoporosis.

Selected adipocytokines in patients with an incidentally discovered pheochromocytoma.

BACKGROUND: Adipose tissue secretes many adipokines and cytokines, which may be an additional risk factor of cardiovascular and metabolic diseases in patients with an incidentally discovered pheochromocytoma (PHEO). The aim of the study was to investigate levels of selected adipocytokines in these patients. METHODS: This prospective study included 12 patients with an incidentally discovered PHEO and 18 healthy participants. In all participants plasma/serum concentrations of triglycerides, HDL and LDL cholesterol, insulin, glucose, adipocytokines (adiponectin, leptin, resistin, TNFα, IL6, and MCP1) were determined, hormonal tests were performed in patients. RESULTS: Patients and controls did not differ significantly in terms of age, sex, and body mass index. Among incidentally discovered PHEO patients, adiponectin levels were lower, while TNFα concentrations higher than in controls. Concentrations of adiponectin correlated with 24-hour urinary excretion of normetanephrine in women. Significantly higher TNFα concentrations were found in hypertensive than in normotensive PHEO patients as well as in non-diabetic PHEO patients than controls. Further, resistin concentration was higher in PHEO patients with diabetes than in non-diabetic ones (P<0.001). Incidentally discovered PHEO tumor size correlated with leptin and IL6 levels. Adiponectin levels were higher, while TNFα and resistin lower among five patients re-examined after tumor resection. CONCLUSIONS: Among patients with an incidentally discovered pheochromocytoma, lower adiponectin, and higher resistin and TNFα levels may constitute additional factors for HT and DM. In our study, for the first time, correlations between incidentally discovered PHEO tumor size and concentrations of leptin as well as IL6 were found.

Vitamin D status including 3-epi-25(OH)D3 among adult patients with thyroid disorders during summer months.

INTRODUCTION: In the context of pleiotropic vitamin D effects, its role has also been investigated in thyroid pathology, in particular autoimmune thyroid diseases (AITD). However, available data concerning vitamin D status in Polish patients with thyroid disorders are inconclusive. In the study we investigated vitamin D status and adequacy of supplementation, as well as sunlight exposure during summer months among adult patients with thyroid diseases. MATERIAL AND METHODS: Adults with diagnosed or suspected thyroid disease were recruited almost entirely in an ambulatory setting between June and September in Northern Poland. Questionnaire examinations were performed, and serum concentrations of 25(OH)D2, 25(OH)D3, 3-epi-25(OH)D3, and 24,25(OH)2D3 were determined by LC-MS/MS. RESULTS: Thirty men and 194 women participated in the study, mean age ± standard deviation (SD): 42 ± 15 years, mean ± SD body mass index (BMI) 26 ± 6 kg/m². Among the participants, 133 declared L-thyroxine treatment, 44 - Hashimoto's thyroiditis, 40 - nodular goitre, and 20 - hyperthyroidism and/or Graves' disease. Mean ± SD 25(OH)D level was 26.9 ± 8.2 ng/ml, and deficiency (< 20 ng/ml) was stated in 12%, insufficiency (20 ≤ 25(OH)D < 30 ng/ml) in 50.4% of study participants. Calcidiol was significantly higher in subjects who declared supplementation, mean ± SD: 29.4 ± 7.5 vs. 25.2 ± 8 ng/ml. Among participants without vitamin D supplementation sunlight exposure correlated with 25(OH)D. The C3 epimer of 25(OH)D3 was detected in all subjects; its concentration correlated strongly with that of 25(OH)D3. 24,25(OH)2D3 levels also strongly correlated with those of 25(OH)D3. CONCLUSIONS: To our knowledge, the current study is the first in Poland to analyse vitamin D status in summer months among patients with thyroid diseases, as well as serum 3-epi-25(OH)D3 and 24,25(OH)2D3 concentrations. The data presented here indicate that vitamin D sufficiency is not attained even in summer months in patients with thyroid diseases.

Adipokine and cytokine levels in patients with adrenocortical cancer, subclinical Cushing's syndrome and healthy controls.

INTRODUCTION: In recent years researchers have focused at hormonal activity in Cushing's syndrome (CS) in connection with metabolic disorders and the role of adipokines and cytokines secreted by the adipose tissue. The aim of the study was to investigate levels of adipokines and cytokines in patients with: subclinical CS (SCS) - in relation to hormonal parameters of hypercortisolemia, and, adrenocortical cancer (ACC). MATERIALS AND METHODS: The study included 20 SCS as well as 7 ACC patients, and 18 healthy participants. Hormonal activity and serum concentrations of adiponectin, leptin, resistin, tumor necrosis factor alpha (TNFα), interleukin 6 (IL6), and monocyte chemoattractant protein 1 (MCP1), were analyzed. RESULTS: In SCS patients compared to healthy volunteers a trend toward higher concentrations of all pro-inflammatory cytokines was noted, however, statistically significant differences were only found for TNFα and IL6 (p = 0.047 and p = 0.028, respectively). Adiponectin concentrations were significantly lower in the SCS group (p = 0.006). Serum adipokine and cytokine levels were independent of the presence of diabetes mellitus (DM) and hypertension (HT) in the SCS group. A significant correlation was found between subclinical glucocorticoid secretion and IL6 concentration (Pearson's r = 0.517, p = 0.02). Acquired results were independent of BMI. In ACC patients compared to controls higher IL6, TNFα and MCP1 levels were recorded. CONCLUSION: It is possible that higher adipokine and pro-inflammatory cytokine concentrations as well as lower anti-inflammatory adiponectin concentrations comprise an additional risk factor of metabolic and cardiovascular diseases in SCS patients. It seems that at least among patients with SCS adipokine and cytokine secretion is independent of hormonal activity (except for IL6).

Liver metastasis of a neuroendocrine neoplasm of unknown primary origin in a female patient with a history of breast cancer.

We report on and discuss a case of a female patient diagnosed with breast cancer in 1996, which was histopathologically assessed as an invasive ductal carcinoma. The patient was admitted to our Department in 2017 with a liver metastasis of a neuroendocrine tumour. On admission she had no symptoms of an endo-crinopathy and was in a good general condition. Due to unknown primary site of the metastasis and given the patient's history of breast cancer, it was suspected that the breast cancer was in fact a neuroendocrine tumour. This hypothesis was confirmed by comparing histopathological specimens of the breast and liver tumours using advanced pathological methods.

Renin-Angiotensin-Aldosterone System in the Pathogenesis of Pregnancy-Induced Hypertension.

Hypertension occurs in 7-10% of pregnant women. Despite the continuous development of medicine, it is still an important risk factor for perinatal mortality of both mothers and fetuses. Pregnant women with hypertension are at greater risk of complications such as: placental abruption, cerebral and cardiac incidents, multiorgan failure, and disseminated intravascular coagulation. The aim of this review was to discuss multilevel disorders of the renin-angiotensin-aldosterone system in the etiopathogenesis of pregnancy-induced hypertension.

Vitamin D deficiency in early autumn among predominantly non-elderly, urban adults in Northern Poland (54°N).

INTRODUCTION: Data on vitamin D status among non-elderly adults from Central Europe are insufficient. Natural sunlight allows for cutaneous vitamin D synthesis only from April through August at latitudes over 54° in the northern hemisphere. In this study we aimed at determining vitamin D status among adults in the first weeks of autumn in northern Poland. MATERIAL AND METHODS: A convenience sample of community-dwelling, predominantly urban and non-elderly adults was recruited in an outpatient clinic. Questionnaire and laboratory examinations were performed from September 26 through November 8. The latter comprised serum alkaline phosphatase activity (ALP), 25-hydroxyvitamin D (25(OH)D), parathyroid hormone (PTH), calcium, and phosphorus concentrations. RESULTS: 180 women and 124 men were enrolled into the study, aged 46+/-14.1 years (mean+/-standard deviation, SD). Mean 25-hydroxyvitamin D concentration of the studied sample was 21.1+/-9.3 ng/ml. More than 50% of studied subjects were vitamin D deficient (i.e. had 25(OH)D concentrations of less than 20 ng/ml), only 15.1% reached vitamin D concentrations of ≥30 ng/ml (sufficiency). Median 25(OH)D concentrations were higher in participants who declared longer sun exposure as well as those who supplemented vitamin D. A negative correlation was found between PTH and 25(OH)D concentrations: r=-0.23, p<0.001 (Spearman rank order test). DISCUSSION: While there are a number of methodological limitations concerning the current study, the acquired results broaden the scarce amount of data on vitamin D status in Central Europe. Our data correspond well with those from previous studies. The presented study should be considered precursory to further research.

Widespread vitamin D deficiency among adults from northern Poland (54°N) after months of low and high natural UVB radiation.

INTRODUCTION: Widespread vitamin D deficiency has been reported worldwide and evidence of its deleterious effects on health has been accumulating. There is insufficient data concerning vitamin D status among the Polish adult population. The aim of the study was to determine vitamin D status and factors influencing it - UVB exposure, supplementation, and diet - among adults in northern Poland following months of low and high natural UVB radiation. MATERIAL AND METHODS: Adults were recruited in an outpatient clinic. All were examined twice in 2012: in winter (in February, March and the first half of April), and autumn (between 25 September and 8 November). Questionnaire examinations were performed, and serum concentrations of 25-hydroxy-vitamin D (25(OH)D), calcium, phosphorus, parathyroid hormone (PTH), and alkaline phosphatase (ALP) were determined. RESULTS: 40 men and 69 women participated in the study (age 48.4 ± 15 years, body mass index (BMI) 25.9 ± 4.3 kg/m2, mean ± SD). Mean 25(OH)D serum level in winter was 13.3 ± 6.6 ng/mL, 81.1% of participants were vitamin D-deficient. Mean 25(OH)D concentration in autumn was 22.8 ± 7.9 ng/mL (42.2% of subjects were vitamin D-deficient). Median 25(OH)D and PTH concentrations between the two examination periods differed significantly (11.9 vs. 22.1 ng/mL, and 46.3 vs. 32.2 pg/mL, respectively). In autumn, negative correlations were found between: 25(OH)D and PTH serum levels, 25(OH)D and BMI values. When compared to respective counterparts, participants declaring vitamin D supplementation, and sunbed use had significantly higher median 25(OH)D concentrations. CONCLUSIONS: UV exposure during the summer was insufficient to provide adequate vitamin D status for almost half of the participants by as soon as the early autumn. Our results suggest all-year-round vitamin D supplementation should be widely implemented.

Vitamin D deficiency during winter months among an adult, predominantly urban, population in Northern Poland.

INTRODUCTION: Vitamin D is vital in the regulation of the calcium-phosphate metabolism, has a direct impact on the musculoskeletal system, and also affects numerous other systems. Widespread vitamin D deficiency and its detrimental effect on health have been reported globally. Data concerning vitamin D status in Polish adult population is scarce. MATERIAL AND METHODS: Ambulatory patients of an outpatient clinic in Gdansk were included in the study. Serum concentrations of 25(OH) D, parathyroid hormone (PTH), alkaline phosphatase (ALP), calcium and phosphorus were determined. In a questionnaire declared UVB exposure, dietary vitamin D and calcium intake, and health status of the subjects were assessed. Non- and parametric tests, logistic regression and population attributable risk were applied in data analysis. RESULTS: 448 adults were examined from February to mid-April 2012, 305 women and 143 men, aged 19 to 86 (mean 46.3 ± 14.9 years). Mean 25-hydroxyvitamin D concentration was 14.3 ± 6.6 ng/mL. 84.4% of subjects were vitamin D deficient (25(OH)D < 20 ng/mL); 13.2% presented insufficient (20-30 ng/mL), and 2.5% (or 11 subjects) sufficient 25(OH)D concentrations. Significantly higher 25(OH)D concentrations were found in subjects who reported more UVB exposure, supplemented vitamin D orally and those who declared more physical activity. 21% of subjects had elevated serum PTH concentration (i.e. > 62 pg/mL); mean parathormone was 48.6 ± 25.2 pg/mL. A linear correlation was found between the logarithm of PTH and logarithm of 25(OH)D concentrations (r = -0.21, p < 0.001). CONCLUSIONS: Results obtained here demonstrate the necessity of implementing a monitoring and prophylaxis programme of vitamin D deficiency in Poland.

Two cases of thyroid sarcoidosis presentation as painful, recurrent goiter in patients with Graves' disease.

Sarcoidosis rarely involves the thyroid gland. Pain in the thyroid gland area was only sporadically reported in patients suffering from this disease. The aim of this paper is to report and discuss the cases of two female patients with Graves' disease who presented painful, rapidly growing, recurrent goiters (after strumectomy in their early adult lives). Invasive treatment was applied and sarcoidosis was revealed histologically. The first patient suffered from dysphagia and dyspnoea due to large goiter; skin lesions were present as well. Sarcoidosis was diagnosed in histological examination of the thyroid tissue specimens. Steroid treatment was ineffective; thus, the thyroid was removed. Two years later thyroid sarcoidosis recurred as a painful goiter and surgical treatment was applied once again. In the second case, thyroid ultrasound findings suggesting malignancy, and prompted the decision to perform thyroidectomy despite the fact that FNAB (fine needle aspiration biopsy) revealed cells indicative of a "granulomatous disease in the post-resection scar" and results of the thorax high-resolution computed tomography scan suggested pulmonary sarcoidosis. Pathological examination confirmed sarcoidosis. However, a papillary cancer focus was also found.