Echocardiographic Findings in Patients with Secondary Hyperparathyreoidism

1Universidade Estadual de Ciências da Saúde de Alagoas, Faculdade de Medicina – Setor de Nefrologia – Maceió, AL – Brasil 2Universidade Estadual de Ciências da Saúde de Alagoas, Faculdade de Medicina – Setor de Cardiologia – Maceió, AL – Brasil 3Hospital das Forças Armadas – Departamento de Medicina Interna – Brasília, DF – Brasil 4Universidade Católica – Setor de Medicina Interna – Brasília, DF – Brasil

Heart disease of uremic patients can relate to common changes in this condition, such as dyslipidemia, prothrombotic states, hyperhomocysteinemia, hemodynamic overload, anemia, oxidative stress, hypoalbuminemia, inflammatory abnormalities and bivalent ions 1,10 .The high prevalence of traditional cardiac risk factors -hypertension, diabetes mellitus, hyperlipidemia, smoking, hypercoagulability and physical inactivity -predisposes patients with CRF to heart disease.The factors act alone or synergistically and cause cardiac abnormalities in this population 11,12 .
One of the factors involved in the origin of cardiovascular changes in uremic patients is secondary hyperparathyroidism (SHPT) 1 .This is the metabolic disorder most often described in patients with CRF, even in the early stages of this condition.The pathophysiology involves changes in the balance between substances such as calcium, phosphorus, calcitriol and parathyroid hormone (PTH) 1,13 .Therefore, the main pathogenetic factors of SHT are hypocalcemia, hyperphosphoremia and deficit of calcitriol.Other factors are increased bone strength to the action of PTH, acidosis, and reduction in vitamin D receptors and calcium receptors on parathyroid hormones 1,13 .
Mortality from cardiovascular causes interfere with the survival of patients with CRF and the current focus is on the specific cardiovascular changes in uremia.There is interest in identifying the echocardiographic changes and their prevalence in relation to PTH levels.
The purpose of this study was to evaluate the prevalence of echocardiographic abnormalities in chronic kidney disease patients with SHPT, comparing the changes in the different levels of circulating PTH.

Methods
A retrospective study at the Nephrology Service of Universidade Estadual de Ciências da Saúde de Alagoas, Maceió, AL, with data taken from medical records from 2005 to 2007, which included 150 patients, of both sexes, with chronic kidney disease on a regular dialysis program.
The study was approved by the Research Ethics Committee of the institution under nº CEP Uncisal 049639/2013 and was conducted according to the CNS Resolution 466/12.
The following exclusion criteria were adopted: diabetic patients; patients under 18; with data suggesting coronary or valvular disease; cardiovascular functional group different from group I; uncontrolled b l o o d p r e s s u r e ( B P ) ; p a t i e n t s u n d e r g o i n g parathyroidectomy.
The study population consisted of 52 patients of both sexes stratified into three groups based on plasma levels of PTH: Group I ≤299 pg/mL (n=10); Group II 300-499 pg/mL (n=21); and Group III ≥ 500 pg/mL (n=21).
We evaluated the following echocardiographic parameters: aortic root, left atrial and ventricular diameter; septal and posterior wall thickness; ejection fraction; end diastolic and systolic volumes.The echocardiographic findings were correlated with calcium levels, phosphoremia, calcium-phosphorus product (Ca x P), hematocrit and hemoglobin levels, and systolic and diastolic blood pressure.
Blood pressure data were taken from dialysis prescriptions: • Predialysis BP: pre-dialysis average systolic blood pressure (SBP) and diastolic blood pressure (DBP) values of the first and final week of the 12 months preceding echocardiography were considered.• Post-dialysis BP: average post-dialysis SBP and DBP of the first and last week of the 12 months preceding echocardiography were considered.That corresponded to 72 checks to obtain the mean and calculation of standard deviation of both pre-dialysis and post-dialysis blood pressures.
Calcium (Ca) and phosphorus (P) dosages were taken using the colorimetric method in Cobas ® 6000 equipment (Roche Diagnostics International Ltd CH-6343 Rotkreuz, Switzerland) and the mean values of the 12 months preceding echocardiography were calculated.Careference value: 8.5-10.5 mg/dL; P -reference value: 3.5-5.5 mg/dL.
Based on average of calcium and phosphorus values in the 12 months before echocardiography, the mean calcium x phosphorus product was calculated: Ca x P -reference value: 20-55 mg 2 /dL.It was figured out how many times, over the 12-month study, the multiplication of calcium level by phosphorus level was ≥55 mg 2 /dL.

Statistical treatment
Considering the assumption and the number of variables, the minimum number calculated to establish statistical power was 10 patients in different study groups.Data were expressed as mean and standard deviation.
Calcium, phosphorus, calcium and phosphorus product, hematocrit and hemoglobin reflect the annual average of 12 measurements.Systolic and diastolic blood pressure reflects the arithmetic mean of 72 annual inspections. The

Discussion
CRF produces changes in various organs and systems and the relationship between cardiac alterations and uremia is often described.In 1827, Richard Bright reported cardiac hypertrophy as a common finding in this condition 14 ; in 1872, Mahomed described major changes in large arteries in patients with chronic kidney disease 15 .In 1944, Raab suggested that substances in the blood of patients with uremia could cause specific heart disease of this condition 16 .In 1981, Drueke et al. 17 described congestive cardiomyopathy in seven of 21 patients undergoing dialysis; all of them had normal coronary arteries and no other cause of cardiomyopathy 17 .
One of the common forms of cardiovascular disease in CRF is ischemic heart disease.End-stage renal failure is also associated with structural and functional cardiac changes, such as left ventricular hypertrophy (LVH), coronary artery disease, valvular disease and pericarditis 18 .
The role of calcium in cardiac metabolism is very important, influencing the contraction and relaxation of the heart [19][20][21] .In severe hypocalcemia, segmental echocardiographic changes may be observed in contractility; however, cases of hypocalcemic cardiomyopathy or heart failure are very rarely reported in these patients [19][20][21] .
Serum calcium is physiologically regulated by the action of PTH.Under normal conditions, its secretion is increased when hypocalcemia occurs, promoting rapid release of calcium stored in the bone tissue resting cells, a phenomenon that partly tends to fix calcium levels; in the kidney, PTH promotes greater tubular reabsorption of calcium and decreases phosphate reabsorption The kidneys are the main organs involved in the production of calcitriol; therefore, the deficit of renal function decreases in the production of this substance, affecting the metabolism of calcium, phosphorus and bone tissue.Calcitriol, the active form of vitamin D, is directly involved in calcium homeostasis by promoting intestinal absorption.
Hypocalcemia by absorptive deficit is a major mechanism of increased secretion of PTH in calcitriol deficiency 13 .
The clinical picture of SHPT is characterized by bone pain, usually diffuse and progressive, with difficulty walking and even immobility, proximal myopathy, muscle weakness, severe itching, vascular calcifications of soft tissues and skin, arthralgia and tendon rupture.More rarely, spontaneous fractures occur with collapsed vertebrae and impact on posture and mobility.
In 2005, Randon et al. 12 reported a significant number of patients who started dialysis treatment and had cardiac abnormalities, especially LVH; besides, about 70% of patients on chronic hemodialysis had HVE 12 .PTH has been recently identified as an important cardiotoxin in CRF and high serum levels of this hormone in uremic patients can have deleterious effects on metabolism and myocardial function 23 .There is a direct and independent relationship of high PTH levels (>280 pg/mL) with the development of LVH in patients undergoing chronic hemodialysis, and SHPT contributes to the high cardiovascular morbidity associated with HVE 17 .
PTH is an independent LVH factor in men older than 59 and women under 60; this effect can occur with very high levels of PTH that change cardiac function 24 .Nagashima et al. 25 reported significant improvement in left ventricular function after parathyroidectomy in patients subjected to 12 years of dialysis presenting SHPT associated with left ventricular dysfunction.
There was a decrease in PTH levels after surgery, suggesting an important role of PTH in ventricular dysfunction 25 .
SHPT can cause LVH through several mechanisms, including direct trophic effects on myocytes and interstitial fibroblasts; and indirect effects such as increased blood pressure, hypercalcemia, anemia and alterations in small and large vessels.LVH partly results from myocardial fibrosis that is independent of hypertension and can significantly contribute to diastolic dysfunction and arrhythmias in patients with end-stage renal disease 18 .

Conclusion
Echocardiography is useful in the evaluation of cardiovascular disease in cases of uremia.
Patients with chronic renal failure with secondary hyperparathyroidism may present echocardiographic abnormalities, some of which correlate with circulating levels of parathyroid hormone.
Although with the limitations typical of retrospective studies, these findings suggest the need to conduct prospective studies that include a bigger number of patients in the different groups.

Potential Conflicts of Interest
This study has no relevant conflicts of interest.

Sources of Funding
This study has been partially funded by the PIBIC research support fund.

Academic Association
This manuscript is part of the Research Project of Paulo Regis Távora Diniz Júnior from Faculdade de Medicina da Universidade Estadual de Ciências da Saúde de Alagoas, Maceió, AL, Brazil.
Parathyroid hormone levels were determined by radioimmunoassay at Instituto H. Pardini, Belo Horizonte, MG, using kit CIS Bio International S.A. (Gifsur-Yvette, Essonne, France) and the mean values of the 12 months preceding echocardiography were considered.PTH -reference value: 4-67 pg/mL.

Table 1 Echocardiographic data of the sample population and by study groups
Student t test was used to establish comparisons of unpaired data among the groups; and the Spearman correlation to detect possible correlations between variables.Statistical significance assigned to p<0.005.
Besides the significance of the variables in the three groups, pairs of groups were compared (group I with group II, group I with group III and group II with group III) applying the Tukey test to determine the population groups presenting statistical significance.Table1shows the echocardiographic data of patients among the three groups.The only variable that was statistically significant was the diastolic posterior wall thickness.Data expressed as mean±standard deviation PTH -parathyroid hormone; RV -right ventricle; LV -left ventricle; ns -no statistical significance 1,[19][20][21].In CRF, hypocalcemia is due to decreased intestinal absorption of calcium secondary to calcitriol deficit and also to a poor intake of this ion 1 .