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The congestive heart failure syndrome includes a systemic illness with wasting of soft tissues and bone. We hypothesized secondary hyperparathyroidism (HPT) would be found in hospitalized patients with decompensated congestive heart failure (CHF), where secondary aldosteronism is expected, and who were either untreated or treated medically.
In 9 consecutive patients (7 males, 2 females; 8 African-American, 1 Caucasian; 33–60 yrs) admitted to the Regional Medical Center during a 28-day period with chronic left ventricular systolic dysfunction (EF<35%) and decompensated CHF (5 untreated; 4 treated with an angiotensin converting enzyme inhibitor, furosemide, and small-dose spironolactone), we measured: plasma parathyroid hormone (PTH); serum calcium corrected for albumin, magnesium, and phosphorus; serum creatinine and calculated creatinine clearance.
Plasma PTH was elevated above the normal range (6-65 pg/mL) in both untreated and treated patients with CHF (204±60 and 134±14 pg/mL, respectively). Serum corrected calcium was normal (8.4-10.2 mg/dL) in both untreated and treated CHF (9.7±0.l and 9.1±0.2 mg/dL, respectively) as were serum magnesium and phosphorus. Calculated creatinine clearance did not differ between untreated and treated patients (74±15 and 83±21 mL/min, respectively).
Secondary HPT was found in 5 untreated and 4 treated patients consecutively hospitalized over a 28-day period with decompensated CHF. Corrected serum calcium was normal. Plasmaionized calcium, a determinant of PTH secretion, was not measured. Although vitamin D levels were not assessed, the presence of hypovitaminosis D in these housebound patients with symptomatic CHF cannot be discounted. HPT may contribute to the systemic illness that accompanies CHF, including bone wasting.
In these patients, SHPT may be related to long-term treatment with furosemide, a potent loop diuretic known to promote hypercalciuria and hypermagnesuria. In primary aldosteronism, the excretion of Ca2+ and Mg2+ is increased at sites of high-density aldosterone receptor binding, including kidneys, colon, sweat, and salivary glands.
In rats receiving aldosterone by implanted mini pump to raise plasma aldosterone levels to those found in human CHF, together with 1% NaCl in drinking water, early and persistent elevations in plasma PTH occur in response to marked urinary and fecal losses of Ca2+ and Mg2+ and a subsequent fall in plasma-ionized [Ca2+]o and [Mg2+]o.15 Evidence of SHPT in these rats is manifested by marked reductions in their bone mineral density, bone Ca2+ and Mg2+ concentrations, and an associated fall in bone strength.
Collectively, these clinical and experimental findings led us to hypothesize that SHPT would be found in patients with secondary aldosteronism and decompensated CHF. This preliminary report represents our early findings on serum PTH found in 9 consecutive patients, who were hospitalized for their decompensated CHF during a 28-day period. They included 5 patients with medically untreated CHF and 4 with CHF who were receiving an angiotensin converting enzyme inhibitor, furosemide, and low-dose spironolactone.
The patient population included in this preliminary study, approved by the institution’s review board, consisted of 9 consecutive patients admitted to the Cardiology Service at the Regional Medical Center during a 28-day period ranging from February 2 to March 1, 2005. All but one were African-Americans, the other Caucasian. Three of these patients (2 males and 1 female, ranging in age from 33 to 55 yrs) had newly diagnosed, never-before-treated heart failure while 2 males (51±1 yrs) had previously diagnosed, but untreated heart failure. Each of these 5 patients had been symptomatic for several months. They presented with symptoms of breathlessness at rest and upon minimal exertion, orthopnea, and paroxysmal nocturnal dyspnea. Each was considered to have New York Heart Association (NYHA) Class IV heart failure.
Signs of CHF included evidence of marked intravascular volume expansion, with jugular venous distention to the angle of the mandible and extravascular volume expansion, expressed as bilateral lower extremity edema and pleural effusion in all 5, ascites in 1, and scrotal edema in 2. The etiologic basis of their CHF was an idiopathic (dilated) cardiomyopathy in all 5. Echocardiography confirmed the presence of systolic dysfunction with depressed ejection fraction of 27±3%, together with left ventricular chamber dilatation at end diastole of 60±2 mm (normal <56 mm). Two patients were in normal sinus rhythm, 2 had a sinus tachycardia and 1 had atrial fibrillation/flutter.
During the same time frame, four patients were admitted with previously diagnosed, treated CHF. Each had decompensated NYHA Class IV CHF of several months’ duration, despite receiving twice-daily oral furosemide with a unit dose of at least 40 mg, together with an angiotensin-converting enzyme inhibitor. At the time of admission, all patients were receiving a once-daily 25 mg oral dose of spironolactone. These treated patients with CHF included 3 males (52±3 yrs) and a 56-year-old female. The etiologic basis of their CHF was ischemic cardiomyopathy in 1 and idiopathic cardiomyopathy in 3. All had jugular venous distension and bilateral lower extremity edema; 2 had pleural effusion, 1 ascites, and 1 scrotal edema. Ejection fraction was 18±3% and left ventricular chamber dimension at end diastole was 75±3 mm. Three had sinus tachycardia and 1 atrial flutter.
None of the 9 patients was receiving insulin, estrogen, a glucocorticoid, growth hormone, or thyroxine. None had disorders affecting bone metabolism, including rheumatoid arthritis, Paget’s disease, osteomalacia, primary hyperparathyroidism, hyperthyroidism, osteogenesis imperfecta, gastric resection, inflammatory bowel disease, or a history of fragility fractures.
At the time of admission, the following were measured: plasma PTH; serum calcium corrected for albumin; magnesium; phosphorus; serum creatinine. Calculated creatinine clearance was determined from the Cockcroft-Gault formula.
Plasma PTH was measured by the intact PTH immunoassay. Forty-one PTH determinations were performed by the laboratory during the month of this study. The results of these assays are presented below.
Values presented are mean±SEM. Data were statistically analyzed by Mann-Whitney rank sum test using SigmaStat statistical software (version 2.0; Systat Software, Inc., Point Richmond, CA). Significant differences between individual means were assigned when P values were <0.05.
Forty-one PTH determinations were performed by the laboratory during February, 2005; 13 were found to be normal (38±4, 6-65 pg/mL) while 28 were elevated (66-1867 pg/mL). Of the 13 with normal PTH, 12 were found in African-Americans ranging in age from 22-65 yrs, of whom 5 were women. Of those with elevated PTH, 29% were found in 12 patients with chronic renal failure (568±205, 79-1867 pg/mL), 22% in our 9 patients with decompensated CHF (173±34, 86-393 pg/mL), and the remaining 17% in 7 patients with various other conditions that included primary HPT, sickle cell disease (2), sarcoidosis, hypovitaminosis D, and protein S deficiency.
In the 5 patients with newly diagnosed, untreated or previously diagnosed, but untreated CHF, plasma PTH (mean±SEM) was 204±60 pg/mL and ranged between 86 and 393 pg/mL, while in the 4 patients with previously diagnosed and treated CHF, plasma PTH was 134±14 pg/mL, ranging from 105 to 164 pg/mL (see Figure). There was no statistical difference in PTH values between untreated and treated patients with decompensated CHF.
The normal range for serum-corrected calcium (based on serum albumin) is 8.4 to 10.2 mg/dL. It was not reduced in patients with either untreated (9.7±0.l mg/dL) or treated (9.1±0.6 mg/dL) CHF. Serum albumin was found to be 2.56±0.13 g/dL in untreated patients and 3.28±0.27 gldL in treated patients (normal range of 3.2-5.5 g/dL). We did not monitor plasma-ionized calcium. Serum magnesium was within the normal range (1.8-2.5 mg/dL) in both untreated and treated patients (2.02±0.52 and 2.47±0.67 mg/dL, respectively) and serum phosphorus was 3.5±0.l and 4.2±0.3 mg/dL in untreated and treated patients, respectively (normal 2.5-4.6 mg/dL).
At the time of admission, serum creatinine in patients with untreated CHF was 1.9±0.7 mg/dL and 1.7±0.8 mg/dL in those with treated CHF. Calculated creatinine clearance was 74±15 mL/min in untreated and 83±21 mL/min in patients treated for their CHF.
This preliminary study, conducted in 9 consecutive patients admitted to the Cardiology Service at the Regional Medical Center in Memphis during a 28-day period, indicates the presence of SHPT in all 5 patients with untreated and all 4 patients with treated CHF. These patients did not have advanced chronic renal failure (calculated creatinine clearance <30 mL/min), where SHPT might be expected, or a disorder known to affect bone metabolism. This is the first report to identify the presence of SHPT in patients with untreated, symptomatic heart failure, where secondary aldosteronism is expected to contribute to the salt-avid state that accounts for their signs and symptoms of CHF.
These findings underscore the possibility that SHPT exists in patients with CHF having chronic left ventricular systolic dysfunction, whether untreated or treated with furosemide. Previous reports have raised the prospect of SHPT in such patients; however, all were treated with a loop diuretic.
This included those with advanced symptomatic heart failure awaiting cardiac transplantation, who had received long-term treatment with a loop diuretic, and those with less severe CHF, but who also were receiving a loop diuretic. In reducing tubular Na+ absorption, a loop diuretic increases urinary Ca2+ and Mg2+ excretion. Amongst nursing home residents, daily furosemide dosage is a predictor of SHPT.
reported elevated PTH levels in similar patients; however, in 18% of patients with advanced heart failure circulating levels of 1,25(OH)2D3 were reduced. This raises the prospect of hypovitaminosis D as contributory to HPT in these symptomatic patients whose exertional intolerance may have confined them indoors, thereby reducing their exposure to sunlight. Reduced serum 25(OH)D and 1,25(OH)2D3 levels were respectively reported in 17% and 26% of patients with advanced CHF awaiting cardiac transplantation, with elevated PTH levels found in 30% of these individuals.
Reduced circulating levels of 25(OH)D and albumin-corrected Ca2+ levels have been reported in patients with symptomatic heart failure, and this included elderly patients and those less than 50 years of age, and in both age groups, plasma PTH levels were increased compared to controls.
Because of their advanced symptomatic CHF, our patients were essentially homebound without exposure to sunlight. A brief (minutes), thrice weekly exposure to UV-B irradiation or daily oral vitamin D3 supplement have raised serum 25(OH)D levels in elderly nursing home residents.
Whether either approach would prove efficacious in patients with CHF remains to be addressed.
A stimulus to PTH secretion is a sustained loss of Ca2+ and Mg2+ in urine and/or feces and accompanying fall in their plasma-ionized concentrations.15 Urinary Ca2+ and Mg2+ excretion are increased in patients with primary aldosteronism, and which are further enhanced by dietary Na+ loading and can be normalized by spironolactone or adrenal surgery.
Studies in rats with aldosteronism, where 1% NaCl in drinking water is combined with elevated plasma aldosterone, created by its release from an implanted minipump to raise aldosterone levels to those found in human CHF, have indicated a marked urinary and fecal excretion of these divalent cations.
A reduction in plasma-ionized [Ca2+]o and [Mg2+]o is found in these rats and is associated with increased plasma PTH levels and bone wasting, as expressed by a reduction in bone mineral density and bone strength.
In the present study, we found plasma PTH to be less elevated, albeit not significantly, in patients with CHF treated with a small 25 mg daily dose of spironolactone; larger doses may be needed to prevent HPT.
Elevations in plasma PTH in rats with aldosteronism are associated with a Ca2+ loading of diverse tissues that include peripheral blood mononuclear cells, cardiac and skeletal muscle; parathyroidectomy prevents this Ca2+ loading.
Reactive oxygen and nitrogen species contribute to signal transduction and amplification that can alter cell behavior and survival, including programmed cell death and necrosis. We have previously reported on an immunostimulatory state with activated lymphocytes and monocytes in rats with aldosteronism and Ca2+ loading of these peripheral blood mononuclear cells.
reported elevations in plasma IL-6 and TNF-α in patients with treated CHF, and that were more markedly elevated in those with cardiac cachexia. These same cytokines are elevated in patients with primary or SHPT.
Plasma levels of IL-6 and TNF-α may prove to be markers of SHPT in patients with CHF.
This preliminary study had several limitations. First, its small sample size. However, these were 9 consecutive hospital admissions followed during a 28-day period of time raising the prospect that SHPT may be more prevalent in patients with decompensated heart failure, both untreated and treated, than previously appreciated. Second, intact PTH was measured at the time of admission when glomerular filtration rate was presumably at its lowest point. We did not obtain plasma PTH levels in asymptomatic patients with known systolic dysfunction where plasma aldosterone levels would be normal.
We also did not measure plasma-ionized calcium or magnesium, which are important determinants of PTH secretion, or plasma levels of 25(OH)D, an index of vitamin D stores. Hypovitaminosis D could contribute to the susceptibility to SHPT due to reduced gastrointestinal absorption of Ca2+. Finally, we did not measure bone mineral density in our study population composed largely of African-Americans. Previous studies have reported bone mineral density to be higher in African-Americans than Caucasians.
Of the 12 patients in whom plasma PTH fell within the normal range during the 28-day period of our study, 11 were African-Americans, 1 was Caucasian.
In summary, the results of this preliminary study suggest the possibility of SHPT in patients with untreated and treated CHF. SHPT may contribute to a systemic illness that accompanies CHF and whose features include oxi/nitrosative stress in such diverse tissues as skin, skeletal muscle, heart, lymphocytes and monocytes, and blood plasma; a proinflammatory phenotype with immune cell activation and elevated plasma levels of IL-6 and TNF-α; and a catabolic state that includes bone loss to eventuate in a wasting syndrome known as cardiac cachexia. Such is the case in rats with SHPT that accompanies exogenous aldosteronism, where PTH-mediated Ca2+ loading of diverse tissues contributes to the appearance of oxi/nitrosative stress and an immunostimulatory state with lymphocyte and monocyte activation and bone wasting.
We gratefully acknowledge the invaluable assistance assistance of Meaeda Nelson, RN, BSN, in patient recruitment and monitoring.
Hormones regulating cardiovascular function in patients with severe congestive heart failure and their relation to mortality. CONSENSUS Trial Study Group.