Severe Hypocalcemia: A Rare Cause of Reversible Heart Failure
Abstract
Despite the crucial role of calcium in myocardial contractility, hypocalcemia has been rarely reported as a cause of heart failure. In this article, the authors describe a case of severe hypocalcemia caused by idiopathic hypoparathyroidism and worsened by concomitant hypomagnesemia. The patient presented with congestive heart failure that improved dramatically with amelioration of plasma calcium levels. This case and other similar cases in the literature revealed that hypocalcemic heart failure is reversible. Measurement of plasma calcium should be included in the initial work-up of all patients with heart failure, and plasma magnesium must also be checked and corrected if hypocalcemia is demonstrated.
The cause-effect relationship between hypocalcemia and heart failure is based on the central role of calcium ions in myocardial contraction, which has been known since the early studies of Ringer in 1885.1 The few case reports that describe heart failure induced by hypocalcemia did not regard the underlying cause, and the dramatic improvement of patient's symptoms and cardiac function with calcium administration. Moreover, the enhanced cardiac contractility exerted by inotropic agents, such as catecholamines and digitalis, is mediated by increasing the availability of calcium ions inside the cardiac cell. Specifically, calcium ions are essential in two major processes involved in the excitation-contraction coupling of the myocardium: the initiation of contraction and the regulation of the extent of myocardial contraction. The latter is determined by the amount of tension developed by the actinmyosin myofilaments, and is directly related to the number of calciumions available.1 In the following sections, we describe a patient with profound hypocalcemia presenting with heart failure, and we review other cases reported in adults.
Case Report
A 55-year-old male presented to the emergency room on August 2, 1999 with a 1-week history of shortness of breath, orthopnea, paroxysmal nocturnal dyspnea, and leg and abdominal swelling. He denied tobacco and alcohol abuse in the last 15 years. The patient had a history of idiopathic hypoparathyroidism diagnosed in 1993, and cataract extraction in his left eye in 1996. The patient was treated with calcium carbonate 500 mg q.i.d. and calcitriol 0.25 mg b.i.d. until December, 1996. He was then lost to follow-up, and stopped taking his medication until his last admission. On examination the patient was mildly disoriented, and had obvious shortness of breath. His blood pressure was 144/95 mm Hg, with a regular pulse of 84, respiratory rate 24/min, and temperature 37°C. He had poor dentition, distended neck veins, and bilateral crackles on chest auscultation. Cardiac auscultation revealed an S3 gallop and 2/6 pansystolic murmur on the apex, radiating to the axillae. There was abdominal distension with a fluid wave, and 3+ pitting bilateral leg edema. Chvostek's and Trousseau's signs were negative.
Laboratory findings on admission showed normal blood counts, sodium, potassium, blood urea nitrogen, bicarbonate, troponin, thyroid-stimulating hormone, and free T4 levels. Chest x-ray showed cardiomegaly, pulmonary congestion, and bilateral pleural effusion. An electrocardiogram showed sinus rhythm, prolonged QT interval (QT corrected for heart rate was 531 ms), and inverted T waves in lateral precordial leads. In the first 24 hours, he was treated with furosemide and captopril. On the second hospitalization day, blood chemistry showed a serum calcium of 3.7 mg/dL (normal [N]=9.2–10.5), albumin 3.1 g/dL (N=3.4–4.7), magnesium of 0.8 mg/dL (N=1.6–2.6), phosphorus of 8.4 mg/dL (N=2.6–4.5), and 25-hydroxy vitamin D3 of 50 ng/mL (N=10–55). Intact parathyroid hormone (PTH) was 16 pg/mL (N=15–65), which was inappropriately low for the degree of concomitant hypocalcemia, consistent with hypoparathyroidism.
Hospital Course. Once hypocalcemia and hypomagnesemia were diagnosed, calcium gluconate and magnesium sulfate infusions were immediately started, in addition to oral calcium carbonate 1000 mg t.i.d., benazepril 20 mg q.d., and hydrochlorothiazide 50 mg qd. After 24 hours of treatment, his serum calcium and magnesium were 4.3 mg/dL and 1.5 mg/dL, respectively. An echocardiogram obtained on the second admission day showed severe four-chamber dilation, moderate to severe mitral regurgitation, and an estimated left ventricular ejection fraction (LVEF) of 20%. On the third hospitalization day, the patient's symptoms improved dramatically when his serum calcium reached 6.8 mg/dL, and on the seventh day (serum calcium 8.7 mg/dL), he became ambulatory. A second echocardiogram obtained 8 days after admission showed normal LVEF, and no mitral regurgitation. He was discharged on the tenth hospitalization day in excellent condition and prescribed the following medications: calcium carbonate 1000 mg t.i.d., calcitriol 0.25 mg b.i.d., magnesium oxide 400 mg b.i.d., benazepril 40 mg q.d., and hydrochlorothiazide 50 mg q.d. Cardiac symptoms did not recur thereafter, until his last follow-up visit on February 22, 2000, more than 6 months after discharge.
Discussion
Heart failure as result of hypocalcemia has been rarely described in adults. Our review of the literature reveals only 13 adult cases of hypocalcemic heart failure in the last 30 years (Table). One finding that may explain, in part, the rarity of heart failure induced by hypocalcemia is the fact that neurologic symptoms are usually the initial symptoms of hypocalcemia, leading to early recognition and treatment. However, for reasons not completely understood, a small subset of patients may be resistant to the development of neurologic complications of hypocalcemia. It appears probable that these patients could have tolerance to such complications in long-standing cases in which plasma calcium levels decrease slowly over years or decades. Thus, in many cases of hypocalcemic heart failure,2–6 including ours, symptoms of neuromuscular irritability of hypocalcemia, such as tingling and tetany, were absent. Apart from the patient's mild disorientation, he did not have neurologic complications. Although Chvostek's and Trousseau's signs are useful clinical indicators that reveal nerve irritability, they can be absent even in severe cases of hypocalcemia.7
| Reference | Age/Gender | Serum Calcium* (mg/dL) | Serum Magnesium (mg/dL) | Time to Reverse Symptoms | Chance in LVEF | Cause of Hypocalcemia |
|---|---|---|---|---|---|---|
| Conor et al.2 | 76/F | 5.4 | 1.5 | 3 Weeks | No change | Surgical HPT |
| Levine and Rheams.3 | 39/F | 6.2 | 1.8 | 1 Week | 25%–50% in 1 week | Surgical HPT |
| Rimailho et al.4 | 61/M | 6 | 1.5 | 10 Days | NA | Idiopathic HPT |
| Wong et al.5 | 17/F | 4.4 | NA | 4 Weeks | 50%–69% | ESRD |
| Ghent et al.6 | 35/M | 3.9 | 1.9 | NA | 15%–60% in 1 month | ESRD |
| Mano et al.8 | 65/F | 5.6 | 2.3 | 1 Week | 50%–80% in 1 week | Idiopathic HPT |
| Suzuki et al.9 | 53/F | 3.6 | 1.4 | 18 Days | 23%–47% in 3 months | Idiopathic HPT |
| Brenton et al.10 | 35/M | 4.2 | NA | 21 Days | NA | Idiopathic HPT |
| Falko et al.11 | 19/M | 5** | 0.9 | 2 Hours | NA | Hungry bone syndrome |
| Giles et al.14 | 47/F | 4.7 | 1.4 | 6 Days | Poor to normal in 5 months | Surgical HPT |
| Bashour et al.15 | 35/F | 4.1** | NA | 6 Weeks | NA | NA |
| Avery et al.16 | 41/F | 5.6 | 1.8 | Promptly | 28%–35% after 3 years | Osteomalacia |
| Present case | 55/M | 4.4 | 0.8 | 7 Days | 20%–50% in 1 week | Idiopathic HPT |
| LVEF=left ventricular ejection fraction; HPT=hypoparathyroidism; NA=not available; ESRD=end-stage renal disease; *Serum calcium corrected for albumin level by the formula: corrected calcium=measured calcium + (4 − plasma albumin in g/dL) × 0.8; **Plasma albumin not reported | ||||||
One common finding in the cases reported was the profound degree of hypocalcemia. Thus, the mean serum calcium level, after correction for albumin level, was 4.9 mg/dL. It is unclear how the myocardium can remain functional until severe hypocalcemia supervenes. One possible explanation is that calcium stores within the sarcoplasmic reticulum in the myocardium may still remain close to normal, and become depleted only when serum calcium drops to extremely low levels. Alternatively, in chronic hypocalcemia, unknown adaptive mechanisms may take place at the level of the myocardial tissue in an attempt to maintain adequate contractility, but these mechanisms no longer operate in severe stages of hypocalcemia. In one patient with hypocalcemic heart failure, electron microscopic examination of cardiac tissue disclosed a dilated sarcoplasmic reticulum and size variability in the mitochondria.8 However, the significance of these morphologic changes is unclear. In another patient, a biopsy from the right ventricle was normal.9 Unfortunately, in both cases, biopsies were obtained after resolution of symptoms and rise of calcium levels close to normal.
Despite its rarity, hypocalcemic heart failure is a very rewarding diagnosis. In most cases, the rapid reversal of symptoms of heart failure, which took a few days to few weeks, occurred after raising serum calcium to close to normal. Our patient became almost asymptomatic, and his LVEF more than doubled in a 1-week period. Unfortunately, measurement of serum calcium is sometimes initially overlooked upon presentation of heart failure. Traditional treatment with diuretics and digoxin has not effectively improved the cardiac condition when hypocalcemia later proved to be the underlying cause.2,6,10 Indeed, in one report,6 hypocalcemic heart failure was treated with calcium replenishment alone. However, since heart failure is a life-threatening condition, we recommend offering other treatment modalities for heart failure in addition to calcium. Aggressive diuresis and the use of angiotensin-converting enzyme inhibitors (such as benazepril) certainly contributed to our patient's fast improvement. Furthermore, it is not always straightforward to rule out concomitant heart disease. Our patient had history of mild, but untreated, hypertension that may have played a secondary role in his cardiac dysfunction. Although unlikely, the patient could have had another type of concomitant cardiomyopathy (e.g., genetic, alcoholic, or viral). The mitral regurgitation demonstrated on the initial echocardiogram disappeared on the following study 1 week later. Therefore, it was most likely functional, and occurred as result of chamber dilation.
One of the cases that best illustrates the cause-effect relationship between hypocalcemia and heart failure is that described by Falko et al.11 They reported on a 19-year-old male with no apparent previous history of heart disease, who had cardiac decompensation as a result of acute hypocalcemia and hypomagnesemia due to hungry bone syndrome following parathyroidectomy. The patient's symptoms resolved 2 hours after treatment with calcium and magnesium. In contrast to calcium, an independent role of hypomagnesemia in causing heart failure is difficult to prove, due to the concomitant hypocalcemia. Meanwhile, hypomagnesemia can lead to heart failure by causing hypocalcemia. In fact, it is well established that hypomagnesemia causes both inhibition of PTH secretion and PTH resistance.7 Therefore, calcium supplementation alone will not reverse hypocalcemia if hypomagnesemia coexists. Likewise, in patients with hypocalcemia owing to magnesium deficiency, magnesium administration alone will not lead to rapid restoration of plasma calcium, due to the fact that, while PTH secretion is resumed within a few minutes following correction of serum magnesium, PTH responsiveness takes several days to be restored.7 Indeed, in one case the delay in the administration of calcium with concomitant hypomagnesemia may have contributed to the refractoriness of heart failure and the patient's death.12 In addition, the patient had severe hypokalemia (potassium 2.9 mEq/L) and profound malnutrition from bulimia. The cause of hypomagnesemia in our patient is not entirely clear, but may be related to hypoparathyroidism.13 His poor dentition and history of cataracts are other features of longstanding hypoparathyroidism.
Conclusions
In summary, profound hypocalcemia is a rare cause of heart failure, which may or may not be preceded by the neurologic symptoms of hypocalcemia. Symptoms of cardiac decompensation as well as cardiac function are markedly improved, if not corrected, after raising calcium in plasma to levels close to normal. If hypomagnesemia coexists, both magnesium and calcium must be administered. Serum calcium and magnesium should be measured upon presentation in every case of heart failure.
