Manifestations of left ventricular dysfunction and arrhythmia in patients with chronic hypoparathyroidism and pseudohypoparathyroidism: a preliminary study

Between October 2017 and April 2018, among nearly 120 patients diagnosed with HP and PHP with a regular follow-up at the Metabolic Bone Disease Outpatient Clinic, Department of Endocrinology of Peking Union Medical College Hospital (PUMCH) in Beijing, a total of 28 subjects who agreed to participate in this study were continuously subjected to echocardiography. Patients with cardiac arrhythmia before the diagnosis of hypoparathyroidism (n = 1) and those diagnosed with post-surgical hypoparathyroidism due to parathyroidectomy (n = 1) were excluded. The remaining 26 patients and 26 age- and sex-matched healthy controls with normal thyroid function and with no CVD or associated risk factors during the same period were finally included in the analysis. The controls came from the health examination center in PUMCH. The patients were evaluated with a 12-lead electrocardiogram (ECG), cardiac markers, echocardiography and 24-h Holter electrocardiography. The controls were evaluated with echocardiography by the same physician as the patient group. All patients received calcium combined with vitamin D analogs (plain vitamin D or calcitriol) at the time of investigation independently to enrollment. The study was conducted according to the principles of the Declaration of Helsinki and approved by the Ethics Committee of PUMCH. Written informed consent was obtained from all included subjects or the parents for subjects aged below 18 years. The diagnosis of HP and PHP was established by the presence of hypocalcemia, and hyperphosphatemia with inappropriately low and normal-to-high intact PTH levels, respectively, while the secondary hyperparathyroidism including chronic kidney disease and vitamin D deficiency (serum 25OHD < 20 ng/ml) [13] was excluded for PHP. All the patients had normal kidney function evaluated by estimated glomerular filtration rate (eGFR) and no history of chronic malabsorption or diarrhea.

Clinical demographics including diagnosis, gender, age of symptom onset, course, age of cardiac evaluation, and comorbidities (including hypertension, diabetes mellitus, and coronary artery disease (CAD)) were self-reported and confirmed by medical records. Parameters such as height, weight, and right arm systolic and diastolic blood pressure were measured by a single experienced physician. Body mass index (BMI) was calculated as weight in kilograms divided by height in squared meters. Body surface area (BSA) was calculated using the formula of Du Bois D and Du Bois EF [14]. Symptoms of dyspnea, shortness of breath, palpitations, history of syncope, chest pain, and edema of extremities were self-reported by patients, and evaluated and established by the same experienced physician.

Venous blood samples were obtained in the morning after an overnight (≥ 10 h) fasting and analyzed during echocardiography and electrocardiography. The concentrations of total serum calcium (Ca), serum phosphorus (P), potassium, magnesium, serum 25(OH) D, glucose, triglycerides, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and creatinine were measured using an automated biochemical analyzer (Beckman Coulter AU5800, USA). Serum intact PTH was measured based on a chemiluminescence immunoassay (Siemens ADVIA Centaur, Germany). Serum P was expressed as multiples of age-specific upper limit of normal range (×ULN). The eGFR was calculated using the abbreviated Modification of Diet in Renal Disease Study formula [15]. Creatine kinase (CK), creatine kinase-myocardial isoenzyme (CKMB), cardiac troponin I (cTnI), and B-type natriuretic peptide (BNP) were measured simultaneously. The intra-assay coefficients of variations (CVs) in 25(OH) D and PTH were 5.9 and 2.6%, with inter-assay CVs 6.5 and 5.8%, respectively. The intra-assay and inter-assay CVs of other biochemical parameters were all < 3.5%. The controls self-reported that their levels of serum calcium were normal on their previous routine physical examination, which were not re-examined at the time of echocardiography examination.

All the included subjects were evaluated using a non-invasive transthoracic echocardiogram (VIVID E9, GE Ultrasound, USA) with an m5s-D probe. M-mode measurements and conventional Doppler echocardiographic examinations were performed according to the American Society of Echocardiography (ASE) guidelines [16]. The parameters of interventricular septum end-diastolic thickness (IVSd), left ventricular posterior wall end-diastolic thickness (LVPWd), left ventricular end-diastolic diameter (LVEDD), and left ventricular ejection fraction (LVEF) were measured. Early diastolic mitral inflow velocity (E) and late diastolic mitral inflow velocity (A) were assessed in the Doppler-mode. Left ventricular mass (LVM, grams) was calculated using the ASE method [16]: 0.8 × {1.04 [(IVSd + LVEDD + LVPWd)³ – (LVEDD)³]} + 0.6. The LVM index (LVMI, g/m²) was calculated by dividing LVM by the BSA. The relative wall thickness (RWT) was calculated using the formula: (2 × LVPWd) / LVEDD.

Resting standard 12-lead ECG was obtained only in 19 patients. Resting heart rate, PR intervals, QRS duration, and corrected QT (QTc) intervals were determined via ECG analysis.

Baseline cardiac rhythm and potential arrhythmias were evaluated using an ambulatory 12-lead electrocardiography in 15 patients over a 24-h period during their normal daily activities (MIC-Dream, JincoMed, Beijing, China). The total 24-h ventricular rates, and the maximal and minimal ventricular rates were measured automatically.

Data were analyzed using SPSS software version 22.0 (Chicago, IL, USA). Categorical variables are expressed as numbers or percentages. Continuous variables are expressed as mean ± standard deviation or median and inter-quartile ranges, as appropriate. The clinical demographics and laboratory results of patients were compared with those of the healthy controls, and between patients diagnosed with HP and PHP using the Student’s t-test or Wilcoxon test. The cardiac parameters were compared using a general linear model adjusted for age at the evaluation, gender and other confounders. Associations between serum calcium, serum phosphorus, PTH and cardiac parameters were evaluated via partial correlation analysis.

The study included 18 patients diagnosed with HP and eight patients with PHP. The patients with HP included three patients with secondary HP following thyroidectomy, which was defined as post-surgical HP. The average age of onset of hypocalcemic symptoms and age at the cardiac evaluation were higher in HP subjects compared with PHP subjects (age of onset 23.9 ± 13.8 vs. 12.9 ± 7.4 years, P = 0.045; age at cardiac evaluation 45.4 ± 15.4 vs. 22.1 ± 6.4 years, p <  0.001, respectively). The disease courses from onset of hypocalcemia were longer in patients diagnosed with HP compared with those with PHP at the evaluation. One patient with HP suffered from diabetes, and four patients with HP had hypertension. No subject had self-reported CAD or related symptoms. The average levels of serum calcium were 2.05 ± 0.16 mmol/L in HP patients and 2.25 ± 0.19 mmol/L in patients with PHP (P = 0.011) during the evaluation. Serum magnesium, serum potassium, fasting blood glucose, and lipid components were within normal limits. The serum phosphorus levels (×ULN) were higher (1.13 ± 0.10 and 0.99 ± 0.12, P = 0.003) and the eGFR was lower (90.4 ± 21.1 and 127.3 ± 29.7 mL/min/1.73m², P = 0.005) in HP than in PHP (Table 1).

The cardiac parameters of patients subjected to echocardiography were compared with age- and sex-matched healthy controls, as shown in Table 2. Adjusting for the age at evaluation and BMI, LVEF, and LVEDD, which reflect left ventricular systolic function, were comparable between patients and controls. The mean left ventricular ejection fractions were 68.4 ± 6.4% and 66.5 ± 7.4% in HP and PHP patients, respectively. Parameters reflecting left ventricular structure including IVSd, LVPWd, LVM, LVMI, and RWT were comparable between patients and controls. Among the 26 patients, LVMIs were less than 95 g/m² in females, and less than 115 g/m² in males. The RWT values were less than 0.42. According to the ASE guidelines, all patients displayed normal cardiac geometry (Fig. 1), except for one female patient with non-surgical HP with an RWT of 0.41 and another female with post-surgical HP with LVMI 93.2 g/m² indicating potentially borderline concentric remodeling and eccentric hypertrophy, respectively. Levels of CK, CKMB, cTnI and BNP were within the normal ranges in both patients with HP and PHP.

Cardiac parameters reflecting left ventricular structure including IVSd, LVPWd, LVM, and RWT were significantly greater in patients with HP than in PHP, and E/A was lower in the HP group. However, after adjusting for confounders including age at evaluation, gender and BMI, only RWT and E/A showed significant differences (P = 0.023 and P = 0.042, respectively). Partial correlation analysis showed that serum calcium, serum P and PTH were not correlated with cardiac parameters after adjusting for age at evaluation and gender (Table 2).

The resting 12-lead ECG revealed normal sinus rhythm in all patients. The average heart rate was 77.5 ± 12.9 beats/min and 73.3 ± 8.2 beats/min in patients with HP and PHP, respectively. Prolongation of QTc intervals was observed in 8/14 patients diagnosed with HP and in 2/5 patients with PHP, with an average QTc of 473.0 ± 20.3 ms and 455.5 ± 6.4 ms, respectively. In patients with HP and PHP, no significant differences in age of onset, disease course, levels of serum Ca, serum P and serum PTH were detected among those with and without QTc prolongation. PR intervals, QRS duration and ST-T segments were all normal. Holter results revealed normal sinus rhythm in all patients, including 12/15 patients (80%) with supraventricular extrasystoles. Among the 12/15 patients with supraventricular extrasystoles, one (6.7%) female patient with non-surgical HP (aged 64 years with hypertension; disease course 26.2 years; serum Ca, 2.04 mmol/L; and serum P, 1.37 mmol/L) manifested 243 episodes of supraventricular extrasystole in 24 h (the incidence in the remaining 11 subjects ranged from 2 to 57 episodes), as well as supraventricular tachycardia (SVT) (52 episodes, 208 times in total) with complaints of palpitations. Among 7/15 patients (46.7%) with ventricular extrasystoles, one (6.7%) female patient with post-surgical HP (aged 54 years; course 41.2 years; serum Ca, 2.1 mmol/L and serum P, 1.79 mmol/L) presented 4063 episodes of ventricular extrasystoles noticed by 24 h (the remaining six subjects presented with 2–16 episodes) with shortness of breath during activity. No patient showed ventricular tachycardia. No atrioventricular block was found (Table 3).