Coexisting Hyponatremia and Decline in Diastolic Blood Pressure Predispose to Atrial Standstill in Hyperkalemic Patients

Abstract

Background: Atrial standstill is one of the important clinical consequences on the heart in severe hyperkalemia, but it occurs even at modest potassium ion elevation. The extent to which other factors might potentiate the electrocardiographic changes induced by hyperkalemia remains unclear.

Methods and Results: This was a retrospective review of the data on 12,639 hospital admissions over a 15-year period. A total of 778 patients with hyperkalemia were identified, 28 of whom had atrial standstill, and had several parameters measured prior to any treatment of hyperkalemia. Patients with atrial standstill were older (P=0.036), had lower diastolic blood pressure (DBP; P<0.0001) and serum sodium concentration (P<0.0001), higher serum potassium (P<0.0001), and high prevalence of angiotensin converting-enzyme inhibitor (ACEI; P=0.009) or mineral corticoid receptor (MR)-blocker (P=0.006), compared with those without atrial standstill. On multivariate logistic regression, DBP <67 mmHg (P=0.006), serum sodium ion <135 mmol/L (P=0.006) and serum potassium ion >6.1 mmol/L (P=0.018) were identified as independent indicators of atrial standstill, after adjusting for sex, age, chronic maintenance hemodialysis, diuretics use or ACEI/angiotensin receptor blocker and MR blocker.

Conclusions: Hyponatremia and decline in DBP are associated with atrial standstill in patients with hyperkalemia. (Circ J 2016; 80: 1781–1786)

The prevalence of hyperkalemia is increased in the elderly population with lowered glomerular filtration rate.^1,2 Daily dietary potassium intake and some medicines contribute to hyperkalemia in persons with underlying urinary potassium excretion impairment, usually associated with acute kidney injury or chronic kidney disease.^3,4 Given that hyperkalemia can lead to life-threatening consequences secondary to fatal arrhythmia, it is important to promptly diagnose and manage this electrolyte disorder. Increased serum potassium can induce changes in surface electrocardiogram (ECG) manifesting as peaked T wave (5.5–6.5 mmol/L), and decreased P-wave amplitude followed by the absence of P wave (6.5–7.5 mmol/L), widened QRS complex (7–8 mmol/L), and, ultimately, a sine wave pattern (>8 mmol/L).⁵ The electrophysiological effect of hyperkalemia, however, appears to vary with the individual, and it is difficult to consistently identify hyperkalemia based on ECG abnormality in medical practice.^6–9 The extent to which other factors might potentiate the ECG changes induced by hyperkalemia remains uncertain. The purpose of this study was therefore to characterize the clinical background in hyperkalemic patients with or without atrial standstill.

Methods

Patients and Study Design

This was a cross-sectional retrospective study performed at First Department of Internal Medicine, Miyazaki University Hospital, Japan. This department has expertise in a broad range of internal medicine fields, such as cardiology, nephrology and gastroenterology. To minimize patient selection bias, we enrolled all patients (n=12,639) admitted between January 1999 and December 2014. Hyperkalemia was defined as serum potassium ion ≥5.5 mmol/L.⁵ Atrial standstill was defined as the absence of P waves with junctional or idioventricular rhythm on surface ECG.^10,11 We selected 127 patients with surface ECG and simultaneous potassium measurement prior to starting any treatment for hyperkalemia. Patients with pacemaker rhythm (n=3) and cardiac arrest (n=2) were excluded from the study. This study was approved by the Human Investigation Review Committee of the University of Miyazaki (No. 2015-245) and conformed to the principles outlined in the Declaration of Helsinki.¹² We notified the patients regarding the study on Homepage.

Data Collection

Body mass index (kg/m²), systolic blood pressure (SBP) and diastolic blood pressure (DBP) were assessed on admission to hospital. Comorbidities included hypertension, diabetes mellitus, dyslipidemia, heart failure, coronary artery disease, peripheral arterial disease, chronic kidney disease, end-stage renal disease on hemodialysis, hyperuricemia, neoplasm, inflammatory bowel disease, and ketoacidosis. Hypertension was defined as SBP ≥140 mmHg, DBP ≥90 mmHg or antihypertensive medication, diabetes mellitus as fasting plasma glucose ≥126 mg/dl, 2-h postprandial glucose ≥200 mg/dl, or taking any medicine for diabetes mellitus, and dyslipidemia as fasting plasma total cholesterol ≥220 mg/dl and/or triglyceride ≥150 mg/dl or taking any medicine for dyslipidemia. Heart failure was defined according to the Framingham criteria.¹³ Chronic kidney disease was defined as kidney damage or glomerular filtration rate <60 ml/min/1.73 m² for ≥3 months, irrespective of cause.¹⁴ Peripheral artery disease referred to vessel disease outside the heart and brain. Hyperuricemia was defined as uric acid >7 mg/dl¹⁵ or taking any medicine for hyperuricemia. Inflammatory bowel disease included ulcerative colitis and Crohn’s disease. Current medicines referred to the medicines that were taken until the time of admission, and included calcium channel blockers, β-blockers, angiotensin-converting enzyme inhibitors (ACEI), angiotensin II type 1 receptor blockers (ARB), mineral corticoid receptor (MR) blockers, aspirin, statins, non-steroidal anti-inflammatory drugs, bisphosphonates and digitalis. Type of diuretic was further divided into calcium sparing (thiazide) or calcium losing (furosemide). Laboratory data included hemoglobin, hematocrit, blood urea nitrogen, creatinine, albumin, sodium ion, potassium ion, chloride ion, calcium ion, aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase and C-reactive protein (CRP). Calcium ion concentration was adjusted as total calcium (mg/dl)–albumin (g/dl)+4, for albumin concentration <4 g/dl.¹⁶

ECG

P-wave duration and amplitude were measured on surface ECG at limb lead II. The PQ interval was measured from the beginning of the P wave to the beginning of QRS complex. The duration of the QRS complex was measured from the lead with the widest QRS complex. The QT interval was measured from the beginning of QRS complex to the end of the T wave. QTc was calculated as QT interval/R-R interval^1/2, according to Bazett’s formula. T-wave amplitude was measured at leads V_2–5, respectively. In a patient with T-wave inversion before admission, T-wave amplitude was calculated by summing the voltages on admission and after recovery from hyperkalemia.

Statistical Analysis

Data are given as absolute numbers or mean±SD. Student’s t-test was used for 2 continuous variables, and Fisher’s exact test for nominal values. The unadjusted association of potassium ion concentration with ECG manifestation was evaluated on Pearson’s rank correlation. Stepwise logistic regression was used to estimate the relative risk of developing atrial standstill in hyperkalemia. Adjusted relative risk is presented as OR with 95% CI. Qualitative covariates were coded as 0=male, 1=female, or any type of comorbidity and medicines (0=no and 1=yes) and chronic maintenance hemodialysis (0=no and 1=yes). In addition, quantitative covariates were divided into 2 categories according to median and coded as follows: age, 0=≤70 years, 1=≥71 years; DBP, 0=≤67 mmHg, 1=≥68 mmHg; sodium ion, 0=≤135 mmol/L, 1=≥136 mmol/L; and potassium ion, 0=≤6.0 mmol/L, 1=≥6.1 mmol/L. Statistical significance was set at P<0.05. Statistical analysis was carried out using IBM SPSS statistics 21 (SPSS Japan, Tokyo, Japan).

Results

Atrial Standstill in Hyperkalemia

There are few studies on the prevalence of atrial standstill associated with hyperkalemia. In this study, 778/12,639 patients (6%) were diagnosed with hyperkalemia, 3.6% (28/778) of whom also had atrial standstill. This was a contrast to a study in which 21% of patients (36/169) with profound bradycardia (heart rate ≤40/min) admitted to the emergency department had hyperkalemia >6.0 mmol/L.¹⁷

Patient Characteristics

Patients with atrial standstill were older (P=0.036), had lower DBP (P<0.0001), lower prevalence of maintenance hemodialysis (P=0.015) and higher prevalence of either ACEI (P=0.009) or MR blocker (P=0.006), and dual/triple agents (ACEI/ARB/MR blockers; P=0.012) than those without atrial standstill (Table 1). In addition, 62% of the total subject group had chronic kidney disease, and the prevalence of this was similar between the 2 groups of patients with (68%, 19/28) vs. without (66%, 62/94) atrial standstill. In serum electrolyte measurements, sodium ion level was significantly decreased (P<0.0001), whereas potassium ion level was significantly increased (P<0.0001) in patients with atrial standstill, vs. without atrial standstill. Neither extent of anemia, renal function, serum calcium ion nor CRP was different between the 2 groups.

Table 1. Patient Characteristics

	Atrial standstill (−)	Atrial standstill (+)	P-value
n	94	28
Age	70±13	75±9	0.036†
Sex (male)	57	19	0.489‡
BMI (kg/m2)	23±4 (90)	23±4 (27)	0.993†
SBP (mmHg)	131±28 (93)	120±33 (26)	0.073†
DBP (mmHg)	70±15 (93)	53±19 (26)	<0.0001†
Comorbidity
Hypertension	67	20	0.859‡
Diabetes mellitus	25	8	0.836‡
Dyslipidemia	22	2	0.057‡
Heart failure	23	10	0.240‡
Coronary artery disease	30	9	0.982‡
Peripheral arterial disease	14	1	0.109‡
Chronic kidney disease	62	19	0.852‡
Maintenance hemodialysis	17	0	0.015‡
Hyperuricemia	22	7	0.862‡
Neoplasm	25	6	0.581‡
Inflammatory bowel disease	1	0	0.584‡
Ketoacidosis	1	0	0.731‡
Medication since admission
Calcium channel blocker	56	14	0.369‡
α-blocker	7	1	0.467‡
β-blocker	23	8	0.662‡
ACEI	5	6	0.009‡
ARB	42	13	0.870‡
MR blocker	8	8	0.006‡
Combination of RAAS blockade (0/1/2/3)	44/44/6/0	10/10/7/1	0.012‡
Loop diuretics	26	13	0.082‡
Thiazide diuretics	2	0	0.436‡
Aspirin	23	12	0.059‡
Thienopiridine	12	2	0.413‡
Statin	21	5	0.611‡
NSAID	8	3	0.721‡
Bisphosphonate	1	0	0.584‡
Digitalis	3	2	0.355‡
Laboratory data
Hemoglobin (g/dl)	10±2	11±2	0.985†
Hematocrit (%)	32±7	32±6	0.978†
Blood urea nitrogen (mg/dl)	61±42	55±31	0.624†
Creatinine (mg/dl)	4.9±4.0	7.4±2.4	0.285†
Albumin (g/dl)	3.4±0.7 (79)	3.4±0.6 (24)	0.875†
Na+ (mmol/L)	136±5	132±5	<0.0001†
K+ (mmol/L)	6.0±0.5	7.0±1.2	<0.0001†
Cl− (mmol/L)	104±6	102±7	0.165†
Ca2+ (mg/dl)	8.6±0.9 (72)	8.5±0.7 (25)	0.409†
Albumin-corrected Ca2+ (mg/dl)	9.3±0.8 (69)	9.1±0.7 (25)	0.252†
AST (IU/L)	231±1,438 (93)	407±887 (28)	0.541†
ALT (IU/L)	101±452 (93)	205±384 (28)	0.274†
LDH (IU/L)	564±2,144 (91)	1,080±2,462 (28)	0.284†
CRP (mg/dl)	3.4±6.4 (82)	4.1±7.6 (27)	0.667†

Data given as mean±SD (n) or n. ^†Unpaired t-test; ^‡chi-squared test. ACEI, angiotensin-converting enzyme inhibitor; ALT, alanine aminotransferase; ARB, angiotensin II type 1 receptor blocker; AST, aspartate aminotransferase; BMI, body mass index; CRP, C-reactive protein; DBP, diastolic blood pressure; LDH, lactate dehydrogenase; MR blocker, mineral corticoid receptor blocker; NSAID, non-steroidal anti-inflammatory drug; RAAS, renin-angiotensin-aldosterone system.

ECG vs. Presence of Atrial Standstill

Resting membrane potential is mainly determined by the equilibrium potential for potassium ion.⁷ The inward rectifier potassium ion current plays a role in stabilizing the resting membrane potential, responsible for shaping the initial depolarization, and final repolarization of the action potential.¹⁸ Progressive extracellular hyperkalemia increases inward rectifier potassium ion current and reduces the excitability of cardiac myocytes through voltage-dependent inactivation of sodium ion channels.¹⁹ It consequently changes ECG parameters, such as P-wave, QRS complex, ST-segment and T-wave.²⁰ Consistent with these features of hyperkalemia,²¹ in the present study serum potassium ion level correlated with duration of QRS complex (r=0.333, P<0.0001) and T-wave amplitude at leads V₂ (r=0.248, P=0.006) and V₃ (r=0.324, P<0.0001) in all subjects (Table 2A). Patients with atrial standstill had prolonged QRS complex (P<0.0001) and elevation of T-wave amplitude at V_3–5 (P≤0.005), compared with those without atrial standstill (Table 2B), possibly reflecting higher potassium concentration. In addition, patients without atrial standstill tended to have increased prevalence of atrial fibrillation, whereas tachyarrhythmia (heart rate >100 beats/min) in relation to overdrive suppression was not observed in those with atrial standstill.

Table 2. (A) Serum K⁺ Level and ECG Morphology, (B) ECG Characteristics vs. Presence of Atrial Standstill

(A)
	r*	P-value	n
P wave
Amplitude (mV)	−0.049	0.661	81
Duration (s)	−0.049	0.660	82
PQ interval (s)	−0.030	0.791	83
QRS complex (s)	0.333	<0.0001	122
QTc (s)	0.008	0.932	122
T wave amplitude (mV)
V2	0.248	0.006	121
V3	0.324	<0.0001	120
V4	0.137	0.137	120
V5	0.080	0.384	120
(B)
Rhythm	Atrial standstill (−)	Atrial standstill (+)	P-value
n	94	28
Atrial fibrillation	10	0	0.072†
Tachyarrhythmia	10	0	0.114†
HR (beats/min)	75±19	38±14	<0.001‡
P wave
Amplitude (mV)	0.64±1.80 (81)	ND	ND
Duration (s)	1.14±2.69 (82)	ND	ND
PQ interval (s)	0.19±0.10 (83)	ND (27)	ND
QRS (s)	0.11±0.02	0.13±0.03	<0.0001‡
QTc (s)	0.45±0.06	0.45±0.06	0.81‡
T wave amplitude (mV)
V2	0.48±0.29 (93)	0.57±0.49	0.21‡
V3	0.51±0.30	0.73±0.52 (26)	0.005‡
V4	0.45±0.31	0.97±1.33 (26)	0.001‡
V5	0.38±0.26	0.72±0.77 (26)	<0.0001‡

(A) *Pearson’s rank correlation. (B) Data given as mean±SD (n) or n. ^†Chi-square test; ^‡unpaired t-test. ECG, electrocardiogram; HR, heart rate; ND, not determined; QTc, corrected QT interval.

Other Indicators of Atrial Standstill

Serum potassium ion level ranged widely regardless of presence of atrial standstill (Figure). This indicates that other factors may contribute to the ECG changes associated with hyperkalemia. On multivariate logistic regression analysis for risk of atrial standstill, DBP <67 mmHg (P=0.006; OR, 5.080; 95% CI: 1.526–16.917), sodium ion <135 mmol/L (P=0.006; OR, 5.178; 95% CI: 1.588–16.882) and serum potassium ion >6.1 mmol/L (P=0.018; OR, 4.231; 95% CI: 1.280–13.980) were extracted as independent covariates after adjusting for sex, age, chronic maintenance hemodialysis, diuretics use or numbers of ACEI/ARB and MR blocker.

Figure.

Serum potassium ion level in patients with (n=28) or without (n=94) atrial standstill (mean±SD). P<0.0001 (unpaired Student’s t-test).

Discussion

This study investigated the clinical background of hyperkalemic patients with atrial standstill.

Of note, the prevalence of ACEI/ARB and MR blocker prescription in patients with atrial standstill was high. The renal protective effects of angiotensin receptor blockade are reduced as potassium ion level is persistently increased.²² In addition, excretion of potassium ion largely depends on the aldosterone effects on collecting tubules as well as on colonic mucosa in patients with end-stage renal disease.²³ Accordingly, ACEI/ARB in combination with MR blockers results in greater increases in potassium ion level, leading to in-hospital death associated with hyperkalemia.^24,25

Increase in serum potassium ion level is manifested on surface ECG, but there was a relatively weak correlation between them in the present study. In support of our work, it is reported that P-wave amplitude, QRS prolongation and T-wave amplitudes are not sensitive or specific for magnitude of hyperkalemia.^21,26 Intraventricular conduction accelerates transiently if potassium ion is elevated moderately, but the conduction is depressed with further rise of potassium ion (so-called supernormal conduction).^27,28 This inhomogeneous conduction change with potassium elevation may disturb the simple linear correlation between ECG parameters and potassium ion level.

Atrial tissues are more sensitive to hyperkalemia than ventricular tissues or Purkinje fibers.^29,30 Pacemaker activity of the sinus node and atrioventricular node, however, is resistant to hyperkalemia, because inward rectifier potassium ion current is negligible in these node cells.³¹ Atrioventricular junctional or ventricular escape rhythm may develop due to the continued propagation of electrical activity from sinus node to ventricles without depolarizing atrial muscle,³⁰ or automaticity at atrioventricular junction and/or Purkinje fibers,²⁷ and all of these mechanisms may generate atrial standstill on surface ECG. In the present study potassium ion level was significantly elevated in patients with atrial standstill, but it was widely distributed in both groups. This is consistent with previous reports in which atrial standstill (described as “sinus arrest” or “sino-ventricular conduction” in the original papers) was noted at moderate elevation of potassium ion, such as 6.4 mmol/L³² and 5.5 mmol/L,³³ whereas little change was observed on ECG even for potassium ion level >8 mmol/L.⁶ It appears that serum potassium ion level itself cannot explain all of the ECG changes. Acid-base imbalance and instability of cellular membrane are suggested to influence the electrophysiological effects of hyperkalemia in cardiac tissues.^33–36 In this study, atrial standstill did not occur in patients on maintenance hemodialysis. In addition, serum creatinine tended to be higher in patients with atrial standstill than in those without atrial standstill. Moreover, 8 patients with atrial standstill and 1 without atrial standstill started maintenance hemodialysis for the first time during hospitalization. This indicates that uremic toxins concomitant with electrolyte imbalance may affect the electrophysiology of the heart.^27,37 On multivariate logistic regression analysis, hyponatremia was an independent covariate for risk of atrial standstill. In electrophysiology, hyponatremia decreases the amplitude of the action potential as well as the rate of rise of the phase 0 action potential upstroke,^7,27 and it may have an additive effect on the depressed conduction velocity of hyperkalemia.⁷ Hyponatremia is also associated with an increased risk of all-cause and cardiovascular mortality,³⁸ but it was not clear whether such a small difference in extracellular concentration of sodium ion between the 2 groups (136 vs. 132 mmol/L) in the present study would produce a sufficient change in the action potential amplitude on electrophysiology under hyperkalemia. Sodium ion <135 mmol/L was associated with poorer prognosis than sodium ion concentration 136–140 mmol/L in heart failure patients with preserved ejection fraction, and it may be relevant to our study.³⁹ Second, decline in DBP was identified as another independent covariate for risk of atrial standstill. Coronary circulation occurs mostly in diastole, and fall in DBP causes ischemic events.⁴⁰ Regional myocardial ischemia induces heterogeneous distribution of extracellular potassium ion, leading to electrical instability.⁴¹ We speculate that these may have at least in part influenced the development of atrial standstill.

It is crucial to treat hyperkalemic patients with atrial standstill with i.v. gluconate calcium, and subsequent hemodialysis to correct electrolyte abnormality.⁴² Gluconate calcium reverses the potassium-induced depression of electrical conduction and ectopic impulse by stabilizing the cellular membrane. Hypertonic saline also stabilizes the membrane potential, and it may be effective in cases of hyponatremia with hyperkalemia.⁴² The underlying mechanisms include the negation of electrophysiological effects of hyperkalemia by increasing the sodium gradient,²⁷ the improvement of cellular perfusion in cardiac pacemaker cells and the dilution of extracellular potassium concentration.⁴³ Hypertonic saline, however, raises potassium ion level, accompanied by increased plasma osmolality in patients with renal failure,⁴⁴ and may induce volume overload hypertonicity.^42,45 The present data indicate that patients with atrial standstill should be treated promptly to remove/shift serum potassium ion but also to correct hemodynamics, if clinical scenario and ECG changes suggest hyperkalemia.

This study has several limitations and unresolved issues. This was a cross-sectional, retrospective, single-center study with a small number of patients, and the lack of pre-admission serum electrolyte concentration and blood pH reduces the validity of the results. In addition, serum calcium ion level was unavailable for all patients, although it can potentially affect the electrophysiology of hyperkalemia.²¹ Direct measurement of ionized calcium ion is more accurate than albumin-corrected calcium,⁴⁶ but this was not able to be assessed at the present institution. More importantly, this study did not evaluate sinus node function on invasive cardiac electrophysiological study.⁴⁷ Therefore, it was difficult to differentiate the disappearance of P waves from the absence of atrial electrical activity or sinus node pacemaker dysfunction on surface ECG.

Conclusions

Serum electrolytes should be monitored frequently in elderly patients with chronic kidney disease, especially those taking ACEI/ARB in combination with MR blocker. In addition, coexisting hyponatremia and decreased DBP may predispose to atrial standstill in hyperkalemic patients.

Acknowledgment

This study was supported by Grants-in-Aid for Scientific Research (C) (26461076 to T.T.) from the Ministry of Education, Culture, Sport, Science and Technology, Japan.

Conflict of Interest

The authors declare no conflicts of interest.

References

• 1.    Drawz  PE,  Babineau  DC,  Rahman  M. Metabolic complications in elderly adults with chronic kidney disease. J Am Geriatr Soc 2012; 60: 310–315.
• 2.    Einhorn  LM,  Zhan  M,  Hsu  VD,  Walker  LD,  Moen  MF,  Seliger  SL, et al. The frequency of hyperkalemia and its significance in chronic kidney disease. Arch Intern Med 2009; 169: 1156–1162.
• 3.    Marino  PL. The ICU book, 4th edn. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins, 2014.
• 4.    Shamseddin  MK,  Parfrey  PS. Sudden cardiac death in chronic kidney disease: Epidemiology and prevention. Nat Rev Nephrol 2011; 7: 145–154.
• 5.    Mount  DB. Fluid and electrolyte disturbances. In: Longo DL, Kasper DL, Jameson JL, Fauci AS, Hauser SL, Loscalzo JL, editors. Harrison’s principles of internal medicine, 18th edn. New York: McGraw-Hill, 2012; 341–359.
• 6.    Martinez-Vea  A,  Bardají  A,  Garcia  C,  Oliver  JA. Severe hyperkalemia with minimal electrocardiographic manifestations: A report of seven cases. J Electrocardiol 1999; 32: 45–49.
• 7.    Parham  WA,  Mehdirad  AA,  Biermann  KM,  Fredman  CS. Hyperkalemia revisited. Tex Heart Inst J 2006; 33: 40–47.
• 8.    Yu  AS. Atypical electrocardiographic changes in severe hyperkalemia. Am J Cardiol 1996; 77: 906–908.
• 9.    Szerlip  HM,  Weiss  J,  Singer  I. Profound hyperkalemia without electrocardiographic manifestations. Am J Kidney Dis 1986; 7: 461–465.
• 10.    Fuenmayor  AAJ,  Rodríguez  SYA. Atrial standstill. Int J Cardiol 2013; 165: e47–e48, doi:10.1016/j.ijcard.2012.10.077.
• 11.    Bellmann  B,  Roser  M,  Muntean  B,  Tscholl  V,  Nagel  P,  Schmid  M, et al. Atrial standstill in sinus node disease due to extensive atrial fibrosis: Impact on dual chamber pacemaker implantation. Europace 2016; 18: 238–245.
• 12.   World Medical Association. World Medical Association Declaration of Helsinki: Ethical principles for medical research involving human subjects. JAMA 2013; 310: 2191–2194.
• 13.    McKee  PA,  Castelli  WP,  McNamara  PM,  Kannel  WB. The natural history of congestive heart failure: The Framingham study. N Engl J Med 1971; 285: 1441–1446.
• 14.    Levey  AS,  Eckardt  KU,  Tsukamoto  Y,  Levin  A,  Coresh  J,  Rossert  J, et al. Definition and classification of chronic kidney disease: A position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int 2005; 67: 2089–2100.
• 15.    Yamanaka  H,  Metabolism  TG. Essence of the revised guideline for the management of hyperuricemia and gout. Japan Med Assoc J 2012; 55: 324–329.
• 16.    Payne  RB,  Little  AJ,  Williams  RB,  Milner  JR. Interpretation of serum calcium in patients with abnormal serum proteins. Br Med J 1973; 4: 643–646.
• 17.    Freeman  K,  Feldman  JA,  Mitchell  P,  Donovan  J,  Dyer  KS,  Eliseo  L, et al. Effects of presentation and electrocardiogram on time to treatment of hyperkalemia. Acad Emerg Med 2008; 15: 239–249.
• 18.    Dhamoon  AS,  Jalife  J. The inward rectifier current (IK1) controls cardiac excitability and is involved in arrhythmogenesis. Heart Rhythm 2005; 2: 316–324.
• 19.    Mirvis  DM,  Goldberger  AL. Electrocardiography. In: Libby P, Bonow RO, Mann DL, Zipes DP, editors. Braunwald’s heart disease: A textbook of cardiovascular medicine, 8th edn. Philadelphia: Saunders Elsevier, 2008; 149–194.
• 20.    Chou  TC. Electrocardiography in clinical practice: Adult and pediatric, 4th edn. Philadelphia: WB Saunders, 1996.
• 21.    El-Sherif  N,  Turitto  G. Electrolyte disorders and arrhythmogenesis. Cardiol J 2011; 18: 233–245.
• 22.    Miao  Y,  Dobre  D,  Heerspink  HJ,  Brenner  BM,  Cooper  ME,  Parving  HH, et al. Increased serum potassium affects renal outcomes: A post hoc analysis of the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trial. Diabetologia 2011; 54: 44–50.
• 23.    Klevay  LM,  Bogden  JD,  Aladjem  M,  Sandstead  HH,  Kemp  FW,  Li  W, et al. Renal and gastrointestinal potassium excretion in humans: New insight based on new data and review and analysis of published studies. J Am Coll Nutr 2007; 26: 103–110.
• 24.    Juurlink  DN,  Mamdani  MM,  Lee  DS,  Kopp  A,  Austin  PC,  Laupacis  A, et al. Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study. N Engl J Med 2004; 351: 543–551.
• 25.    Fried  LF,  Emanuele  N,  Zhang  JH,  Brophy  M,  Conner  TA,  Duckworth  W, et al. Combined angiotensin inhibition for the treatment of diabetic nephropathy. N Engl J Med 2013; 369: 1892–1903.
• 26.    Montague  BT,  Ouellette  JR,  Buller  GK. Retrospective review of the frequency of ECG changes in hyperkalemia. Clin J Am Soc Nephrol 2008; 3: 324–330.
• 27.    Fisch  C. Relation of electrolyte disturbances to cardiac arrhythmias. Circulation 1973; 47: 408–419.
• 28.    Moore  EN,  Spear  JF,  Fisch  C. “Supernormal” conduction and excitability. J Cardiovasc Electrophysiol 1993; 4: 320–337.
• 29.    Vassalle  M,  Hoffman  BF. The spread of sinus activation during potassium administration. Circ Res 1965; 17: 285–295.
• 30.    Hariman  RJ,  Chen  CM. Effects of hyperkalaemia on sinus nodal function in dogs: Sino-ventricular conduction. Cardiovasc Res 1983; 17: 509–517.
• 31.    Noma  A,  Nakayama  T,  Kurachi  Y,  Irisawa  H. Resting K conductances in pacemaker and non-pacemaker heart cells of the rabbit. Jpn J Physiol 1984; 34: 245–254.
• 32.    Bonvini  RF,  Hendiri  T,  Anwar  A. Sinus arrest and moderate hyperkalemia. Ann Cardiol Angeiol (Paris) 2006; 55: 161–163.
• 33.    Mehta  NJ,  Chhabra  VK,  Khan  IA. Sinus arrest or sinoventricular conduction in mild hyperkalemia. J Emerg Med 2001; 20: 163–164.
• 34.    Surawicz  B,  Chlebus  H,  Mazzoleni  A. Hemodynamic and electrocardiographic effects of hyperpotassemia: Differences in response to slow and rapid increases in concentration of plasma K. Am Heart J 1967; 73: 647–664.
• 35.    Lyons  CJ,  Burgess  MJ,  Abildskov  JA. Effects of acute hyperkalemia on cardiac excitability. Am Heart J 1977; 94: 755–763.
• 36.    Kagiyama  Y,  Hill  JL,  Gettes  LS. Interaction of acidosis and increased extracellular potassium on action potential characteristics and conduction in guinea pig ventricular muscle. Circ Res 1982; 51: 614–623.
• 37.    Peng  YS,  Ding  HC,  Lin  YT,  Syu  JP,  Chen  Y,  Wang  SM. Uremic toxin p-cresol induces disassembly of gap junctions of cardiomyocytes. Toxicology 2012; 302: 11–17.
• 38.    Liu  M,  Fang  F,  Yu  CM. Noncardiac comorbidities in heart failure with preserved ejection fraction: Commonly ignored fact. Circ J 2015; 79: 954–959.
• 39.    Kusaka  H,  Sugiyama  S,  Yamamoto  E,  Akiyama  E,  Matsuzawa  Y,  Hirata  Y, et al. Low-normal serum sodium and heart failure-related events in patients with heart failure with preserved left ventricular ejection fraction. Circ J 2016; 80: 411–417.
• 40.    Messerli  FH,  Panjrath  GS. The J-curve between blood pressure and coronary artery disease or essential hypertension: Exactly how essential? J Am Coll Cardiol 2009; 54: 1827–1834.
• 41.    Coronel  R,  Fiolet  JW,  Wilms-Schopman  FJ,  Schaapherder  AF,  Johnson  TA,  Gettes  LS, et al. Distribution of extracellular potassium and its relation to electrophysiologic changes during acute myocardial ischemia in the isolated perfused porcine heart. Circulation 1988; 77: 1125–1138.
• 42.    Kovesdy  CP. Management of hyperkalaemia in chronic kidney disease. Nat Rev Nephrol 2014; 10: 653–662.
• 43.    Kaplan  JL,  Eynon  CA,  Dalsey  WC,  Braitman  LE,  Clas  D,  De Garavilla  L. Hypertonic saline treatment of severe hyperkalemia in nonnephrectomized dogs. Acad Emerg Med 2000; 7: 965–973.
• 44.    Conte  G,  Dal Canton  A,  Imperatore  P,  De Nicola  L,  Gigliotti  G,  Pisanti  N, et al. Acute increase in plasma osmolality as a cause of hyperkalemia in patients with renal failure. Kidney Int 1990; 38: 301–307.
• 45.    Weisberg  LS. Management of severe hyperkalemia. Crit Care Med 2008; 36: 3246–3251.
• 46.    Calvi  LM,  Bushinsky  DA. When is it appropriate to order an ionized calcium? J Am Soc Nephrol 2008; 19: 1257–1260.
• 47.    Park  JK,  Park  J,  Uhm  JS,  Pak  HN,  Lee  MH,  Joung  B. Combined algorithm using a poor increase in inferior P-wave amplitude during sympathetic stimulation and sinus node recovery time for the diagnosis of sick sinus syndrome. Circ J 2015; 79: 2148–2156.