Clinical Significance of Incident Hypokalemia and Hyperkalemia in Treated Hypertensive Patients in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial

Alderman, Michael H.; Piller, Linda B.; Ford, Charles E.; Probstfield, Jeffrey L.; Oparil, Suzanne; Cushman, William C.; Einhorn, Paula T.; Franklin, Stanley S.; Papademetriou, Vasilios; Ong, Stephen T.; Eckfeldt, John H.; Furberg, Curt D.; Calhoun, David A.; Davis, Barry R.

doi:10.1161/hypertensionaha.111.180554

Cited by 66 publications

(49 citation statements)

References 22 publications

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“…Thus, event rates in subjects with ESVEA and accompanying hypokalemia were almost 14× greater compared with the event rates seen when no ESVEA or hypokalemia were present. According to this study and previous studies, hypokalemia seems to be independently associated with a worse prognostic outcome in terms of cardiovascular-related events, 6,[17][18][19] and data from the present study suggest that mild hypokalemia interacts with excessive supraventricular ectopy to increase the risk of stroke significantly. Earlier studies has shown ESVEA as a predictor of atrial fibrillation and stroke.…”

Section: Discussionsupporting

confidence: 84%

“…6 One of the suggested mechanisms is prolongation of the repolarization phase of the myocardial action potential because of a reduced repolarizing outward potassium current. 7,8 Prolongation of the repolarization phase can cause early after-depolarizations, which potentially could lead to arrhythmia.…”

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confidence: 99%

“…12 Mild hypokalemia is a common finding and is generally not considered harmful in a clinical setting, and it may occur as a primary condition or secondary to many medications, such as diuretics and laxatives. 6,13 Both hypokalemia and ESVEA are independently associated with increased risk of stroke, and both conditions are relatively common in the general…”

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confidence: 99%

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Mild Hypokalemia and Supraventricular Ectopy Increases the Risk of Stroke in Community-Dwelling Subjects

Mattsson

Kumarathurai

Larsen

et al. 2017

Stroke

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Background and Purpose-Stroke is independently associated with the common conditions of hypokalemia and supraventricular ectopy, and we hypothesize that the combination of excessive supraventricular ectopic activity and hypokalemia has a synergistic impact on the prognosis in terms of stroke in the general population. Methods-Subjects (55-75 years old) from the Copenhagen Holter Study cohort (N=671) with no history of atrial fibrillation or stroke were studied-including baseline values of potassium and ambulatory 48-hour Holter monitoring. Excessive supraventricular ectopic activity is defined as ≥30 premature atrial complexes per hour or any episodes of runs of ≥20. Hypokalemia was defined as plasma-potassium ≤3.6 mmol/L. The primary end point was ischemic stroke. Cox models were used. Results-Hypokalemia was mild (mean, 3.4 mmol/L; range, 2.7-3.6). Hypokalemic subjects were older (67.0±6.94 versus 64.0±6.66 years; P<0.0001) and more hypertensive (165.1±26.1 versus 154.6±23.5 mm Hg; P<0.0001). Median followup time was 14.4 years (Q1-Q3, 9.4-14.7 years). The incidence of stroke was significantly higher in the hypokalemic group (hazard ratio, 1.84; 95% confidence interval, 1.04-3.28) after covariate adjustments, as well as in a competing risk analysis with death (hazard ratio, 1.51; 95% confidence interval, 1.12-2.04). Excessive supraventricular ectopic activity was also associated with stroke (hazard ratio, 2.23; 95% confidence interval, 1.33-3.76). The combination of hypokalemia and excessive supraventricular ectopic activity increased the risk of events synergistically. Stroke rate was 93 per 1000 patient-year (P<0.0001) in this group (n=17) compared with 6.9 (n=480); 11 (n=81), and 13 (n=93) per 1000 patient-year in the groups without the combination. Conclusions-The combination of hypokalemia and excessive supraventricular ectopy carries a poor prognosis in terms of stroke.

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Section: Discussionsupporting

confidence: 84%

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confidence: 99%

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Mild Hypokalemia and Supraventricular Ectopy Increases the Risk of Stroke in Community-Dwelling Subjects

Mattsson

Kumarathurai

Larsen

et al. 2017

Stroke

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“…To the Editor: I read with interest the article by Alderman et al 1 on the clinical significance of hypokalemia and hyperkalemia in the antihypertensive treatment and prevention of cardiovascular complications. The conclusion was that, in most patients, concerns about potassium levels should not influence the clinician's decision about initiating hypertension treatment with low-moderate doses of thiazides.…”

Section: Serum Potassium Thiazides Aldosterone and Mineralocorticomentioning

confidence: 99%

Serum Potassium, Thiazides, Aldosterone, and Mineralocorticoid Receptors

Armanini

Bordin²,

Clari

2012

Hypertension

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Alderman et al 1 on the clinical significance of hypokalemia and hyperkalemia in the antihypertensive treatment and prevention of cardiovascular complications. The conclusion was that, in most patients, concerns about potassium levels should not influence the clinician's decision about initiating hypertension treatment with low-moderate doses of thiazides. Chlorthalidone reduces the risk of congestive heart failure, in comparison with lisinopril and amlodipine, 1 but it also activates the renin-angiotensinaldosterone system. We address the issue that, beyond plasma potassium levels, during thiazides, the activation of the renin-angiotensinaldosterone system and, in particular, the stimulation of mineralocorticoid receptors (MRs) are key determinants in the inflammatory process and the progression of cardiovascular disease.The Randomized Aldactone Evaluation Study and Eplerenone Post-AMI Heart Failure Efficacy and Survival Study 2 have shown that low doses of spironolactone (SP) or eplerenone, added to the standard therapy including thiazides for treatment of severe heart failure, improve survival by 30%. An interesting demonstration that the positive effect of SP is not attributed to amelioration of serum potassium but to the blocking of MRs comes from the study by Ma et al. 3 These authors showed that, in hypertensive patients, SP could reduce plasminogen activator inhibitor 1 concentration in serum, whereas triamterene was ineffective; hydrochlorothiazide indeed worsened plasminogen activator inhibitor 1 concentration, which is a known marker of inflammation. The conclusion was that the principal effect of SP in the reduction of cardiovascular risk is the blocking of MR and not the increase of potassium. We also found that canrenone is able to protect MRs from the inflammatory action of aldosterone in mononuclear leukocytes in vitro, whereas amiloride is not. 4 From all of these considerations, it can be concluded that thiazides can reduce blood pressure and ameliorate congestive heart failure but can only partially protect from cardiovascular risk because of an increase of aldosterone, leading to inflammatory reaction at the level of the kidney, heart, and lymphocytes, independent from the sodium intake. SP or its derivatives improve serum potassium, reduce insulin resistance, and prevent the inflammatory effect of aldosterone. SP activates all of the components of the renin-angiotensin-aldosterone system, but MRs are blocked, neutralizing the proinflammatory effect of aldosterone. These discrepancies point out the fundamental role of MR even in situations of volume depletion and activation of the renin-angiotensin-aldosterone system. 5 Previous studies have ascribed to angiotensin II a key role in the onset and progression of cardiovascular damage, but it is more likely that the increase of aldosterone and MR-mediated effect is the principal factor involved in the inflammatory reaction at the level of the target tissues.From all of these considerations it follows that the treatment of hypertension with MR an...

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“…The fact that hypokalemia and hyperkalemia each predict increases in mortality has been reported in multiple community studies and in studies of a variety of disease populations including hypertension, CKD, atherosclerosis, and others [3,4,5,6,7,8]. All of this suggests that closer monitoring of serum potassium and more aggressive prevention or correction/repletion of even modest hypo or hyperkalemia may be appropriate.…”

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confidence: 97%