Protection against severe hypokalemia but impaired cardiac repolarization after intense rowing exercise in healthy humans receiving salbutamol

Intense exercise induces pronounced hyperkalemia, followed by transient hypokalemia in recovery. We investigated whether the β2 agonist salbutamol attenuated the exercise hyperkalemia and exacerbated the postexercise hypokalemia, and whether hypokalemia was associated with impaired cardiac repolarization (QT hysteresis). Eleven healthy adults participated in a randomized, counterbalanced, double-blind trial receiving either 1,000 µg salbutamol (SAL) or placebo (PLAC) by inhalation. Arterial plasma potassium concentration ([K+]a) was measured at rest, during 3 min of intense rowing exercise, and during 60 min of recovery. QT hysteresis was calculated from ECG ( n = 8). [K+]a increased above baseline during exercise (rest, 3.72 ± 0.7 vs. end-exercise, 6.81 ± 1.4 mM, P < 0.001, mean ± SD) and decreased rapidly during early recovery to below baseline; restoration was incomplete at 60 min postexercise ( P < 0.05). [K+]a was less during SAL than PLAC (4.39 ± 0.13 vs. 4.73 ± 0.19 mM, pooled across all times, P = 0.001, treatment main effect). [K+]a was lower after SAL than PLAC, from 2 min preexercise until 2.5 min during exercise, and at 50 and 60 min postexercise ( P < 0.05). The postexercise decline in [K+]a was correlated with QT hysteresis ( r = 0.343, n = 112, pooled data, P = 0.001). Therefore, the decrease in [K+]a from end-exercise by ~4 mM was associated with reduced QT hysteresis by ~75 ms. Although salbutamol lowered [K+]a during exercise, no additive hypokalemic effects occurred in early recovery, suggesting there may be a protective mechanism against severe or prolonged hypokalemia after exercise when treated by salbutamol. This is important because postexercise hypokalemia impaired cardiac repolarization, which could potentially trigger arrhythmias and sudden cardiac death in susceptible individuals with preexisting hypokalemia and/or heart disease. NEW & NOTEWORTHY Intense rowing exercise induced a marked increase in arterial potassium, followed by a pronounced decline to hypokalemic levels. The β2 agonist salbutamol lowered potassium during exercise and late recovery but not during early postexercise, suggesting a protective effect against severe hypokalemia. The decreased potassium in recovery was associated with impaired cardiac QT hysteresis, suggesting a link between postexercise potassium and the heart, with implications for increased risk of cardiac arrhythmias and, potentially, sudden cardiac death.

Download Full-text

Non-invasive detection of exercise-induced cardiac conduction abnormalities in sudden cardiac death survivors in the inherited cardiac conditions

EP Europace ◽

10.1093/europace/euaa248 ◽

2020 ◽

Author(s):

Kevin Ming Wei Leong ◽

Fu Siong Ng ◽

Matthew J Shun-Shin ◽

Michael Koa-Wing ◽

Norman Qureshi ◽

...

Keyword(s):

Sudden Cardiac Death ◽

Cardiac Death ◽

Recovery Period ◽

Lower Score ◽

Cardiac Conduction ◽

Protective Mechanism ◽

Significant Difference ◽

Exercise Treadmill ◽

Inherited Cardiac Conditions ◽

Exercise Induced

Abstract Aims Rate adaptation of the action potential ensures spatial heterogeneities in conduction across the myocardium are minimized at different heart rates providing a protective mechanism against ventricular fibrillation (VF) and sudden cardiac death (SCD), which can be quantified by the ventricular conduction stability (V-CoS) test previously described. We tested the hypothesis that patients with a history of aborted SCD due to an underlying channelopathy or cardiomyopathy have a reduced capacity to maintain uniform activation following exercise. Methods and results Sixty individuals, with (n = 28) and without (n = 32) previous aborted-SCD event underwent electro-cardiographic imaging recordings following exercise treadmill test. These included 25 Brugada syndrome, 13 hypertrophic cardiomyopathy, 12 idiopathic VF, and 10 healthy controls. Data were inputted into the V-CoS programme to calculate a V-CoS score that indicate the percentage of ventricle that showed no significant change in ventricular activation, with a lower score indicating the development of greater conduction heterogeneity. The SCD group, compared to those without, had a lower median (interquartile range) V-CoS score at peak exertion [92.8% (89.8–96.3%) vs. 97.3% (94.9–99.1%); P < 0.01] and 2 min into recovery [95.2% (91.1–97.2%) vs. 98.9% (96.9–99.5%); P < 0.01]. No significant difference was observable later into recovery at 5 or 10 min. Using the lowest median V-CoS scores obtained during the entire recovery period post-exertion, SCD survivors had a significantly lower score than those without for each of the different underlying aetiologies. Conclusion Data from this pilot study demonstrate the potential use of this technique in risk stratification for the inherited cardiac conditions.

Download Full-text

Antiarrhythmic mechanisms during exercise

Journal of Applied Physiology ◽

10.1152/jappl.1996.80.6.1853 ◽

1996 ◽

Vol 80 (6) ◽

pp. 1853-1862 ◽

Cited By ~ 41

Author(s):

D. J. Paterson

Keyword(s):

Sudden Cardiac Death ◽

Cardiac Death ◽

Protective Mechanism ◽

Chemical Stress ◽

Ionic Balance ◽

Vigorous Exercise ◽

Arterial Blood ◽

Mutual Antagonism ◽

Increased Risk

Exercise disturbs cardiac sympathovagal and ionic balance. In arterial blood, vigorous exercise can double plasma K(+), decrease pH by 0.4 unit, and raise catecholamines 15-fold. If any of these changes are experienced at rest, there is an increased risk of arrhythmia and cardiac arrest, yet in exercise they are usually tolerated. How the heart is protected from the chemical stress caused by exercise is not fully understood but may be related to a collective antiarrhythmic effect of these chemical changes, so when they combine there is a mutual antagonism. Catecholamines can offset the harmful cardiac effects of hyperkalemia and acidosis in isolated hearts and whole hearts in vivo and improve action-potential characteristics in K(+)-depolarized ventricular myocytes. This results from an increase in the inward Ca2(+) current that is modulated by both adrenergic and nonadrenergic hormones. Conversely, hyperkalemia can reduce or abolish the incidence of norepinephrine-induced arrhythmias. The efficacy of the mutual antagonism is reduced when the combination of acidosis, hyperkalemia, and high levels of norepinephrine are superimposed on a heart with regional ischemia or a small infarct. However, the heart may be at greatest risk in the postexercise period when plasma K(+) is low and the adrenergic tone is high. Little is known about this period, but abnormal regulation of electrolyte and cardiac sympathovagal balance may increase the incidence of arrhythmia, especially if there is underlying ischemia. Although regular physical activity can reduce the incidence of sudden cardiac death, recent epidemiological studies show that vigorous exercise can trigger myocardial infarction and sudden cardiac death, especially in habitually sedentary subjects with coronary artery disease. This may be partly related to disruption of the normal protective mechanism that allows the heart to cope with the chemical stress caused by exercise.

Download Full-text

Association between digoxin use and sudden cardiac death in individuals with the rs10494366 variant of the NOS1AP gene

European Heart Journal ◽

10.1093/ehjci/ehaa946.3394 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

N Soroush ◽

A Aarnoudse ◽

F Shokri ◽

M Van Den Berg ◽

F Ahmadizar ◽

...

Keyword(s):

Sudden Cardiac Death ◽

Cardiac Death ◽

Smoking Status ◽

Adaptor Protein ◽

Therapeutic Window ◽

P Value ◽

Qtc Interval ◽

Total Study Population ◽

Increased Risk

Abstract Background Digoxin is one of the oldest cardiovascular medications still used to treat heart failure and atrial fibrillation. Due to its narrow therapeutic window, it is associated with life threatening intoxication and arrhythmias, and with QTc-shortening. Common genetic variation in the nitric oxide synthase-1 adaptor protein (NOS1AP) has been associated with QTc interval prolongation. Purpose We investigated whether the rs10494366 variant of the NOS1AP gene modified the risk of SCD in patients using digoxin. Methods In a prospective population-based cohort study, we included data of the three cohorts, started as of January 1st, 1991 until January 1st 2014. Digoxin current use on the date of cardiac death in cases and the same day of follow-up in the remainder of the cohort was a time-dependent exposure. The main outcome was SCD defined as sudden and unexpected death as a result of cardiac causes, according to international criteria. Identification and adjudication of SCD was performed independently, before the start of this study. We used Cox proportional hazard regression analysis to investigate the associations between NOS1AP rs10494366 variant and incident SCD among digoxin users compared to non-users. Associations were adjusted for age, sex (model 1) in addition to BMI, prevalent diabetes, myocardial infarction, baseline hypertension and smoking status (past, current, never) (model 2). Results We included 14,594 individuals, with a mean age of 65.3 (SD 10.3) years. Almost 59% were female. The cumulative incidence of SCD was 9.5% (609 cases) by the end of follow up. Among them, 98 (16%) individuals were exposed to digoxin at the time of death. In model 1, NOS1AP rs10494366 variant was not associated with SCD in the total study population. However, an interaction term of the gene with the daily dose of digoxin was significantly associated with increased risk of SCD (p-value 0.0001). In model 2, the risk of SCD in current users of digoxin was 4.2 [95% CI 1.3–13.8] for the GG genotype; 2.1 [95% CI 1.1–4.2] for the GT genotype, and 1.5 [95% CI 0.7–3.2] for the TT genotype. Conclusion NOS1AP rs10494366 variant modified the risk of sudden cardiac death in users of digoxin. Our study suggests that individuals with the homozygous minor GG allele have a fourfold increased risk of sudden cardiac death. Funding Acknowledgement Type of funding source: None

Download Full-text

N-terminal pro-brain natriuretic peptide and sudden cardiac death in hypertrophic cardiomyopathy

Heart ◽

10.1136/heartjnl-2020-317701 ◽

2020 ◽

pp. heartjnl-2020-317701

Author(s):

Guixin Wu ◽

Jie Liu ◽

Shuiyun Wang ◽

Shiqin Yu ◽

Ce Zhang ◽

...

Keyword(s):

Hypertrophic Cardiomyopathy ◽

Sudden Cardiac Death ◽

Brain Natriuretic Peptide ◽

Natriuretic Peptide ◽

Cardiac Death ◽

Cardiac Fibrosis ◽

Discrimination Performance ◽

Net Reclassification Improvement ◽

C Statistic ◽

Increased Risk

ObjectiveElevated levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) are associated with heart failure-related death in hypertrophic cardiomyopathy (HCM), but the relationship between NT-proBNP level and sudden cardiac death (SCD) in HCM remains undefined.MethodsThe study prospectively enrolled 977 unrelated patients with HCM with available NT-proBNP results who were prospectively enrolled and followed for 3.0±2.1 years. The Harrell’s C-statistic under the receiver operating characteristic curve was calculated to evaluate discrimination performance. A combination model was constructed by adding NT-proBNP tertiles to the HCM Risk-SCD model. The correlation between log NT-proBNP level and cardiac fibrosis as measured by late gadolinium enhancement (LGE) or Masson’s staining was analysed.ResultsDuring follow-up, 29 patients had SCD. Increased log NT-proBNP levels were associated with an increased risk of SCD events (adjusted HR 22.27, 95% CI 10.93 to 65.63, p<0.001). The C-statistic of NT-proBNP in predicting SCD events was 0.80 (p<0.001). The combined model significantly improved the predictive efficiency of the HCM Risk-SCD model from 0.72 to 0.81 (p<0.05), with a relative integrated discrimination improvement of 0.002 (p<0.001) and net reclassification improvement of 0.67 (p<0.001). Furthermore, log NT-proBNP levels were significantly correlated with cardiac fibrosis as detected either by LGE (r=0.257, p<0.001) or by Masson’s trichrome staining in the myocardium (r=0.198, p<0.05).ConclusionNT-proBNP is an independent predictor of SCD in patients with HCM and may help with risk stratification of this disease.

Download Full-text

Vital exhaustion and sudden cardiac death in the Atherosclerosis Risk in Communities Study

Heart ◽

10.1136/heartjnl-2017-311825 ◽

2017 ◽

Vol 104 (5) ◽

pp. 423-429 ◽

Cited By ~ 2

Author(s):

Brittany M Bogle ◽

Nona Sotoodehnia ◽

Anna M Kucharska-Newton ◽

Wayne D Rosamond

Keyword(s):

Risk Factors ◽

Sudden Cardiac Death ◽

Cardiac Death ◽

Disease Risk ◽

Ventricular Tachyarrhythmia ◽

Atherosclerosis Risk In Communities ◽

Vital Exhaustion ◽

Increased Risk ◽

Atherosclerosis Risk ◽

Aric Study

ObjectiveVital exhaustion (VE), a construct defined as lack of energy, increased fatigue and irritability, and feelings of demoralisation, has been associated with cardiovascular events. We sought to examine the relation between VE and sudden cardiac death (SCD) in the Atherosclerosis Risk in Communities (ARIC) Study.MethodsThe ARIC Study is a predominately biracial cohort of men and women, aged 45–64 at baseline, initiated in 1987 through random sampling in four US communities. VE was measured using the Maastricht questionnaire between 1990 and 1992 among 13 923 individuals. Cox proportional hazards models were used to examine the hazard of out-of-hospital SCD across tertiles of VE scores.ResultsThrough 2012, 457 SCD cases, defined as a sudden pulseless condition presumed due to a ventricular tachyarrhythmia in a previously stable individual, were identified in ARIC by physician record review. Adjusting for age, sex and race/centre, participants in the highest VE tertile had an increased risk of SCD (HR 1.48, 95% CI 1.17 to 1.87), but these findings did not remain significant after adjustment for established cardiovascular disease risk factors (HR 0.94, 95% CI 0.73 to 1.20).ConclusionsAmong participants of the ARIC study, VE was not associated with an increased risk for SCD after adjustment for cardiovascular risk factors.

Download Full-text

Abstract 2415: Long-Term Baroreflex Activation Therapy Increases the Threshold for the Induction of Lethal Ventricular Arrhythmias in Dogs with Chronic Advanced Heart Failure

Circulation ◽

10.1161/circ.118.suppl_18.s_722 ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Mengjun Wang ◽

Valerio Zaca ◽

Alice Jiang ◽

Itamar Ilsar ◽

Matthew Ebinger ◽

...

Keyword(s):

Heart Failure ◽

Sudden Cardiac Death ◽

Cardiac Death ◽

Ventricular Arrhythmias ◽

Lv Function ◽

Baroreflex Activation Therapy ◽

Increased Risk ◽

Lv Remodeling ◽

Activation Therapy

Heart failure (HF) is associated with a high incidence of ventricular tachycardia (VT) and fibrillation (VF). Patients with HF in whom these lethal arrhythmias can be induced by electrophysiological (EP) testing carry a high risk of sudden cardiac death. We showed that chronic electrical carotid baroreflex activation therapy (BAT) with the Rheos® System (CVRx, Inc.) improves LV function, attenuates LV remodeling and restores autonomic sympathetic-parasympathetic balance in dogs with HF. This study examined the effects of long-term therapy with BAT on the induction of VT or VF in dogs with coronary microembolization-induced HF (LV ejection fraction ~20%). Eleven dogs with HF underwent EP testing at baseline prior to therapy and after 3 and 6 months of therapy with BAT and again 6 weeks after withdrawal of BAT therapy (n = 7) or no therapy at all (Control, n = 4). Programmed ventricular stimulation was performed from the right ventricular apex and included delivery of up to 4 extrastimuli at progressively shorter coupling intervals (in steps of 10 msec). The extrastimuli were delivered following 8 ventricular paced beats with a drive cycle length between 600 and 200 msec. If a sustained monomorphic VT or VF could not be induced, isoproterenol infusion was initiated to increase the sinus rate by ~30% and the EP stimulation protocol was repeated. At baseline, a sustained VT or VF was induced in all 11 dogs (100%). After 3 and 6 months of follow-up, all Control dogs (100%) were induced into sustained VT or VF. After 3 months of BAT, only 3 of 7 dogs (43%) were induced into sustained VT or VF. After 6 months of BAT, only 2 of 7 dogs (29%) were induced into sustained VT or VF. Finally after withdrawal of BAT therapy, all dogs (100%) were again induced into systained VT or VF. In addition to improving LV function and attenuating LV remodeling, long-term monotherapy with BAT markedly increases the threshold for lethal ventricular arrhythmias in dogs with chronic HF. This is a marked improvement over inducibility of lethal arrhythmias seen in historical untreated controls. This benefit of BAT supports the continued exploration of this device as a therapeutic modality for treating patients with chronic HF and increased risk of sudden cardiac death.

Download Full-text

Airflow obstruction, impaired lung function and risk of sudden cardiac death: a prospective cohort study

Thorax ◽

10.1136/thoraxjnl-2020-215632 ◽

2021 ◽

pp. thoraxjnl-2020-215632

Author(s):

Yun-Jiu Cheng ◽

Zhen-Guang Chen ◽

Feng-Juan Yao ◽

Li-Juan Liu ◽

Ming Zhang ◽

...

Keyword(s):

Sudden Cardiac Death ◽

Lung Function ◽

Cardiac Death ◽

Airflow Obstruction ◽

Partial Likelihood ◽

Race And Gender ◽

Increased Risk ◽

Impaired Lung Function ◽

And Gender ◽

Lung Health

BackgroundGrowing evidence suggests that compromised lung health may be linked to cardiovascular disease. However, little is known about its association with sudden cardiac death (SCD).ObjectivesWe aimed to assess the link between impaired lung function, airflow obstruction and risk of SCD by race and gender in four US communities.MethodsA total of 14 708 Atherosclerosis Risk in Communities (ARIC) study participants who underwent spirometry and were asked about lung health (1987–1989) were followed. The main outcome was physician-adjudicated SCD. Fine-Gray proportional subdistribution hazard models with Firth’s penalised partial likelihood correction were used to estimate the HRs.ResultsOver a median follow-up of 25.4 years, 706 (4.8%) subjects experienced SCD. The incidence of SCD was inversely associated with FEV1 in each of the four race and gender groups and across all smoking status categories. After adjusting for multiple measured confounders, HRs of SCD comparing the lowest with the highest quintile of FEV1 were 2.62 (95% CI 1.62 to 4.26) for white males, 1.80 (95% CI 1.03 to 3.15) for white females, 2.07 (95% CI 1.05 to 4.11) for black males and 2.62 (95% CI 1.21 to 5.65) for black females. The above associations were consistently observed among the never smokers. Moderate to very severe airflow obstruction was associated with increased risk of SCD. Addition of FEV1 significantly improved the predictive power for SCD.ConclusionsImpaired lung function and airflow obstruction were associated with increased risk of SCD in general population. Additional research to elucidate the underlying mechanisms is warranted.

Download Full-text

Abstract 14760: Myocardial Scarring by Magnetic Resonance Predicts Sudden Cardiac Death in Pediatric Patients With Hypertrophic Cardiomyopathy

Circulation ◽

10.1161/circ.142.suppl_3.14760 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Lars Grosse-Wortmann ◽

Laurine van der Wal ◽

Aswathy Vaikom House ◽

Lee Benson ◽

Raymond Chan

Keyword(s):

Risk Factors ◽

Risk Factor ◽

Hypertrophic Cardiomyopathy ◽

Sudden Cardiac Death ◽

Cardiac Death ◽

Pediatric Patients ◽

Risk Markers ◽

C Statistic ◽

Increased Risk ◽

Traditional Risk Factors

Introduction: Cardiovascular magnetic resonance (CMR) with late gadolinium enhancement (LGE) has been shown to be an independent predictor of sudden cardiac death (SCD) in adults with hypertrophic cardiomyopathy (HCM). The clinical significance of LGE in pediatric HCM patients is unknown. Hypothesis: LGE improves the SCD risk prediction in children with HCM. Methods: We retrospectively analyzed the CMR images and reviewed the outcomes pediatric HCM patients. Results: Amongst the 720 patients from 30 centers, 73% were male, with a mean age of 14.2±4.8 years. During a mean follow up of 2.6±2.7 years (range 0-14.8 years), 34 experienced an episode of SCD or equivalent. LGE (Figure 1A) was present in 34%, with a mean burden of 14±21g, or 2.5±8.2g/m2 (6.2±7.7% of LV myocardium). The presence of ≥1 adult traditional risk factor (family history of SCD, syncope, LV thickness >30mm, non-sustained ventricular tachycardia on Holter) was associated with an increased risk of SCD (HR=4.6, p<0.0001). The HCM Risk-Kids score predicted SCD (p=0.002). The presence of LGE was strongly associated with an increased risk (HR=3.8, p=0.0003), even after adjusting for traditional risk factors (HR adj =3.2, p=0.003) or the HCM Risk-Kids score (HR adj =3.5, p=0.003). Furthermore, the burden of LGE was associated with increased risk (HR=2.1/10% LGE, p<0.0001). LGE burden remained independently associated with an increased risk for SCD after adjusting for traditional risk factors (HRadj=1.5/10% LGE, p=0.04) or HCM Risk-Kids (HRadj=1.9/10% LGE, p=0.0018, Figure 1B). The addition of LGE burden improved the predictive model using traditional risk markers (C statistic 0.67 vs 0.77, p=0.003) and HCM Risk-Kids (C statistic 0.68 vs 0.74, p=0.045). Conclusions: Quantitative LGE is an independent risk factor for SCD in pediatric patients with HCM and improves the performance of traditional risk markers and the HCM Risk-Kids Score for SCD risk stratification in this population.

Download Full-text