Papel dos Níveis de Sódio na Fibrilação Atrial na Insuficiência Cardíaca: Jogador Ativo ou Bystander?

Aydın Akyüz; Derya Baykız; Demet Özkaramanlı Gür; Sümeyra Gökçek; Muhammet Mucip Efe; Şeref Alpsoy

doi:10.36660/abc.20210139

. 2022 Jan 11;118(4):712–718. [Article in Portuguese] doi: 10.36660/abc.20210139

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Papel dos Níveis de Sódio na Fibrilação Atrial na Insuficiência Cardíaca: Jogador Ativo ou Bystander?

Aydın Akyüz ¹, Derya Baykız ², Demet Özkaramanlı Gür ¹, Sümeyra Gökçek ¹, Muhammet Mucip Efe ¹, Şeref Alpsoy ¹

PMCID: PMC9007004 PMID: 35137792

Resumo

Fundamento

A coexistência de hiponatremia e fibrilação atrial (FA) aumenta a morbidade e mortalidade em pacientes com insuficiência cardíaca (IC). No entanto, não está estabelecido se a hiponatremia está relacionada à FA ou não.

Objetivo

O objetivo do nosso estudo foi buscar a possível associação de hiponatremia com FA em pacientes que apresentam IC com fração de ejeção reduzida (ICFrE).

Métodos

Este estudo observacional, transversal e unicêntrico incluiu 280 pacientes ambulatoriais consecutivos com diagnóstico de ICFr com 40% ou menos. Com base nas concentrações de sódio ≤135 mEq/L ou superior, os pacientes foram classificados em hiponatremia (n=66) e normonatremia (n=214). Um valor de p<0,05 foi considerado significativo.

Resultados

A média de idade foi de 67,6±10,5 anos, 202 (72,2%) eram do sexo masculino, o nível médio de sódio no sangue foi de 138±3,6 mEq/L e a fração de ejeção média foi de 30±4%. Ao todo, 195 (69,6%) pacientes foram diagnosticados com doença arterial coronariana. A FA foi detectada em 124 (44.3%) pacientes. A taxa de FA foi maior em pacientes com hiponatremia em comparação com aqueles com normonatremia (n=39 [59,1%] vs. n=85 [39,7%), p=0,020). Na análise de regressão logística, a hiponatremia não foi relacionada à FA (OR=1.022, IC 95%=0,785–1.330, p=0,871). Idade aumentada (OR=1.046, IC 95%=1.016–1.177, p=0,003), presença de DAC (OR=2.058, IC 95%=1,122–3.777, p=0,020), frequência cardíaca em repouso (OR=1.041, IC 95%=1.023–1.060, p<0,001) e diâmetro do átrio esquerdo (OR=1.049, IC 95%=1.011–1.616, p=0,002) foram considerados preditores de FA.

Conclusão

A FA foi uma taxa mais elevada em pacientes ambulatoriais com ICFr e hiponatremia. No entanto, não há associação entre os níveis de sódio e FA em pacientes com ICFrEF.

Keywords: Hiponatremia, Fibrilação Atrial, Insuficiência Cardíaca

Introdução

A insuficiência cardíaca (IC) é categorizada com base na fração de ejeção (FE) como FE reduzida ≤0,40 (ICrFE), FE preservada ≥0,50 (ICpFE) ou FE média (<0,50, mas >0,40). Sua taxa vem aumentando gradativamente, estando relacionada a altas taxas de hospitalização e mortalidade.^{1 , 2}

Anemia, infecção, isquemia miocárdica, insuficiência renal, fibrilação atrial (FA) e anormalidades eletrolíticas são fatores predisponentes comuns para o agravamento da IC e podem contribuir para o desenvolvimento de sintomas clínicos de IC, como dispneia, fadiga e edema ou atividade limitada.

Embora as alterações no sódio, pelo menos teoricamente, possam contribuir para o risco de arritmia, sabe-se que distúrbios do equilíbrio eletrolítico de potássio, cálcio e magnésio desencadeiam arritmias. Define-se hiponatremia como concentração sérica de sódio ≤135 mEq/L, uma das anormalidades eletrolíticas mais comuns, associada a resultados desfavoráveis em pacientes com IC com prevalência de cerca de 13,8%–33,7%.^{3 - 5}

A prevalência de FA em pacientes com ICrFE varia de <10% a 50%.^{5 - 7} A FA na IC é uma arritmia incapacitante comum associada à gravidade da doença, alta morbidade e mortalidade. A FA leva à IC e vice-versa.^{1 , 8 - 10} Embora a relação entre FA e o desequilíbrio eletrolítico seja teoricamente bem conhecida, a associação de hiponatremia com o desenvolvimento de FA na IC não está bem documentada na literatura. Pela primeira vez, uma associação causal entre hiponatremia e desenvolvimento de FA foi descrita em um estudo recente de Cavusoglu et al.¹¹ Algum ceticismo, entretanto, ainda existe sobre o papel da baixa concentração de sódio no desenvolvimento de FA na IC, o que demonstrou a necessidade de mais estudos.¹²

Considerando essa possível relação, objetivamos investigar se há uma associação independente ou predisposição recíproca entre hiponatremia e FA em nossos pacientes com ICrFE.

Métodos

Neste estudo transversal, pacientes nas classes funcionais I–IV da New York Heart Association (NYHA) em atendimento ambulatorial com diagnóstico de IC sistólica crônica com fração de ejeção (FE) de 40% ou menos foram recrutados consecutivamente. O protocolo do estudo foi aprovado pelo comitê de ética local (2019.152.09.12). Todos os indivíduos forneceram consentimento informado por escrito antes de se inscreverem no estudo.

Pacientes com menos de 18 anos, pacientes com doença cardíaca congênita, doença valvar moderada a grave, miocardite ativa, síndromes coronarianas agudas nos últimos 3 meses, doenças inflamatórias, neoplasias, doença renal crônica ou hepática grave com taxa de filtração glomerular estimada (eTFG) ≤30 mL/min, cardiomiopatia hipertrófica, distúrbios da tireoide, doença pulmonar obstrutiva crônica, anemia grave e aqueles com ICpFE ou sintomas agudamente descompensados de classe IV da NYHA que necessitariam de suporte inotrópico no mês anterior foram excluídos.

Os pacientes foram divididos em 2 grupos com base nos níveis de sódio (≤135 mEq/L e >135 mEq/L: hiponatremia e normonatremia. O estudo utilizou 280 pacientes (202 homens e 78 mulheres). Realizou-se análise de potência de acordo com a comparação dos grupos hiponatremia e normonatremia na presença de FA. A potência do estudo foi de 83,7% com 95% de confiabilidade. Portanto, o tamanho da amostra do estudo foi adequado para validar os resultados.

Idade, sexo, tabagismo atual, presença de diabetes mellitus (DM), hipertensão (HT) ou hiperlipidemia (HL), medicamentos utilizados e tempo de doença foram registrados para todos os indivíduos na primeira consulta médica. Utilizou-se eletrocardiograma (ECG) de 12 derivações feito em repouso para determinar a frequência cardíaca de repouso e o ritmo sinusal ou fibrilação atrial. Todos os pacientes com ritmo sinusal normal no ECG de repouso foram investigados por um registrador de ECG ambulatorial de três canais por 24 horas (MT-200, Schiller AG, Baar, Suíça) para descartar FA paroxística.

Todos os pacientes foram submetidos a ecocardiografia transtorácica detalhada (GE Vingmed Ultrasound AS, Horten, Noruega) como parte do protocolo do estudo. Utilizou-se o método de Simpson modificado para calcular a FE ventricular esquerda. Foram medidos os diâmetros diastólico ventricular esquerdo (VE) e sistólico atrial esquerdo (AE). As velocidades de regurgitação tricúspide foram determinadas por ecocardiografia Doppler de onda contínua e a pressão sistólica da artéria pulmonar (PSAP) foi calculada de acordo com as recomendações das diretrizes atuais.¹³

Estabeleceu-se o diagnóstico de hipertensão (HT) como pressão sistólica ≥140 mm Hg e/ou pressão diastólica ≥90 mm Hg em mais de duas ocasiões ou uso de qualquer medicação anti-hipertensiva. Diagnosticou-se DM como glicemia de jejum superior a 126 mg/dL ou uso de medicamentos antidiabéticos. Definiu-se doença arterial coronariana (DAC) com base em angiografia coronária como estreitamento do diâmetro ≥50% em artéria coronária epicárdica.

Amostras de sangue venoso em jejum foram coletadas na parte da manhã para determinar glicose de jejum, creatinina, colesterol de lipoproteína de baixa densidade (LDL), ácido úrico, sódio, potássio, proteína C-reativa ultrassensível (PCRus) e níveis de hemoglobina. Calculou-se a osmolalidade sérica (miliosmoles por quilograma) como (2 × Na) + (BUN/2.8) + (glucose/18), conforme descrito anteriormente.¹⁴

Mediu-se a concentração sérica da porção N-terminal do pró-hormônio do peptídeo natriurético tipo B (NT-pro-BNP) pelo imunoensaio tipo sanduíche Elecsys proBNP (Elecsys 2010, Roche Diagnostics). A faixa analítica variou entre 5 a 35000 pg/mL. Os coeficientes de variação (CV) interensaio e intraensaio de NT-proBNP nas faixas baixa e alta foram relatados como 8,8%–11,6% e 9,9–12,2%, respectivamente. O kit de PCRus humano (kit ELISA de proteína C-reativa de alta sensibilidade, DRG International Inc, NJ, EUA) incluiu CV% interensaio e intraensaio <4,1% e <7,5%; a dose mínima detectável de PCR-us foi de 0,01 mg/L.

Análise estatística

A análise estatística foi realizada por meio do software preditivo Analysis Software Statistics 18 (SPSS Inch, Chicago, Illinois, EUA). As variáveis foram testadas para verificar a normalidade da distribuição pelo teste de Kolmogorov-Smirnov. As variáveis com distribuição normal foram apresentadas como média±desvio padrão (DP), as sem distribuição normal foram apresentadas como mediana e intervalo interquartil. Dois testes t de amostra independente foram usados para comparar dados normalmente distribuídos e o teste U de Mann-Whitney foi usado para comparar dados não normalmente distribuídos. As variáveis categóricas foram apresentadas em números (porcentagem). As comparações entre as variáveis categóricas dos dois grupos foram feitas pelo teste do qui-quadrado. Realizamos análises de regressão logística univariada e multivariada para avaliar os preditores de FA. Para a análise multivariada, as variáveis com valores de p <0,1 foram inseridas no modelo por um método forward stepwise . Para verificar o melhor ponto de sensibilidade e especificidade do valor de corte de sódio para a previsão de FA, utilizou-se a análise da curva ROC ( Receiver Operator Characteristic ). Considerou-se significativo um p bicaudal <0,05.

Results

De 376 pacientes ambulatoriais consecutivos com diagnóstico de IC, 96 com características que satisfaziam os critérios de exclusão não foram incluídos no estudo. Os motivos de exclusão foram síndrome coronariana aguda em 20, doença pulmonar obstrutiva crônica em 10, eTFG ≤30 mL/min em 49, distúrbios inflamatórios em 17 pacientes e nenhuma angiografia coronária anterior para definir a etiologia em oito pacientes. Portanto, o tamanho da amostra foi composto por pacientes classificados em dois grupos de acordo com suas concentrações de sódio, da seguinte forma: o grupo hiponatremia tinha 66 pacientes e o grupo normonatremia tinha 214 pacientes.

Os dados demográficos e as características da população do estudo são apresentados na Tabela 1 . Na população geral do estudo, a média de idade foi de 67,6±10,5 anos; o nível médio de sódio no sangue foi de 138±3,6 mEq/L, e o número (%) de pacientes com FA foi 124 (44,3%). Dos pacientes com FA, 96 pacientes tinham FA permanente, enquanto 28 pacientes (22,5%) tinham FA paroxística. Os níveis de sódio no grupo hiponatremia e no grupo normonatremia foram 132±3,7 e 140±2,7 mEq/L, respectivamente.

Tabela 1. – Características clínicas, variáveis laboratoriais e ecocardiográficas, e medicamentos.

Variáveis	Todos os pacientes n=280	Hiponatremia Grupo n=66	Grupo normonatremia n=214	Valor de p
Idade, anos	67.6±10,5	67±11	68±10	0,820
Sexo masculino, n (%)	202 (72,2)	47 (71,2)	155 (72,4)	0,847
Hipertensão, n (%)	185 (66,1)	41 (62,1)	144 (67,3)	0,438
Diabetes mellitus, n (%)	96 (34,3)	32 (48,5)	64 (29,9)	0,005
Doença arterial coronariana, n (%)	195 (69,6)	44 (66,7)	151 (70,6)	0,548
Fibrilação atrial, n (%)	124 (44,3)	39 (59,1)	85 (39,7)	0,020
NYHA classe I–II n (%)	176 (62,9)	45 (68,2)	131 (61,2)	0,306
NYHA classe I–II +AF, n (%)		23/45 (51,1) ^a	42/131 (32,1) ^c	0,022
NYHA classe III–IV, n (%)	104 (37,1)	21 (31,8)	83 (38,8)	0,306
NYHA classe III–IV +AF, n (%)		15/21 (71,4) ^b	44/83 (53%) ^d	0,028
Duração da doença (anos)	5,5 (3–12)	5,1 (4–11)	5,4 (3–9)	0,546
Frequência cardíaca em repouso (bpm)	82,5 ±19	82±12	84±19	0,215
Exames laboratoriais
Glicemia de jejum (mg/dL)	125±55	136±61	121±52	0,041
Creatinina (mg/dL)	124±0,3	1.25±0,30	1.24±0,3	0,662
Colesterol LDL (mg/dL)	103±42	106±49	102±40	0,461
Ácido úrico (mg/dL)	7.4±2,4	7.6±2,4	7.3±2,3	0,294
Sódio (mEq/L)	138±3,6	132±3,7	140±2,7	<0,001
Potássio (mEq/L)	4.4±0,5	4.5±0,5	4.3±0,5	0,513
PCRus (mg/dL)	3,8 (1,5–7,3)	4,2 (1,8–6,7)	3,6 (1,2–7,8)	0,367
NT-ProBNP, pg/mL	2605 (903–6825)	2916 (1170–9566)	2378 (867–6015)	0,199
Osmolalidade (mOsm/kg)	291±9	283±9	294±7	<0,001
Hemoglobina (g/dL)	12.8±2	12.5±1,7	12.9±1,9	0,393
Parâmetros ecocardiográficos
Diâmetro AE (mm)	46±7	45±6	46±7	0,546
Diâmetro diastólico do VE (mm)	59±7	59±7	60±8	0,634
Fração de ejeção (%)	30±4	29±4	31±4	0,518
PSAP (mmHg)	42±14	40±13	42±14	0,343
Medicações
IECA/BRA n (%)	184 (65,7)	38 (57,6)	146 (68,2)	0,070
ARM, n (%)	157 (56,1)	44 (66,7)	113 (52,8)	0,021
Diuréticos, n (%)	208 (74,3)	48 (72,7)	160 (74,8)	0,194
Betabloqueadores, n (%)	236 (84,3)	54 (81,8)	182 (85)	0,183
Digoxina, n (%)	56 (20)	19 (28,8)	37 (17,3)	0,022

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IECA: Inibidor da enzima conversora da angiotensina; BRA: Bloqueador do receptor de angiotensina; FA: Fibrilação atrial; PCRus: Proteína C-reativa de alta sensibilidade; AE: Átrio esquerdo; LDL: Lipoproteína de baixa densidade, VE: Ventrículo esquerdo; mOsm/kg: Miliosmoles por quilograma; ARM: Antagonista dos receptores de mineralocorticoides; NT-proBNP: porção N-terminal do pró-hormônio do peptídeo natriurético tipo B; PSAP: Pressão sistólica da artéria pulmonar. Entre a e b, p=0120; entre c e d, p=0,002.

O grupo com hiponatremia apresentou maior proporção de FA e DM do que o grupo com normonatremia. As proporções de pacientes com hipertensão, DAC, diabetes mellitus e classe funcional III–IV da NYHA foram semelhantes nos dois grupos. A glicose de jejum, as taxas de antagonista dos receptores de mineralocorticoides (ARM) e o uso de digoxina foram maiores no grupo com hiponatremia em comparação com o grupo com normonatremia. A osmolalidade foi menor no grupo com hiponatremia, conforme naturalmente esperado. Idade, sexo, duração da doença, frequência cardíaca em repouso, creatinina, colesterol LDL, ácido úrico, potássio, PCRus, NT-proBNP, hemoglobina, diâmetro diastólico LA e VE, FE (%) e valores de PSAP foram semelhantes nos dois grupos. Pacientes com FA apresentaram menores níveis de sódio em comparação com aqueles sem FA (136±4,3 vs. 138±3,0 mEg/L, p=0,001) (Figura 1A) ( Tabela 1 ).

Em pacientes com hiponatremia, as taxas de FA foram significativamente maiores em pacientes em classes funcionais NYHA mais elevadas. Embora não tenha havido diferença em termos de taxas de FA entre as classes I–II e III–IV da NYHA em pacientes com hiponatremia e ICrFE, as taxas de FA mostraram diferença estatisticamente significativa em pacientes com normonatremia e IC ( Tabela 1 ).

Os resultados da análise de regressão logística univariada e multivariada para preditores independentes de FA revelaram idade avançada, frequência cardíaca de repouso e diâmetro do AE. O uso de diurético e digoxina apresentou forte correlação com a presença de FA ( Tabela 2 ).

Tabela 2. – Análises de regressão logística univariada e multivariada para a presença de fibrilação atrial.

		Razão de chances	IC 95%	p
Análises univariadas
Idade	0,076±0,023	1,079	1,031–1.170	0,001
Sexo masculino	0,652±0,270	1,919	1,131–3.256	0,016
Hipertensão	0,336±0,432	1,399	0,600–3.260	0,437
Diabetes mellitus	0,246±0,487	1,279	0,492–3.325	0,613
Doença arterial coronariana	-0,805±0,451	0,447	0,185–1.081	0,074
Capacidade funcional	0,026±0,419	1,027	0,451–2.334	0,950
Duração da doença	1,196±0,576	0,827	0,271–2.493	0,729
Frequência cardíaca em repouso	0,041±0,008	1,042	1,026–1.059	<0,001
Glicemia de jejum	0,001±0,005	1,001	0,990–1.011	0,924
Creatinina	-0,025±0,182	0,976	0,682–1.395	0,892
Colesterol LDL	-0,007±0,003	0,993	0,987–0.999	0,024
Ácido úrico	0,172±0,100	1,188	0,976–1.446	0,086
Níveis de sódio	0,022±0,134	1,022	0,785–1.330	0,871
Potássio	-0,727±0,391	0,483	0,225–1.039	0,063
PCRus	-0,012±0,016	0,988	0,958–1.020	0,461
NT-ProBNP	0,001±0,001	1,000	0,999–1.001	0,071
Osmolalidade	-0,065±0,060	0,937	0,834–1.054	0,279
Hemoglobina	-0,174±0,131	0,840	0,650–1.086	0,183
Diâmetro do AE	0,046±0,013	1,047	1,021–1.516	<0,001
IECA/BRA	-0,047±0,288	0,954	0,543–1.677	0,870
ARM	-0,163±0,290	0,850	0,481–1.501	0,575
Diuréticos	1,448±0,364	4,256	2,086–8.685	<0,001
Betabloqueadores	-0,165±0,388	0,848	0,396–1.814	0,671
Digoxina	1,876±0,365	6,526	3,193–13.340	<0,001
Análise multivariada
Idade	0,045±0,015	1,046	1,016–1.177	0,003
Doença arterial coronariana	-0,805±0,451	2,058	1,122–3.777	0,020
Frequência cardíaca em repouso	0,041±0,009	1,041	1,023–1.060	<0,001
Diâmetro do AE	0,044±0,017	1,049	1,011–1.616	<0,001

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IECA: Inibidor da enzima conversora da angiotensina; BRA: Bloqueador do receptor de angiotensina; PCRus: Proteína C-reativa ultrassensível; AE: Átrio esquerdo; LDL: Lipoproteína de baixa densidade; NT-proBNP: Porção N-terminal do pró-hormônio do peptídeo natriurético tipo B; ARM: Antagonista dos receptores de mineralocorticoides.

A análise ROC (AUC=0,458, IC 95%=0,397–0,527) revelou que os níveis de sódio no sangue ≤135 mEq/L têm baixa sensibilidade (55%) e especificidade (41%) diagnóstica para prever FA. Com o valor de corte do nível de sódio ajustado para ≤130 mEq/L, encontravam-se valores de maior sensibilidade (70%) e baixa especificidade (31%) (Figura 1B).

Discussão

Relatamos uma prevalência de FA maior em pacientes ambulatoriais com ICrFE e hiponatremia do que naqueles com ICrFE e normonatremia, independentemente dos níveis de osmolalidade plasmática e outros fatores de confusão. Há dois estudos na literatura que mostram taxas mais elevadas de FA em pacientes com ICrFE e hiponatremia,^{5 , 11} com os quais nossos resultados são concordantes. No entanto, a hiponatremia não foi um fator estimulante para o desenvolvimento de FA no estudo. A hiponatremia é sensível, de leve a moderada, mas não é específica para predizer o desenvolvimento de FA. Ou seja, a FA não está presente em todos os pacientes com hiponatremia e ICrFE.

Os fatores predisponentes e determinantes importantes para o desenvolvimento de FA foram idade avançada, presença de DAC, aumento da frequência cardíaca em repouso e dimensão do AE, estabelecidos como preditores de FA por estudos prévios.^{9 , 10 , 15} Relatamos uma taxa de FA mais alta em pacientes com hiponatremia, independentemente de sua classe funcional NHYA, conforme documentado anteriormente.^{5 , 11} Portanto, a coexistência de hiponatremia e FA pode demonstrar gravidade da IC. As taxas de FA nos pacientes com normonatremia e IC foram maiores nas classes NHYA III–IV, o que também significa que a presença da classe NYHA III–IV é um motivo importante para o uso de diuréticos. Portanto, a hiponatremia parece ser apenas uma variável bystander .

Os motivos mais comuns de hiponatremia em pacientes com IC são o uso de diuréticos e a resposta neuro-hormonal, incluindo um desequilíbrio autonômico em favor do sistema nervoso simpático ou ativação do sistema renina-angiotensina (SRA).^{1 , 5 , 16}

Muitos fatores têm sido responsáveis pela associação de hiponatremia com aumento do risco de FA. A insuficiência cardíaca reduz o volume sistólico e o enchimento arterial, resultando na estimulação dos barorreceptores arteriais, liberação de arginina vasopressina (AVP) e ativação de SRA. A ativação do SRA leva ao aumento dos níveis de aldosterona e angiotensina II. A angiotensina II alerta o centro de sede do cérebro e estimula a liberação de AVP. O aumento subsequente dos níveis de aldosterona, angiotensina II, sistema simpático e liberação de AVP induz a redução do fluxo sanguíneo renal, aumento da retenção de água e reabsorção de sódio.^{4 , 17} Como resultado dessas alterações neuro-hormonais, ocorrem hipervolemia e hiponatremia. Alguns estudos mostraram níveis aumentados de renina, angiotensina II, aldosterona, epinefrina, norepinefrina e dopamina em pacientes com IC e hiponatremia em comparação com aqueles com IC e normonatremia.^{16 - 19}

A hiponatremia também pode ser preditor de maior ativação neuro-hormonal que sugere gravidade da IC.⁴ Diuréticos, principalmente tiazidas, muitas vezes resultam em hiponatremia, que promove retenção de água devido ao aumento da ativação de AVP nos túbulos distais.^{20 , 21} A hipervolemia leva não apenas à hiponatremia mas também ao estiramento do miocárdio atrial, câmara cardíaca e dilatação da veia pulmonar.²² A hiponatremia, teoricamente, também pode contribuir para o desenvolvimento de FA, causando alterações eletrofisiológicas no potencial de ação do miócito.²³ No entanto, na prática clínica, parece não ser um determinante da FA.

A frequência cardíaca rápida induzida pela FA afeta negativamente a função do ventrículo esquerdo, facilita a taquicardia e predispõe à apoptose e à fibrose miocárdica. Independentemente da presença de IC, a frequência cardíaca irregular e a perda da contração atrial resultam em redução significativa de 7–9% e 20% no débito cardíaco, respectivamente.²⁴ Quando a IC e a FA coexistem, duas entidades interrelacionadas fazem o débito cardíaco diminuir sinergicamente, aumentando a mortalidade.⁸ Há uma relação de causa-efeito comum entre essas duas entidades.

A hiponatremia é frequentemente observada em pacientes com IC descompensada aguda devido ao alto uso de diuréticos e alto tônus simpático desencadeando a ativação do SRA.^{5 , 21} Nossos achados não são concordantes com o estudo de Cavusoglu et al., que apresentou hiponatremia com prevalência de 24% e FA com prevalência de 33%.¹¹ Bavishi et al. verificaram que a prevalência de hiponatremia e FA em pacientes ambulatoriais com ICrFE foi de 14,8% e 37,6%, respectivamente.⁵ Nosso estudo apresentou uma taxa de hiponatremia de 23,5%, mas uma taxa de FA maior, de 44,3%, porque realizamos ECG Holter ambulatorial para verificar a presença de FA paroxística ou persistente. As taxas de FA são mais altas do que esperávamos no monitoramento ambulatorial Holter ECG de 24 horas em pacientes com IC.^{2 , 15}

Limitações do estudo

Apresentamos dados ausentes relacionados às doses de diuréticos e níveis de albumina que podem afetar os níveis de sódio.

Conclusão

Os achados atuais fornecem informações sobre a patogênese da FA em pacientes com IC estabelecida. Embora a hiponatremia desempenhe um papel fundamental na deterioração do estado da IC, verificamos que a baixa concentração de sódio sérico, ≤135 mEq/L, não está relacionada à probabilidade de FA.

Vinculação acadêmica

Não há vinculação deste estudo a programas de pós-graduação.

Aprovação ética e consentimento para participação

Este estudo foi aprovado pelo Comitê de Ética da Faculdade de Medicina da Universidade Hospital Namık Kemal de Tekirdağ sob o número de protocolo 2019.152.09.12. Todos os procedimentos deste estudo estavam de acordo com a Declaração de Helsinque de 1975, atualizada em 2013. O consentimento informado foi obtido de todos os participantes incluídos no estudo.

Fontes de financiamento: O presente estudo não teve fontes de financiamento externas.

Referências

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Arq Bras Cardiol. 2022 Jan 11;118(4):712–718. [Article in English]

Role of Sodium Levels on Atrial Fibrillation in Heart Failure: Active Player or a Bystander?

Aydın Akyüz ¹, Derya Baykız ², Demet Özkaramanlı Gür ¹, Sümeyra Gökçek ¹, Muhammet Mucip Efe ¹, Şeref Alpsoy ¹

Abstract

Background

The coexistence of hyponatremia and atrial fibrillation (AF) increases morbidity and mortality in patients with heart failure (HF). However, it is not established whether hyponatremia is related to AF or not.

Objective

Our study aims to seek a potential association of hyponatremia with AF in patients with reduced ejection fraction heart failure (HFrEF).

Methods

This observational cross-sectional single-center study included 280 consecutive outpatients diagnosed with HFrEF with 40% or less. Based on sodium concentrations ≤135 mEq/L or higher, the patients were classified into hyponatremia (n=66) and normonatremia (n=214). A p-value <0.05 was considered significant.

Results

Mean age was 67.6±10.5 years, 202 of them (72.2%) were male, mean blood sodium level was 138±3.6 mEq/L, and mean ejection fraction was 30±4%. Of those, 195 (69.6%) patients were diagnosed with coronary artery disease. AF was detected in 124 (44.3%) patients. AF rate was higher in patients with hyponatremia compared to those with normonatremia (n=39 [59.1%] vs. n=85 [39.7%), p= 0.020). In the logistic regression analysis, hyponatremia was not related to AF (OR=1.022, 95% CI=0.785–1.330, p=0.871). Advanced age (OR=1.046, 95% CI=1.016–1.177, p=0.003), presence of CAD (OR=2.058, 95% CI=1.122–3.777, p=0.020), resting heart rate (OR=1.041, 95% CI=1.023–1.060, p<0.001), and left atrium diameter (OR=1.049, 95% CI=1.011–1.616, p=0.002) were found to be predictors of AF.

Conclusion

AF was higher in outpatients with HFrEF and hyponatremia. However, there is no association between sodium levels and AF in patients with HFrEF.

Keywords: Hyponatremia, Atrial Fibrillation, Heart Failure

Introduction

Heart failure (HF) is categorized based on ejection fraction (EF) as reduced EF≤0.40 (HFrEF), preserved EF≥ 0.50 (HFpEF), or midrange EF (<0.50 but >0.40). Its rate is gradually increasing and is related to high rates of hospitalization and mortality.^{1 , 2}

Anemia, infection, myocardial ischemia, renal failure, atrial fibrillation (AF), and electrolyte abnormalities are common predisposing factors for HF worsening and may contribute to the development of clinical symptoms of HF such as dyspnea, fatigue, and edema or limited activity.

Although sodium abnormalities, at least theoretically, may contribute to the risk of arrhythmia, disorders of electrolyte balance in potassium, calcium, and magnesium are well-known to have triggered arrhythmias. Hyponatremia is defined as serum sodium concentration ≤135 mEq/L, one of the most common electrolyte abnormalities, associated with poor outcome in patients with HF with a prevalence of about 13.8%–33.7%.^{3 - 5}

The prevalence of AF in patients with HFrEF ranges from <10% to 50%.^{5 - 7} AF in HF is a common disabling arrhythmia associated with severity of disease, high morbidity, and mortality. AF leads to HF and vice versa.^{1 , 8 - 10} Although the relationship between AF and electrolyte imbalance is theoretically well-known, the association of hyponatremia with AF development in HF has not been well-documented in the literature. For the first time, a causative association between hyponatremia and AF development was claimed in a recent study by Cavusoglu et al.¹¹ Some skepticism, however, still exists about the role of low sodium concentration on AF development in HF, which demonstrated the need for further studies.¹²

Considering this potential relationship, we aimed to investigate whether there is an independent association or reciprocal predisposition between hyponatremia and of AF in our patients with HFrEF.

Methods

In this cross-sectional study, patients under the New York Heart Association (NYHA) functional classes I–IV admitted to the outpatient clinic with diagnosis of chronic systolic HF with ejection fraction (EF) of 40% or less were consecutively recruited. The study protocol was approved by the local Ethics committee (2019.152.09.12). All of the subjects provided written informed consent before enrolling in the study.

Patients younger than 18 years, patients with congenital heart disease, moderate to severe valvular disease, active myocarditis, acute coronary syndromes within the last 3 months, inflammatory disorders, malignancies, severe hepatic or chronic kidney disease with an estimated glomerular filtration rate (eGFR) ≤30 mL/min, hypertrophic cardiomyopathy, thyroid disorders, chronic obstructive pulmonary disease, severe anemia, and those with HFpEF or acutely decompensated symptoms showing NYHA class IV who would require inotropic support within the previous month were excluded.

Patients were divided into 2 groups based on sodium levels (≤135 mEq/L and >135 mEq/L: hyponatremia, and normonatremia. The study used 280 patients (202 males and 78 females). Power analysis was performed according to the comparison of hyponatremia and normonatremia groups in the presence of AF. The power of the study was 83.7% with 95% reliability. Therefore, the study sample size was suitable to validate the results.

Age, gender, current smoking status, presence of diabetes mellitus (DM), hypertension (HT), or hyperlipidemia (HL), medications used and disease duration were recorded for all subjects at the first medical consultation. A 12-lead resting electrocardiogram (ECG) was used to determine resting heart rate and sinus rhythm or atrial fibrillation. All patients with normal sinus rhythm in resting ECG were investigated using a 24-hour three-channel ambulatory ECG recorder (MT-200, Schiller A.G, Baar, Switzerland) to rule out paroxysmal AF.

All patients underwent detailed transthoracic echocardiography (GE Vingmed Ultrasound AS, Horten, Norway) as part of the study protocol. The modified Simpson method was used to calculate left ventricular EF. Left ventricle diastolic (LV) and left atrium systolic (LA) diameters were measured. Tricuspid regurgitation velocities were determined by continuous-wave Doppler echocardiography, and systolic pulmonary artery pressure (sPAP) was calculated according to the recommendations of current guidelines.¹³

Diagnosis of hypertension (HT) was established as systolic pressure ≥140 mm Hg and/or diastolic pressure ≥90 mm Hg on more than two occasions or use of any antihypertensive medication. DM was diagnosed as fasting blood glucose higher than 126 mg/dL or being on antidiabetic medication. Coronary artery disease (CAD) was defined based on a coronary angiogram as diameter narrowing ≥50% in an epicardial coronary artery.

Fasting venous blood samples were collected in the morning hours to determine fasting glucose, creatinine, low-density lipoprotein (LDL) cholesterol, uric acid, sodium, potassium, high-sensitivity C-reactive protein (hs-CRP), and hemoglobin levels. Serum osmolality (milliosmoles per kilogram) was calculated as (2 × Na) + (BUN/2.8) + (glucose/18) as described previously.¹⁴

Serum N terminal pro B-type natriuretic peptide (NT-pro-BNP) concentration was measured using Elecsys proBNP sandwich immunoassay (Elecsys 2010, Roche Diagnostics). The analytical range was between 5 to 35000 pg/mL. Interassay and intraassay coefficients of variation (CV) of NT-proBNP in the low and high ranges were reported as 8.8%–11.6% and 9.9–12.2%, respectively. Human hsCRP kit (High-Sensitivity C-Reactive Protein ELISA kit, DRG International Inc, NJ, USA) included inter-assay and intra-assay CV% <4.1% and <7.5%; the minimum detectable dose of hs-CRP was 0.01 mg/L.

Statistical analysis

Statistical analysis was performed using the predictive Analysis Software Statistics 18 (SPSS Inch, Chicago, Illinois, USA). The variables were tested to check the normality of distribution by the Kolmogorov–Smirnov test. Variables with normal distributions were presented as mean±standard deviation (SD), those without normal distributions were presented as median and interquartile range. Two independent sample t-tests were used to compare normally distributed data and the Mann-Whitney U test was used to compare non-normally distributed data. The categorical variables were presented as numbers (percentage). Comparisons between the categorical variables of the two groups were made by chi-square test. We performed logistic univariate and multivariate regression analyses to assess the predictors of AF. For the multivariate analysis, variables with p values <0.1 were entered into the model by a forward stepwise method. To verify the best cut-off sodium value point of sensitivity and specificity for the prediction of AF, receiver operator characteristic (ROC) curve analysis was used. A two-tailed p<0.05 was considered significant.

Results

Of 376 consecutive outpatients diagnosed with HF, 96 with characteristics satisfying the exclusion criteria were not included in the study. The reasons for exclusion were acute coronary syndrome in 20, chronic obstructive pulmonary disease in 10, eGFR ≤30 mL/min in 49, inflammatory disorders in 17 patients, and no prior coronary angiography to define the etiology in eight patients. Therefore, the sample size consisted of patients classified into two groups according to their sodium concentrations, as follows: the hyponatremia group included 66 patients, and the normonatremia group included 214 patients.

Demographic data and characteristics of the study population are presented in Table 1 . In the overall study population, the mean age was 67.6±10.5 years; mean blood sodium level was 138±3.6 mEq/L, and the number (%) of patients with AF was 124 (44.3%). Of patients with AF, 96 patients had permanent AF while 28 patients (22.5%) were determined to have paroxysmal AF. Sodium levels in the hyponatremia group and in the normonatremia group were 132±3.7 and 140±2.7 mEq/L, respectively.

Table 1. – Clinical characteristics, laboratory and echocardiographic variables, and medications.

Variables	All Patients n=280	Hyponatremia Group n=66	Normonatremia Group n=214	p-value
Age, years	67.6±10.5	67±11	68±10	0.820
Male, n (%)	202 (72.2)	47 (71.2)	155 (72.4)	0.847
Hypertension, n (%)	185 (66.1)	41 (62.1)	144 (67.3)	0.438
Diabetes mellitus, n (%)	96 (34.3)	32 (48.5)	64 (29.9)	0.005
Coronary artery disease, n (%)	195 (69.6)	44 (66.7)	151 (70.6)	0.548
Atrial fibrillation, n (%)	124 (44.3)	39 (59.1)	85 (39.7)	0.020
NYHA class I-II n (%)	176 (62.9)	45 (68.2)	131 (61.2)	0.306
NYHA class I-II +AF, n (%)		23/45 (51.1)^a	42/131 (32.1)^c	0.022
NYHA class III-IV, n (%)	104 (37.1)	21 (31.8)	83 (38.8)	0.306
NYHA class III- IV +AF, n (%)		15/21 (71.4)^b	44/83 (53%)^d	0.028
Disease duration (years)	5.5 (3–12)	5.1 (4–11)	5.4 (3–9)	0.546
Resting heart rate (bpm)	82.5 ±19	82±12	84±19	0.215
Laboratory measurements
Fasting glucose (mg/dL)	125±55	136±61	121±52	0.041
Creatinine (mg/dL)	124±0.3	1.25±0.30	1.24±0.3	0.662
LDL cholesterol (mg/dL)	103±42	106±49	102±40	0.461
Uric acid (mg/dL)	7.4±2.4	7.6±2.4	7.3±2.3	0.294
Sodium (mEq/L)	138±3.6	132±3.7	140±2.7	<0.001
Potassium (mEq/L)	4.4±0.5	4.5±0.5	4.3±0.5	0.513
Hs-CRP (mg/dL)	3.8 (1.5–7.3)	4.2 (1.8–6.7)	3.6 (1.2–7.8)	0.367
NT-proBNP, pg/mL	2605 (903–6825)	2916 (1170–9566)	2378 (867–6015)	0.199
Osmolality (mOsm/kg)	291±9	283±9	294±7	<0.001
Hemoglobin (g/dL)	12.8±2	12.5±1.7	12.9±1.9	0.393
Echocardiographic parameters
LA diameter (mm)	46±7	45±6	46±7	0.546
LV diastolic diameter (mm)	59±7	59±7	60±8	0.634
Ejection fraction (%)	30±4	29±4	31±4	0.518
sPAP (mmHg)	42±14	40±13	42±14	0.343
Medications
ACEI/ARB, n (%)	184 (65.7)	38 (57.6)	146 (68.2)	0.070
MRA, n (%)	157 (56.1)	44 (66.7)	113 (52.8)	0.021
Diuretic, n (%)	208 (74.3)	48 (72.7)	160 (74.8)	0.194
Betablockers, n (%)	236 (84.3)	54 (81.8)	182 (85)	0.183
Digoxin, n (%)	56 (20)	19 (28.8)	37 (17.3)	0.022

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ACEI: Angiotensinogen-converting enzyme inhibitor; ARB: Angiotensin receptor blocker; AF: Atrial fibrillation; Hs-CRP: High-sensitivity C-reactive protein; LA: Left atrium; LDL: Low-density lipoprotein; LV: Left ventricle; mOsm/kg: Milliosmoles per kilogram, MRA: Mineralocorticoid receptor antagonist; NT-proBNP: N terminal pro B-type natriuretic peptide; sPAP: Systolic pulmonary artery pressure. Between a and b, p=0120; between c and d, p=0.002.

The hyponatremia group had a higher ratio of AF and DM than the normonatremia group. The ratios of patients with hypertension, CAD, diabetes mellitus, and NYHA functional class III–IV were similar within the two groups. Fasting glucose, rates of mineralocorticoid receptor antagonist (MRA), and digoxin use were higher in the hyponatremia group compared to the normonatremia group. Osmolality was lower in the hyponatremia group, as naturally expected. Age, gender, disease duration, resting heart rate, creatinine, LDL cholesterol, uric acid, potassium, hs-CRP, NT-proBNP, hemoglobin, LA and LV diastolic diameter, EF (%), and sPAP values were similar in the two groups. Patients with AF had lower sodium levels compared to those without AF (136±4.3 vs. 138±3.0 mEg/L, p=0.001) (Figure 1A) ( Table 1 ).

In patients with hyponatremia, the rates of AF were found to be significantly higher in patients with higher NYHA functional classes. Although there was no difference in terms of AF rates between NYHA class I–II and III–IV in patients with hyponatremia and HFrEF, AF rates showed statistically significant difference in patients with normonatremia and HF ( Table 1 ).

The results of univariate and multivariate logistic regression analysis to show the independent predictors of AF revealed advanced age, resting heart rate, and LA diameter. Diuretic and digoxin usage were found to be strongly correlated with the presence of AF ( Table 2 ).

Table 2. – Univariate and multivariate logistic regression analyses for the presence of atrial fibrillation.

		Odds ratio	95% CI	p-value
Univariate analyses
Age	0.076±0.023	1.079	1.031–1.170	0.001
Male gender	0.652±0.270	1.919	1.131–3.256	0.016
Hypertension	0.336±0.432	1.399	0.600–3.260	0.437
Diabetes mellitus	0.246±0.487	1.279	0.492–3.325	0.613
Coronary artery disease	-0.805±0.451	0.447	0.185–1.081	0.074
Functional capacity	0.026±0.419	1.027	0.451–2.334	0.950
Disease duration	1.196±0.576	0.827	0.271–2.493	0.729
Resting heart rate	0.041±0.008	1.042	1.026–1.059	<0.001
Fasting glucose	0.001±0.005	1.001	0.990–1.011	0.924
Creatinine	-0.025±0.182	0.976	0.682–1.395	0.892
LDL cholesterol	-0.007±0.003	0.993	0.987–0.999	0.024
Uric acid	0.172±0.100	1.188	0.976–1.446	0.086
Sodium levels	0.022±0.134	1.022	0.785–1.330	0.871
Potassium	-0.727±0.391	0.483	0.225–1.039	0.063
Hs-CRP	-0.012±0.016	0.988	0.958–1.020	0.461
NT-proBNP	0.001±0.001	1.000	0.999–1.001	0.071
Osmolality	-0.065±0.060	0.937	0.834–1.054	0.279
Hemoglobin	-0.174±0.131	0.840	0.650–1.086	0.183
LA diameter	0.046±0.013	1.047	1.021–1.516	<0.001
ACEI/ARB	-0.047±0.288	0.954	0.543–1.677	0.870
MRA	-0.163±0.290	0.850	0.481–1.501	0.575
Diuretic	1.448±0.364	4.256	2.086–8.685	<0.001
Beta-blockers	-0.165±0.388	0.848	0.396–1.814	0.671
Digoxin	1.876±0.365	6.526	3.193–13.340	<0.001
Multivariate analysis
Age	0.045±0.015	1.046	1.016–1.177	0.003
Coronary artery disease	-0.805±0.451	2.058	1.122–3.777	0.020
Resting heart rate	0.041±0.009	1.041	1.023–1.060	<0.001
LA diameter	0.044±0.017	1.049	1.011–1.616	<0.001

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ACEI: Angiotensinogen-converting enzyme inhibitor; ARB: Angiotensin receptor blocker; Hs-CRP: High-sensitivity C-reactive protein; LA: Left atrium; LDL: Low-density lipoprotein; NT-proBNP: N terminal pro B-type natriuretic peptide; MRA: Mineralocorticoid receptor antagonist.

The ROC analysis (AUC=0.458, 95% CI=0.397–0.527) revealed that blood sodium levels ≤135 mEq/L have poor diagnostic sensitivity (55%) and specificity (41%) for predicting AF. If the cut-off value of sodium level was adjusted to ≤130 mEq/L, higher sensitivity (70%) and poor specificity (31%) values were found (Figure 1B).

Discussion

We report that the prevalence of AF was higher in outpatients with HFrEF and hyponatremia than in those with HFrEF and normonatremia, irrespective of the plasma osmolality levels and other confounding factors. There have been two studies in the literature showing higher rates of AF in patients with HFrEF and hyponatremia,^{5 , 11} which our results were concordant with. However, hyponatremia was not an inciting factor for the development of AF in the study. Hyponatremia is mild-moderate sensitive, but not specific for predicting the development of AF. Namely, AF is not present in every patient with hyponatremia and HFrEF.

The important predisposing and determining factors for AF development were advanced age, presence of CAD, increased resting heart rate and LA dimension, which were established as predictors of AF by previous studies.^{9 , 10 , 15} We reported a higher AF rate in patients with hyponatremia, irrespective of their NHYA functional class, as documented previously.^{5 , 11} Therefore, the coexistence of hyponatremia and AF may demonstrate HF severity. The rates of AF in the patients with normonatremia and HF were higher in NHYA class III–IV, which also means that the presence of NYHA III–IV status is an important reason for diuretic usage. Therefore, hyponatremia appears to be only a bystander variable.

The most common reasons for hyponatremia in patients with HF are diuretic usage and neurohormonal response, including an autonomic imbalance in favor of the sympathetic nervous system or renin-angiotensin system (RAS) activation.^{1 , 5 , 16}

Many factors have been responsible for the association of hyponatremia with an increased risk for AF. Heart failure reduces stroke volume and arterial filling, which results in stimulation of arterial baroreceptors, arginine vasopressin (AVP) release, and RAS activation. RAS activation leads to increased aldosterone and angiotensin II levels. Angiotensin II alerts the thirst center of the brain and stimulates AVP release. The subsequent increase levels of aldosterone, angiotensin II, sympathetic system, and AVP release induce reduced renal blood flow, enhanced water retention, and sodium reabsorption.^{4 , 17} As a result of these neurohormonal changes, hypervolemia and hyponatremia occur. Some studies have shown increased levels of renin, angiotensin II, aldosterone, epinephrine, norepinephrine, and dopamine in patients with HF and hyponatremia compared to those with HF and normonatremia.^{16 - 19}

Hyponatremia may also be a predictor of higher neurohormonal activation that suggests HF severity.⁴ Diuretics, especially thiazides, often result in hyponatremia, which promotes water retention due to enhanced AVP activation in the distal tubules.^{20 , 21} Hypervolemia leads not only to hyponatremia but also to atrial myocardial stretch, cardiac chamber, and pulmonary vein dilatation.²² Hyponatremia, theoretically, may also contribute to the development of AF, causing electrophysiological changes in the myocyte action potential.²³ However, in clinical practice, it appears not to be a determinant of AF.

AF-induced rapid heart rate deleteriously affects left ventricle function, facilitates tachycardia, and predisposes apoptosis and myocardial fibrosis. Irrespective of the presence of HF, irregular heart rate and loss of atrial contraction results in a significant 7–9% and 20% reduction in cardiac output, respectively.²⁴ When HF and AF co-exist, two intertwined entities make cardiac output decrease synergistically, and mortality increases.⁸ There is a common cause-effect relationship between these two entities.

Hyponatremia is frequently seen in patients with acute decompensated HF due to high diuretic usage and high sympathetic tonus triggering RAS activation.^{5 , 21} Our findings are not concordant with that of the study of Cavusoglu et al. showing hyponatremia with a prevalence of 24%, and AF with a prevalence of 33%.¹¹ Bavishi et al. found that the prevalence of hyponatremia and AF in outpatients with HFrEF was 14.8% and 37.6%, respectively.⁵ Our study has presented a hyponatremia rate of 23.5%, but a higher AF rate of 44.3%, because we performed ambulatory Holter ECG to find the presence of paroxysmal or persistent AF. AF rates are higher than we expected in ambulatory 24-hour Holter ECG monitoring in patients with HF.^{2 , 15}

Study limitations

We presented missing data related to diuretic doses and albumin levels, which could affect the sodium levels.

Conclusion

Current findings yield insights on the pathogenesis of AF in patients with established HF. Although hyponatremia plays a key role in the deterioration of HF status, we found that low serum sodium concentration ≤135 mEq/L is not related to the probability of AF.

Study Association

This study is not associated with any thesis or dissertation work.

Ethics approval and consent to participate

This study was approved by the Ethics Committee of the Hospital Namık Kemal University Medical Faculty, Tekirdağ under the protocol number 2019.152.09.12. All the procedures in this study were in accordance with the 1975 Helsinki Declaration, updated in 2013. Informed consent was obtained from all participants included in the study.

Sources of Funding: There were no external funding sources for this study.

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PERMALINK

Papel dos Níveis de Sódio na Fibrilação Atrial na Insuficiência Cardíaca: Jogador Ativo ou Bystander?

Aydın Akyüz

Derya Baykız

Demet Özkaramanlı Gür

Sümeyra Gökçek

Muhammet Mucip Efe

Şeref Alpsoy

Resumo

Fundamento

Objetivo

Métodos

Resultados

Conclusão

Introdução

Métodos

Análise estatística

Results

Tabela 1. – Características clínicas, variáveis laboratoriais e ecocardiográficas, e medicamentos.

Tabela 2. – Análises de regressão logística univariada e multivariada para a presença de fibrilação atrial.

Discussão

Limitações do estudo

Conclusão

Referências

Role of Sodium Levels on Atrial Fibrillation in Heart Failure: Active Player or a Bystander?

Aydın Akyüz

Derya Baykız

Demet Özkaramanlı Gür

Sümeyra Gökçek

Muhammet Mucip Efe

Şeref Alpsoy

Abstract

Background

Objective

Methods

Results

Conclusion

Introduction

Methods

Statistical analysis

Results

Table 1. – Clinical characteristics, laboratory and echocardiographic variables, and medications.

Figure 1. – A) Shows the comparison of sodium levels between the patients who have heart failure with normal sinus and atrial fibrillation. B) Demonstrates the ROC analysis that shows a poor diagnostic sensitivity and specificity of sodium levels to predict the possibility.

Table 2. – Univariate and multivariate logistic regression analyses for the presence of atrial fibrillation.

Discussion

Study limitations

Conclusion

ACTIONS

PERMALINK

RESOURCES

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