Chronic obstructive pulmonary disease (COPD) is a chronic lung disease characterized by irreversible airflow limitation and progressive decline of lung function, and it is the third leading cause of death in the world [1, 2]. Several cohort studies reported that cardiovascular disease (CVD) is one of the top three leading causes of death in patients with COPD, following respiratory infections and respiratory failure [3‐5]. Moreover, previous history of CVD can additionally increase risks of death in elderly COPD patients with pneumonia [6].

Patients with COPD tend to have concurrent CVDs with a prevalence of 28–70% [7]. Hyperlipidemia (45%) and hypertension (43%) have been found to be the most common cardiovascular risk factors [8]. Increased risks of acute cardiovascular events (CVEs) namely acute coronary syndrome (ACS) [9], arrhythmias [7] and sudden cardiac death [10] have also been reported in the patients with COPD. A large cohort study demonstrated that the prevalence of heart failure among patients with COPD is significantly increased, leading to a higher all-cause mortality [11]. During a period of acute exacerbation (AE), aggravated hypoxia and systemic inflammation are precipitating factors for acute CVEs, especially in the high-risk population [10, 12, 13]. Therefore, clinicians should remain vigilant for early acute CVEs following AECOPD and identify risk factors, especially the use of potentially-inappropriate medication. However, knowledge of risk factors of CVEs in patients with AECOPD is still incomplete.

Traditional risk factors of CVDs include previous history, hypertension, diabetes, hyperlipidemia and hyperuricemia. In addition, serious side effects of certain drugs might be the chief culprits of some CVE cases. A case–control study reported that theophylline could increase the risk of arrhythmias and acute heart failure by 80% [14]. Moreover, a meta-analysis showed that fluoroquinolones increased the risk of arrhythmias and cardiovascular death by 80% and 71% [15]. The relationship between inhaled beta-receptor agonists (bronchodilators) and CVDs is still highly debated, for beta-receptor antagonist is well-known therapy of cardiac remodeling and heart failure [14]. In the patients with COPD, initiation of inhaled bronchodilators has been related to short-term elevated risks of severe CVEs [16], and adding a second bronchodilator to the previous monotherapy also slightly increased the risk of heart failure after a one year period [17]. On the other hand, dual bronchodilators (beta-receptor agonists and muscarinic receptor antagonist) have been shown to improve left ventricular filling by reducing lung hyperinflation [18].

Herein, we performed a nested case–control study in a prospective COPD cohort in Shanghai, with the aim of screening the predictive factors of acute CVEs following the onset of AECOPD.

We demonstrated that the development of acute CVEs during AECOPD period was not only associated with increased hospital mortality but also with increased risks of short-term re-AE after discharge. Moreover, previous LVD, increased HR, electrolyte disturbance and diuretics use were identified as independent risk predictors of CVEs.

In line with our findings of increased HR and acute CVEs, other investigators also noted that increased resting HR was associated with a shortened life expectancy and increased cardiovascular mortality in COPD patients irrespective of the spirometric grading [21]. However, the relationship between electrolyte imbalance and CVEs remains to be confirmed. Our findings partly validated previous results of poor outcomes of hyperphosphatemia (only for male) [22] and hypocalcemia [23] in AECOPD patients. Whereas, no statistical difference in sodium, potassium and chlorides levels was observed between acute CVEs and non-CVEs group in our cohort. Another study also reported no correlation between electrolyte imbalance and QTc prolongation in hospitalized patients with COPD [24]. As for diuretics use, a retrospective study reported that prescription of loop diuretics increased the risks of AE and death in the elderly patients with COPD [25]. In our cohort, we defined the diuretic usage as using loop diuretics and spironolactone, and found that diuretic usage was independently associated with acute CVEs. Contrarily, thiazide diuretics were recommended as the first-line antihypertensive agents for COPD patients, since it did not cause an increase in the numbers of AE [26]. Thus, mild diuretics and low-dosage might be more suitable for patients with AECOPD.

We speculate that cardiovascular risks of diuretics might result from electrolyte imbalance, hypovolemia or pre-existing heart failure. Moreover, increased HR is also one of the signs of hypovolemia. Two typical cases of acute CVEs in our cohort demonstrated that inappropriate usage of diuretics could result in electrolyte imbalance or hypovolemia. Patient A was a typical case, whose electrolyte disturbance led to worsening of his previous LVD. Before admission, he had edema of both lower extremities and took oral diuretics on his own. On day 1 in hospitalization, he suddenly complained of dyspnea and orthopnea. Immediate laboratory tests showed he had hypokalemia (2.6 mmol/L), and hypochloridemia (96 mmol/L). Then, he was given potassium supplementation, digitalis, amrinone, intravenous and oral diuretics, along with noninvasive mechanical ventilation. On day 15, he recovered and was discharged from hospital. Patient B was another typical example, whose hypovolemia led to the occurrence of arrhythmia. He had no edema of both lower extremities before admission. He was prescribed with intravenous diuretics on day 1–4 and converted into oral diuretics on day 5–7. On day 7 of hospitalization, he suddenly presented with a newly onset of atrial fibrillation. Immediate laboratory tests showed he had hypovolemia (erythrocyte counts = 5.88*10¹² and hemoglobin = 184 g/L). He was given appropriate fluid infusion to expand blood volume, and discontinued diuretics. He was also given propafenone for cardioversion and oral amiodarone for maintenance. On day 9, sinus rhythm was restored and patient was discharged from hospital on day 12. Thus, the above two cases suggested that electrolytes and blood volume should be closely monitored during the AE period, especially in the patients receiving diuretics. As a golden standard of hemodynamic assessment, right heart catheterization is, however, limitedly carried out in patients with AECOPD due to its invasiveness and patients’ poor status. Hence, new echocardiographic parameters are recommended in the clinical setting, including tricuspid annular plane systolic excursion (TAPSE) and systolic S′ velocity of the tricuspid annulus. [27]

Similar to our results of increased NT-proBNP in acute CVEs group, NT-proBNP levels [28] were previously found to be strong indicators of death in patients with AECOPD. Likewise, Smith GL reported that increased urea nitrogen was associated with cardiovascular mortality in the elderly. [29] Although Smith GL showed the association of increased creatinine level with myocardial infarction (> 88.4 mmol/L) and heart failure (> 97.2 mmol/L) [29], we did not confirm this association in our study. Theophylline, fluoroquinolone and inhaled bronchodilators in AE period, which were previously regarded as cardiovascular risk factors [14‐16], were not statistically associated with acute CVEs in our cohort.

Since nearly half of AEs are caused by lower respiratory bacterial infection [30], we tried to gain insights from some studies of Community-Acquired Pneumonia (CAP) and associated cardiac complications. Similar to our study, two observational studies reported that incident CVEs was a strong negative indicator of 30-day survival of patients with CAP [31, 32]. In the comprehensive analysis of three CAP studies (25–40% of subjects with chronic respiratory diseases), several risk factors for acute CVEs including age, preexisting coronary heart disease, diabetes, congestive heart failure, pleural effusion, increased pulse, urea nitrogen, and blood glucose had been identified [31‐33]. These finding are consistent with our results.

Some limitations should be noted before interpreting this study. As a nested case–control study, absolute causal relationship cannot be confirmed, and incidence and mortality of acute CVEs in patients with AECOPD cannot be calculated. Second, due to a limited number of acute CVEs and statistical efficacy, some risk factors might have been missed. We plan to further validate our results in a large-scale and multicenter cohort with more outcomes of CVEs. Third, some baseline information in the stable period was missing, and use of cardioprotective medications e.g. anti-platelet agents and statins was not fully recorded,, which might result in biases [14, 34]. Fourth, baseline comorbidities were reported by patients themselves and not validated by detailed laboratory tests, which might have led to recall bias. Fifth, we did not take some useful scales of cardiovascular risk assessment into consideration [35].

Cardiac complications in AE period were significantly associated with poor outcomes in patients with COPD. Patients with previous history of LVD and 20% increase in HR were susceptible to cardiac complications and needed close monitoring. Furthermore, diuretics use in AE period might be associated with underlying cardiovascular risks, and electrolytes and blood volume should be carefully assessed.