Abnormal Heart Rate Recovery in Stable Heart Failure Patients

Ahmet Yilmaz, M.D., Alim Erdem, M.D., Zekeriya Kucukdurmaz, M.D., Hekim Karapinar, M.D., Ibrahim Gul, M.D., Savas Sarikaya, M.D., Rafet Dizman, M.D. Pacing Clin Electrophysiol. 2013;36(5):591-595.

Abstract
Background: Heart rate decrease after exercise, that is associated with reactivation of parasympathetic system, is important, as it is also associated with mortality. Previous studies have shown that this is an independent mortality predictor in patients having no coronary artery disease and having normal left ventricular function. In our study, we aimed to study heart rate recovery (HRR) after exercise in patients having impaired left ventricular function. Methods: One hundred and two consecutive patients (68 males, 34 females) requested to perform an exercise stress test were included in our study. Patients were divided into two groups as those having a normal heart rate reserve (Group1, n = 72) and those having an abnormal heart rate reserve (Group2, n = 30). Results: In Group1 and Group2, resting heart rate averages were found to be 83.61 18.01/min and 85.10 13.40/min, respectively (P > 0.05), and maximum heart rates during exercise were 141.42 19.70/min and 121.17 19.01/min while those in Group1 had statistically significantly higher heart rates (P < 0.001). A statistically significant positive association was found in the correlation test carried out between the maximum heart rate during the treadmill exercise test and ejection fraction (EF) value (r = 0.201; P < 0.05). Metabolic equivalents of task values obtained during the treadmill exercise test in Group1 and Group2 were 9.48 2.28 and 8.36 2.50, respectively, and the difference between the said values was statistically significant (P < 0.05). Conclusions: We believe that the association between low EF and abnormal HRR is worth studying and randomized large-scale studies are needed to determine mortality risk.

Introduction
Heart rate decrease after exercise is important, as it is associated with mortality. The said decrease in heart rate has been thought to be associated with reactivation of parasympathetic system. According to a protocol conducted at the end of the first minute of an exercise, a reduction of 12 beats/min after a slow cessation of exercise and 18 beat/min after a sudden cessation of exercise are expected.[1] The term abnormal heart rate recovery (HRR) is used for lower results, and previous studies have shown that this is an independent mortality predictor in patients having no coronary artery disease and having normal left ventricular function. In our study, we studied HRR after exercise in patients having impaired left ventricular function.

Method
Study Population
One hundred and two consecutive stable heart failure patients (68 males, 34 females) who applied to our clinic and requested to perform an exercise stress test were included in our study. Patients were divided into two groups as those having a normal heart rate reserve (Group 1, n = 72) and those having an abnormal heart rate reserve (Group 2, n = 30). Those admitted with decompensated heart failure, having peripheral artery disease, rheumatic diseases limiting effort, atrial fibrillation, and/or permanent cardiac pacemaker, anemia (Hb < 10 g/dL), chronic obstructive pulmonary disease, and severe chest pain increasing by exercise or electrocardiography (ECG) abnormalities were excluded from the study. Functional conditions of the patients were classified according to the criteria of New York Heart Association (NYHA). Cardiac medications used by the patients were classified as -blockers, angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), diuretics (furosemide and spironolactone), and calcium channel blockers (CCB) (Table I). Previous heart failure diagnosis was done based on American College of Cardiology/American Heart Association/European Society of Cardiology guidelines.

Table I. Medication Usage Properties of the Groups

Group 1 (Normal HRR) (n = 72) Group 2 (Abnormal HRR) (n = 30) P Value

-blocker (%) Statin (%) Vasodilator (%) Diuretics (%)

HRR = heart rate recovery.

54.2% (n = 39) 34.7% (n = 25) 8.3% (n = 6) 27.8% (n = 20)

60% (n = 18) 46.7% (n = 14) 10% (n = 3) 23.3% (n = 7)

P > 0.05 P > 0.05 P > 0.05 P > 0.05

Hypertension was defined as a resting systolic blood pressure 140 mmHg and/or diastolic blood pressure 90 mmHg or having a preexisting hypertension diagnosis. Using hypoglycemic agents and/or having a fasting blood glucose 126 mg/dL and HbA1c >6.5 mg/dL was enough to make a diagnosis of diabetes mellitus. A history of myocardial infarction or having epicardial coronary artery lesions detected by coronary angiography or a history of hospitalization for unstable angina pectoris were the conditions of making a diagnosis of coronary artery disease. Patients were classified as smokers if they consumed cigarettes regularly during the last 1 year before the study. Cardiopulmonary Exercise Test. A symptom (dyspnea or fatigue) limited exercise test was performed without ceasing the administration of any medication. Blood pressure was measured before the test, every 3 minutes during the test and after the test. Heart rate was measured once in every minute during the test, during maximum exercise, and at the first minute of recovery. The formula used in evaluating the chronotropic response was ([maximum heart rate-resting heart rate]/[220-age-resting heart rate]), and values 0.80 were regarded as chronotropic incompetence. The test was stopped when maximum workload was reached and patients were allowed to rest without cooling down phase. Heart rate reserve was defined as the difference between the maximum exercise heart rate and the one measured 1 minute after resting. Values 18 beats were interpreted as abnormal. The study was approved by the Ethics Committee of the Cumhuriyet University Medical School (Sivas, Turkey) and informed consent was obtained from the patients.

Statistical Analysis
Continues variables were given as averages and standard deviation. Intergroup differences were presented by using 2 test and student t-test. Statistical analysis were carried out using SPSS for Windows v.13.0 program (IBM, Armonk, NY, USA). Note that P value was regarded as significant.

Results
Baseline characteristics of both groups are shown in Table II. Average age was 55.68 10.05 and 60.50 9.00 years in Group 1 and Group 2, respectively (P < 0.05). The ratio of female patients was 40.0% in Group 2 compared to 30.6% females in Group 1, but it was not statistically significant (P > 0.05). The average ejection fraction (EF) was 52.13% 11.95 in Group 1 and 45.13% 11.74 in Group 2 and the difference between the groups was statistically significant (P = 0.05). With respect to the ratio of patients having diagnosis of coronary artery disease diagnosis, the difference between the groups was statistically significant, with a 47.2+ (n = 34) in group 1 and 80% (n = 24) in Group 2 (P < 0.05).

Table II. Demographic Parameters of the Groups

Group 1 (Normal HRR) (n = 72) Group 2 (Abnormal HRR) (n = 30) P Value

Age (year) Female gender (%) Rest heart rate/minute Hypertension (%) Diabetes mellitus (%) Smoking (%)
HRR = heart rate recover

55.68 10.05 30.6% (n = 22) 83.61 18.01 50% (n = 36) 6.9% (n = 5) 27.8% (n = 20)

60.50 9.00 40% (n = 12) 85.10 13.40 43.3% (n = 13) 10% (n = 3) 40% (n = 12)

P < 0,05 P > 0,05 P > 0.05 P > 0.05 P > 0.05 P < 0.05

The ratio of smokers was 27.8% (n = 20) in Group 1 and 40% (n = 12) in Group 1, which was a statistically significant difference (P < 0.05). Hypertension and diabetes mellitus were present in 50% (n = 36) and 6.9% (n = 5) in Group 1, respectively while 43.3% (n =

13) of the patients had hypertension and 10% (n = 3) had diabetes mellitus in Group 2. No significant difference was found between the Groups in terms of these parameters (P > 0.05). In Group 1 and Group 2, resting heart rate averages were found to be 83.61 18.01/min and 85.10 13.40/min, respectively (P > 0.05). Maximum heart rates of Group 1 and Group 2 patients during treadmill exercise test were 141.42 19.70/min and 121.17 19.01/min while those in Group 1 had statistically significantly higher heart rates (P < 0.001). A statistically significant positive association was found in the correlation test carried out between the maximum heart rate during the treadmill exercise test and left ventricular ejection fraction (LVEF) value (r = 0,201; P < 0.05) (Fig. 1). Metabolic equivalents of task (METS) values obtained during the effort test in Group 1 and Group 2 were 9.48 2.28 and 8.36 2.50, respectively and the difference between the said values was statistically significant (P < 0.05). Average body mass indices were found to be 27.75 3.71 and 26.15 3.13 in Group 1 and Group 2, respectively (P < 0.05).

Figure 1. Relation between the ejection fraction and the maximal heart rate during exercise. EF = ejection fraction; MHR = maximal heart rate

Discussion
Studies conducted in recent years have shown that HRR has a prognostic value in healthy volunteers and patients having a coronary artery disease with preserved left ventricular function.[14] Moreover, delayed HRR measured up to 2 minutes after maximal exercise has been suggested to predict all-cause mortality.[5,6] In normal individuals, cardiac output goes up by an increase in heart rate and stroke volume during exercise test. The increase in heart rate is caused by the disappearance of vagal tonus and dominance of sympathetic tonus. The decrease in heart rate right after the exercise can be explained by parasympathetic reactivation. Reactivation of parasympathetic system causes a decrease in myocardial inotropic response and peripheral vasodilation along with an increase in heart rate. Although the factors playing a role in HRR are not known clearly, it has been thought that cardiac venous return, increased stress in atrial receptor, and impairment of sympathetic/parasympathetic stimulation balance in favor of parasympathetic system have been thought to be the major factors.[711] Other than these, compliance of major arteries may affect the baroreceptor sensitivity and heart rate after exercise. [12] Previous studies have found a significant correlation between HRR and arterial stiffness in healthy volunteers.[13] In the literature, there are limited data on the association between heart failure and HRR.[14] As it has been known for a long time, heart failure is presenting with autonomic dysfunction and neurohumoral activation. Studies on this subject have revealed that parasympathetic activity is diminished while sympathetic stimulation is increased during heart failure.[15,16] Blunted response to vagal stimulation can be related with end-organ responsiveness. In a study, it has been shown that muscarinic receptor density is decreased in a model of heart failure in dogs.[17] Moreover, activation of renin-angiotensinaldosteron system[18] and increased endothelial release[19] could be playing a role too. Factors stated above are no more than a speculation, as the vagal efferent stimulation to the heart cannot be directly measured in conscious people. In our study, in terms of maximal rate, functional capacity (determined by METS), resting heart rate, EF, coronary artery disease, and smoking, a statistically significant difference was found between those having normal and abnormal HRR. Having a lower EF and METS functional capacity in the group having abnormal HRR can be explained by "blunting of the neurohormonal response" occurring in heart failure through above-mentioned mechanisms. Higher frequency of coronary artery disease, smoking, EF, and DM, although

it is not statistically significant, in the group having abnormal HRR increases the mortality risk, which is already high.

Limitation
The primary limitation of our study was the small sample size. A small sample size has low statistical power and, thus, may yield false-negative results. Thus, our results cannot be extended to the general population. However, we believe that our findings provide a valuable indication of the association between low EF and abnormal HRR. Furthermore, we did not have enough data for the dosage of -blockers. In conclusion, we believe that the association between low EF and abnormal HRR shown in our study is worth studying and randomized large-scale studies are needed to determine mortality risk.

References
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