HHS Public Access Author manuscript Author Manuscript
Circ Res. Author manuscript; available in PMC 2017 August 19. Published in final edited form as: Circ Res. 2016 August 19; 119(5): 582–583. doi:10.1161/CIRCRESAHA.116.309392.
Heart Rate Recovery: Coming Back Full-Circle to the Baroreceptor Reflex Michael S Lauer, MD Office of Extramural Research, National Institutes of Health, Bethesda, MD
Author Manuscript
Keywords heart rate recovery; epidemiology In the current issue of Circulation Research, McCrory et al report on the association of heart rate recovery following simple orthostatic challenge – otherwise known as “standing up” – with all-cause mortality.1 The authors measured heart rate changes in the first 110 seconds after standing up in 4475 participants of an Irish population-based cohort study. Immediately after standing heart rate, as expected, increased, but in most subjects started to fall towards resting levels within 10 seconds. The rate of decline between 10 to 20 seconds postorthostatic challenge – or heart rate recovery HRR10-20 – was lower in older subjects and in subjects with a history of vascular disease. It was also an independent predictor of 4-year mortality: the lower the HRR10-20 the greater the mortality
Author Manuscript
To put these findings in perspective, we go back 28 years, when Schwartz et al published a report on a series of experiments that linked baroreceptor function with cardiac response to acute stress.2 The investigators produced an anterior myocardial infarction in 301 dogs and compared their baroreceptor sensitivity to 85 controls. They assessed baroreceptor sensitivity by injecting phenylephrine and measuring the regression slope relating fall in heart rate (or more precisely increase in RR interval) with increase in blood pressure. Among the 192 dogs that survived 4 weeks after myocardial infarction, baroreceptor sensitivity was markedly decreased compared to controls. The investigators then subjected these 192 dogs to treadmill exercise with acute circumflex artery occlusion during the last minute of exercise. There were 106 dogs who developed ventricular fibrillation with the “double-whammy” of exercise and acute ischemia.
Author Manuscript
What distinguished the dogs that developed exercise- and ischemia-induced ventricular fibrillation from those that did not? The investigators found a remarkably strong gradient between post-MI baroreceptor sensitivity and risk of ventricular fibrillation – as baroreceptor sensitivity declined risk of ventricular fibrillation increased. The authors, synthesizing this experiment with prior work, postulated that “analysis of baroreceptor reflex is a powerful tool for risk stratification not only after, but even before, the occurrence of an MI.”2
Please address all correspondence to Dr. Lauer at One Center Drive, Building 1, Room 144, Bethesda, MD 20892; phone 301-496-1096; [email protected]. Disclosures: None to report
Lauer
Page 2
Author Manuscript
In the clinical sphere, we cannot routinely inject phenylephrine and measure regression slopes between blood pressure and RR intervals, but it turns out that there is a measure that is largely, if not entirely, influenced by baroreceptor function.3 That measure is heart rate recovery following exercise. During exercise heart rate rises in response to vagal inhibition and sympathetic activation, whereas after exercise heart rate recovery occurs in response to cardiac vagal reactivation4 and to sympathetic deactivation.3
Author Manuscript
Recent work has demonstrated that events during early exercise and immediate recovery are almost entirely manifestations of vagal function.3 During early exercise, vagal inhibition reflects changes in central command and responses to muscle mechanoreceptors. However, during immediate recovery – the first 20 or 30 seconds after exercise ends, arguably the mirror image of early exercise – it seems as if neither central command nor mechanoreceptors play a role. Instead, the immediate fall in heart rate, which reflects the immediate increase in cardiac vagal tone, occurs in response to the activity of arterial baroreceptors.3 A number of clinical investigators and population epidemiologists have demonstrated strong associations between attenuated heart rate recovery and mortality. This association is seen in healthy adults5, in patients with suspected coronary disease6,7, and in patients with known coronary disease8; the association is also seen with treadmill9 and bicycle exercise10 and with different recovery protocols.11 One large epidemiological study reported that the association between attenuated heart rate recovery and death is largely manifest through sudden cardiac death.10 The work to date on heart rate recovery following exercise has painted a picture by which we can understand how decreased baroreceptor sensitivity in a post-MI dog model2 translates into prognostic implications in the clinic.
Author Manuscript
The report by McCrory et al1 adds an important chapter in the growing literature on heart rate recovery by taking us back full-circle to the primary physiological event of interest – the baroreceptor reflex. From a mechanistic perspective, the study enables us to isolate the baroreceptor response from the more complex events that occur during moderate to vigorous exercise. It also offers an opportunity for the clinical community to leverage the prognostic properties of heart rate recovery without having to put patients (and the system) through the inconveniences and efforts of formal exercise testing.
Author Manuscript
If, as it seems, baroreceptor sensitivity is central to cardiovascular health, the obvious question is what interventions might work to improve baroreceptor sensitivity and reduce risks of premature events – especially sudden cardiac death which despite many advances remains a leading cause of mortality.12 There are a number of candidates, including most prominently physical activity. While the work of McCrory solidifies the strong association between baroreceptor dysfunction, attenuated heart rate recovery, and mortality, we cannot yet jump to the conclusion that routine screening with heart rate recovery is clinically wise – we've learned before that prediction does not equal prevention.13 At the same time, though, it gives us greater confidence that further research in this area may be well worth the effort.
Circ Res. Author manuscript; available in PMC 2017 August 19.
Lauer
Page 3
Author Manuscript
References
Author Manuscript Author Manuscript
1. McCrory C, Berkman L, Nolan H, O'Leary N, Foley M, Kenny RA. Speed of Heart Rate Recovery in Response to Orthostatic Challenge: A Strong Risk Marker of Mortality. Circ Res . 2016 2. Schwartz PJ, Vanoli E, Stramba-Badiale M, De Ferrari GM, Billman GE, Foreman RD. Autonomic mechanisms and sudden death. New insights from analysis of baroreceptor reflexes in conscious dogs with and without a myocardial infarction. Circulation. 1988; 78:969–979. [PubMed: 3168199] 3. Coote JH. Recovery of heart rate following intense dynamic exercise. Exp Physiol. 2010; 95:431– 40. [PubMed: 19837772] 4. Imai K, Sato H, Hori M, Kusuoka H, Ozaki H, Yokoyama H, Takeda H, Inoue M, Kamada T. Vagally mediated heart rate recovery after exercise is accelerated in athletes but blunted in patients with chronic heart failure. J Am Coll Cardiol. 1994; 24:1529–1535. [PubMed: 7930286] 5. Cole CR, Foody JM, Blackstone EH, Lauer MS. Heart rate recovery after submaximal exercise testing as a predictor of mortality in a cardiovascularly healthy cohort. Ann Intern Med. 2000; 132:552–555. [PubMed: 10744592] 6. Cole CR, Blackstone EH, Pashkow FJ, Snader CE, Lauer MS. Heart-rate recovery immediately after exercise as a predictor of mortality. N Engl J Med. 1999; 341:1351–1357. [PubMed: 10536127] 7. Shetler K, Marcus R, Froelicher VF, Vora S, Kalisetti D, Prakash M, Do D, Myers J. Heart rate recovery: validation and methodologic issues. J Am Coll Cardiol. 2001; 38:1980–1987. [PubMed: 11738304] 8. Vivekananthan DP, Blackstone EH, Pothier CE, Lauer MS. Heart rate recovery after exercise is a predictor of mortality, independent of the angiographic severity of coronary disease. J Am Coll Cardiol. 2003; 42:831–838. [PubMed: 12957428] 9. Nishime EO, Cole CR, Blackstone EH, Pashkow FJ, Lauer MS. Heart rate recovery and treadmill exercise score as predictors of mortality in patients referred for exercise ECG. JAMA. 2000; 284:1392–1398. [PubMed: 10989401] 10. Jouven X, Empana J-P, Schwartz PJ, Desnos M, Courbon D, Ducimetière P. Heart-Rate Profile during Exercise as a Predictor of Sudden Death. N Engl J Med. 2005; 352:1951–1958. [PubMed: 15888695] 11. Watanabe J, Thamilarasan M, Blackstone EH, Thomas JD, Lauer MS. Heart rate recovery immediately after treadmill exercise and left ventricular systolic dysfunction as predictors of mortality: the case of stress echocardiography. Circulation. 2001; 104:1911–1916. [PubMed: 11602493] 12. Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, Das SR, de Ferranti S, Després J-P, Fullerton HJ, Howard VJ, Huffman MD, Isasi CR, Jiménez MC, Judd SE, Kissela BM, Lichtman JH, Lisabeth LD, Liu S, Mackey RH, Magid DJ, McGuire DK, Mohler ER, Moy CS, Muntner P, Mussolino ME, Nasir K, Neumar RW, Nichol G, Palaniappan L, Pandey DK, Reeves MJ, Rodriguez CJ, Rosamond W, Sorlie PD, Stein J, Towfighi A, Turan TN, Virani SS, Woo D, Yeh RW, Turner MB. Heart Disease and Stroke Statistics—2016 Update. Circulation. 2015 13. Lauer MS. Screening asymptomatic subjects for subclinical atherosclerosis: not so obvious. J Am Coll Cardiol. 2010; 56:106–108. [PubMed: 20620725]
Author Manuscript Circ Res. Author manuscript; available in PMC 2017 August 19.
Circ Res. Author manuscript; available in PMC 2017 August 19. Published in final edited form as: Circ Res. 2016 August 19; 119(5): 582–583. doi:10.1161/CIRCRESAHA.116.309392.
Heart Rate Recovery: Coming Back Full-Circle to the Baroreceptor Reflex Michael S Lauer, MD Office of Extramural Research, National Institutes of Health, Bethesda, MD
Author Manuscript
Keywords heart rate recovery; epidemiology In the current issue of Circulation Research, McCrory et al report on the association of heart rate recovery following simple orthostatic challenge – otherwise known as “standing up” – with all-cause mortality.1 The authors measured heart rate changes in the first 110 seconds after standing up in 4475 participants of an Irish population-based cohort study. Immediately after standing heart rate, as expected, increased, but in most subjects started to fall towards resting levels within 10 seconds. The rate of decline between 10 to 20 seconds postorthostatic challenge – or heart rate recovery HRR10-20 – was lower in older subjects and in subjects with a history of vascular disease. It was also an independent predictor of 4-year mortality: the lower the HRR10-20 the greater the mortality
Author Manuscript
To put these findings in perspective, we go back 28 years, when Schwartz et al published a report on a series of experiments that linked baroreceptor function with cardiac response to acute stress.2 The investigators produced an anterior myocardial infarction in 301 dogs and compared their baroreceptor sensitivity to 85 controls. They assessed baroreceptor sensitivity by injecting phenylephrine and measuring the regression slope relating fall in heart rate (or more precisely increase in RR interval) with increase in blood pressure. Among the 192 dogs that survived 4 weeks after myocardial infarction, baroreceptor sensitivity was markedly decreased compared to controls. The investigators then subjected these 192 dogs to treadmill exercise with acute circumflex artery occlusion during the last minute of exercise. There were 106 dogs who developed ventricular fibrillation with the “double-whammy” of exercise and acute ischemia.
Author Manuscript
What distinguished the dogs that developed exercise- and ischemia-induced ventricular fibrillation from those that did not? The investigators found a remarkably strong gradient between post-MI baroreceptor sensitivity and risk of ventricular fibrillation – as baroreceptor sensitivity declined risk of ventricular fibrillation increased. The authors, synthesizing this experiment with prior work, postulated that “analysis of baroreceptor reflex is a powerful tool for risk stratification not only after, but even before, the occurrence of an MI.”2
Please address all correspondence to Dr. Lauer at One Center Drive, Building 1, Room 144, Bethesda, MD 20892; phone 301-496-1096; [email protected]. Disclosures: None to report
Lauer
Page 2
Author Manuscript
In the clinical sphere, we cannot routinely inject phenylephrine and measure regression slopes between blood pressure and RR intervals, but it turns out that there is a measure that is largely, if not entirely, influenced by baroreceptor function.3 That measure is heart rate recovery following exercise. During exercise heart rate rises in response to vagal inhibition and sympathetic activation, whereas after exercise heart rate recovery occurs in response to cardiac vagal reactivation4 and to sympathetic deactivation.3
Author Manuscript
Recent work has demonstrated that events during early exercise and immediate recovery are almost entirely manifestations of vagal function.3 During early exercise, vagal inhibition reflects changes in central command and responses to muscle mechanoreceptors. However, during immediate recovery – the first 20 or 30 seconds after exercise ends, arguably the mirror image of early exercise – it seems as if neither central command nor mechanoreceptors play a role. Instead, the immediate fall in heart rate, which reflects the immediate increase in cardiac vagal tone, occurs in response to the activity of arterial baroreceptors.3 A number of clinical investigators and population epidemiologists have demonstrated strong associations between attenuated heart rate recovery and mortality. This association is seen in healthy adults5, in patients with suspected coronary disease6,7, and in patients with known coronary disease8; the association is also seen with treadmill9 and bicycle exercise10 and with different recovery protocols.11 One large epidemiological study reported that the association between attenuated heart rate recovery and death is largely manifest through sudden cardiac death.10 The work to date on heart rate recovery following exercise has painted a picture by which we can understand how decreased baroreceptor sensitivity in a post-MI dog model2 translates into prognostic implications in the clinic.
Author Manuscript
The report by McCrory et al1 adds an important chapter in the growing literature on heart rate recovery by taking us back full-circle to the primary physiological event of interest – the baroreceptor reflex. From a mechanistic perspective, the study enables us to isolate the baroreceptor response from the more complex events that occur during moderate to vigorous exercise. It also offers an opportunity for the clinical community to leverage the prognostic properties of heart rate recovery without having to put patients (and the system) through the inconveniences and efforts of formal exercise testing.
Author Manuscript
If, as it seems, baroreceptor sensitivity is central to cardiovascular health, the obvious question is what interventions might work to improve baroreceptor sensitivity and reduce risks of premature events – especially sudden cardiac death which despite many advances remains a leading cause of mortality.12 There are a number of candidates, including most prominently physical activity. While the work of McCrory solidifies the strong association between baroreceptor dysfunction, attenuated heart rate recovery, and mortality, we cannot yet jump to the conclusion that routine screening with heart rate recovery is clinically wise – we've learned before that prediction does not equal prevention.13 At the same time, though, it gives us greater confidence that further research in this area may be well worth the effort.
Circ Res. Author manuscript; available in PMC 2017 August 19.
Lauer
Page 3
Author Manuscript
References
Author Manuscript Author Manuscript
1. McCrory C, Berkman L, Nolan H, O'Leary N, Foley M, Kenny RA. Speed of Heart Rate Recovery in Response to Orthostatic Challenge: A Strong Risk Marker of Mortality. Circ Res . 2016 2. Schwartz PJ, Vanoli E, Stramba-Badiale M, De Ferrari GM, Billman GE, Foreman RD. Autonomic mechanisms and sudden death. New insights from analysis of baroreceptor reflexes in conscious dogs with and without a myocardial infarction. Circulation. 1988; 78:969–979. [PubMed: 3168199] 3. Coote JH. Recovery of heart rate following intense dynamic exercise. Exp Physiol. 2010; 95:431– 40. [PubMed: 19837772] 4. Imai K, Sato H, Hori M, Kusuoka H, Ozaki H, Yokoyama H, Takeda H, Inoue M, Kamada T. Vagally mediated heart rate recovery after exercise is accelerated in athletes but blunted in patients with chronic heart failure. J Am Coll Cardiol. 1994; 24:1529–1535. [PubMed: 7930286] 5. Cole CR, Foody JM, Blackstone EH, Lauer MS. Heart rate recovery after submaximal exercise testing as a predictor of mortality in a cardiovascularly healthy cohort. Ann Intern Med. 2000; 132:552–555. [PubMed: 10744592] 6. Cole CR, Blackstone EH, Pashkow FJ, Snader CE, Lauer MS. Heart-rate recovery immediately after exercise as a predictor of mortality. N Engl J Med. 1999; 341:1351–1357. [PubMed: 10536127] 7. Shetler K, Marcus R, Froelicher VF, Vora S, Kalisetti D, Prakash M, Do D, Myers J. Heart rate recovery: validation and methodologic issues. J Am Coll Cardiol. 2001; 38:1980–1987. [PubMed: 11738304] 8. Vivekananthan DP, Blackstone EH, Pothier CE, Lauer MS. Heart rate recovery after exercise is a predictor of mortality, independent of the angiographic severity of coronary disease. J Am Coll Cardiol. 2003; 42:831–838. [PubMed: 12957428] 9. Nishime EO, Cole CR, Blackstone EH, Pashkow FJ, Lauer MS. Heart rate recovery and treadmill exercise score as predictors of mortality in patients referred for exercise ECG. JAMA. 2000; 284:1392–1398. [PubMed: 10989401] 10. Jouven X, Empana J-P, Schwartz PJ, Desnos M, Courbon D, Ducimetière P. Heart-Rate Profile during Exercise as a Predictor of Sudden Death. N Engl J Med. 2005; 352:1951–1958. [PubMed: 15888695] 11. Watanabe J, Thamilarasan M, Blackstone EH, Thomas JD, Lauer MS. Heart rate recovery immediately after treadmill exercise and left ventricular systolic dysfunction as predictors of mortality: the case of stress echocardiography. Circulation. 2001; 104:1911–1916. [PubMed: 11602493] 12. Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, Das SR, de Ferranti S, Després J-P, Fullerton HJ, Howard VJ, Huffman MD, Isasi CR, Jiménez MC, Judd SE, Kissela BM, Lichtman JH, Lisabeth LD, Liu S, Mackey RH, Magid DJ, McGuire DK, Mohler ER, Moy CS, Muntner P, Mussolino ME, Nasir K, Neumar RW, Nichol G, Palaniappan L, Pandey DK, Reeves MJ, Rodriguez CJ, Rosamond W, Sorlie PD, Stein J, Towfighi A, Turan TN, Virani SS, Woo D, Yeh RW, Turner MB. Heart Disease and Stroke Statistics—2016 Update. Circulation. 2015 13. Lauer MS. Screening asymptomatic subjects for subclinical atherosclerosis: not so obvious. J Am Coll Cardiol. 2010; 56:106–108. [PubMed: 20620725]
Author Manuscript Circ Res. Author manuscript; available in PMC 2017 August 19.
