Skip to main content
PMC home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2012 Oct 4.
Published in final edited form as: Cleve Clin J Med. 2009 Apr;76(Suppl 2):S13–S17. doi: 10.3949/ccjm.76.s2.03

Depression and heart rate variability in patients with coronary heart disease

ROBERT M CARNEY 1, KENNETH E FREEDLAND 2
PMCID: PMC3463999  NIHMSID: NIHMS409903  PMID: 19376975

Abstract

Depression is common in patients with coronary heart disease (CHD) and is a risk factor for cardiac morbidity and mortality in these patients. Depression is associated with autonomic nervous system dysfunction, which may at least partially explain this increased risk. Low heart rate variability (HRV), which reflects excessive sympathetic and/or inadequate parasympathetic modulation of heart rate, is a strong predictor of mortality in patients with CHD. Most studies—both in patients with stable CHD and in patients with a recent acute coronary event—have found HRV to be lower in depressed patients than in their nondepressed counterparts. This manuscript provides an overview of this literature and concludes that HRV may account for a substantial part of the risk associated with depression in CHD.

Depression is a common psychiatric disorder in patients with coronary heart disease (CHD). Whereas the lifetime prevalence of major depression in the United States is estimated to be about 16%,1 with an annual rate of about 7%, approximately 20% of patients with CHD have major depression at any point in time.2–5 About the same proportion have minor depression.3 During the 12 months following an acute coronary event, as many as 30% of patients may develop major depression;6 the prevalence of minor depression during this 12-month period has not been reported but is also estimated to be about 30%. Thus, up to 60% of patients with an acute coronary event experience symptoms of depression within the 12 months following the event.

In addition to being highly comorbid with CHD, depression is also a significant risk factor for cardiac morbidity and mortality in patients with CHD. This risk is present from the time of initial diagnosis of CHD by cardiac catheterization and angiography7,8 as well as after an acute myocardial infarction (MI),6,9–11 an episode of unstable angina,12 or coronary artery bypass graft surgery.13–15 A recent meta-analysis of more than 20 studies of depression following acute MI found that major depression more than doubles the risk of mortality in the months following the acute event.16 Another meta-analysis found that just having symptoms of depression at various times in the course of CHD doubles the risk of death, and that clinical depression is associated with an even higher risk.17

Depression has been associated with many behavioral and biological abnormalities that could help explain the increased mortality risk in depressed patients with cardiac disease, including reduced adherence to treatment regimens, increased prevalence of smoking and diabetes, platelet dysfunction and coagulant processes, inflammatory processes, and alterations in hypothalamic-pituitary-adrenal axis and autonomic nervous system (ANS) function.18,19 Any or all of these might contribute to the increased risk for cardiac morbidity and mortality in depressed patients. Of all these possibilities, however, ANS dysfunction probably has received the most attention.20 Excessive sympathetic or reduced parasympathetic nervous system activity in patients with CHD may promote myocardial ischemia, ventricular tachycardia, ventricular fibrillation, and even sudden cardiac death.21–23

Studies dating back to the 1960s have found plasma and urinary catecholamine levels and resting heart rate (HR)to be elevated in medically well psychiatric patients with major depression compared with nondepressed controls.24–30 Studies of patients with CHD have also found elevated resting and 24-hour HRs in depressed compared with nondepressed patients.31,32 Additional evidence of ANS dysfunction in depressed CHD patients includes increased HR response to orthostatic challenge;32 increased QT interval variability, reflecting abnormal ventricular repolarization;33 abnormal HR response to ventricular arrhythmias (turbulence);34 and an increased incidence of ventricular tachycardia.35 All of these factors have been related to ANS dysfunction, and all are predictors of mortality in cardiac patients.

Many, though not all, studies of medically well depressed psychiatric patients have also found reduced HR variability (HRV), reflecting abnormal ANS modulation of HR. Low HRV is an excellent predictor of cardiac-related mortality36–39 and thus may further help to explain the relationship of depression to increased risk of mortality.

MEASUREMENT OF HEART RATE VARIABILITY

Analysis of HRV is a widely used method for studying cardiac autonomic modulation of HR.36 Low HRV generally reflects excessive sympathetic and/or inadequate parasympathetic modulation of HR36 and is a strong predictor of mortality in patients with CHD.37–39

Three methods of deriving HRV

In large prognostic or epidemiologic studies, HRV is usually measured over a 24-hour period and is derived from electrocardiographic (ECG) data by one of three methods: time domain analysis, frequency domain analysis, and nonlinear statistical models.

Time domain indices are based on descriptive statistical analyses of the HR time series. These include the standard deviation of all normal-to-normal intervals (SDNN) and the root mean square of successive N-N differences (rMSSD).

Frequency domain indices

Fast Fourier transforms and spectral analyses of ECG data are used to characterize HRV in the frequency domain. Frequency domain indices are defined by specific frequency ranges:

  • Ultra low frequency (ULF; < 0.0033 Hz)

  • Very low frequency (VLF; 0.0033 to 0.04 Hz)

  • Low frequency (LF; 0.04 to 0.15 Hz)

  • High frequency (HF; 0.15 to 0.4 Hz).

These indices are usually log-transformed to produce approximately normal distributions. Efferent vagal activity is largely responsible for the HF component, whereas LF power seems to reflect both sympathetic and parasympathetic activity.36 There is less certainly about the contributions to ULF.36 While not completely understood, VLF power is known to be unaffected by beta-blockade but nearly abolished by atropine, suggesting that the parasympathetic nervous system is the predominant determinant of VLF.40

Nonlinear statistical models

HRV has also been characterized by nonlinear mathematical models, such as those based on chaos theory and fractals. Nonlinear methods quantify the structure of the HR time series, including its regularity and self-similarity. These indices include the short-term fractal scaling exponent and approximate entropy.

HEART RATE VARIABILITY AND DEPRESSION IN CHD

Some studies have assessed HRV and depression following acute MI,41–45 whereas others have focused on HRV in medically stable patients with CHD. 46–49 Most of the studies have used frequency domain indices to calculate HRV.

HRV in post-MI patients with depression

In the largest study of depressed post-MI patients published to date,41 24-hour HRV levels were compared between 380 patients with a recent MI who had either major or minor depression and 425 post-MI patients who were not depressed. In univariate analyses, the four frequency domain indices of HRV (ULF, VLF, LF, and HF) were significantly lower in the depressed than in the nondepressed patients. After adjustment for possible confounders, all the indices except HF remained significantly lower in depressed patients than in nondepressed patients.

HRV in depressed patients with stable coronary disease

Most46–48 but not all49 studies have also found HRV to be lower in depressed than in nondepressed patients with stable CHD. The one exception was reported by Gehi et al,49 who assessed participants from the Heart and Soul Study cohort who had stable CHD at the time HRV was determined. Of the 873 outpatients with stable CHD who received 24-hour ambulatory ECG monitoring, 195 were found to have major depression. No differences between depressed and nondepressed patients were found on any time domain or frequency domain measure of HRV. This is the largest study to date of medically stable CHD patients assessed for depression and HRV, but its results differ from those of most smaller studies. The authors noted that although there was no difference in HRV between depressed and nondepressed patients, HRV in the nondepressed patients was similar to that in depressed patients in other samples.50 They speculated that the participants in their study, who were largely recruited from a Veterans Affairs hospital, may have been sicker than most participants in other studies and that this might have obscured depression-related differences in HRV.50

What is the clinical significance of HRV differences?

When evaluating differences in HRV between depressed and nondepressed patients, it is important to look past statistical comparisons and consider the clinical significance of these differences—ie, whether they are large enough to affect clinical outcomes or to be responsible for the depressed patients’ increased risk of death.

In the Cardiac Arrhythmia Pilot Study, HRV was assessed 1 year after acute MI in 331 patients.51 All measured indices of HRV were strong predictors of mortality. Patients with VLF power of less than 600 ms2 (natural logarithm of VLF power [LnVLF] < 6.4) were found to have a 4.4 relative risk of death over the next 2 years.51 In a study of a similar group of medically stable (ie, event-free for ≥ 6 months) patients with CHD,48 47% of those who were moderately to severely depressed, 29% of those who were mildly depressed, and 13% of those who were not depressed had VLF power below this cutpoint.

In the Multicenter Post-Infarction Program study, which evaluated patients in the immediate post–acute MI period, an LnVLF less than 5.2 was associated with a relative risk of 4.7 for cardiac mortality over the next 2.5 years.37 In our own study of post-MI patients, 7% of the nondepressed participants and 16% of the depressed participants had VLF power below this value, a difference that was significant even after adjusting for covariates (P = .006).41 Thus, mean 24-hour HRV is low enough in depressed patients with medically stable CHD and in those with recent acute MI to have prognostic significance.

How much of depression’s effect is due to low HRV?

In an attempt to determine whether low HRV accounts for at least part of the effect of depression on mortality, a statistical mediation model was applied to data collected in a follow-up study of the 311 depressed patients with recent acute MI described above,41 who were enrolled in the Enhancing Recovery in Coronary Heart Disease (ENRICHD) trial,52 and 367 patients who met the ENRICHD medical inclusion criteria but were without depression.53 VLF was selected as the index of HRV for this study because of its prognostic importance in post-MI patients. As noted earlier, VLF was significantly lower in the depressed patients.41 During a median follow-up of 24 months, there were 47 deaths within the overall study population of 766 patients (6.1%).53 Consistent with earlier studies, the depressed patients were at higher risk for all-cause mortality, even after adjusting for potential confounders (hazard ratio = 2.8; 95% confidence interval [CI], 1.4 to 5.4; P < .003). When the LnVLF was entered into the model, the hazard ratio for depression dropped to 2.1 (95% CI, 1.1 to 4.2; P = .03), indicating that the LnVLF accounted for about one-quarter of the total mortality risk. Thus, the study results suggest that low HRV at least partially mediates the effect of depression on survival after acute MI.

A role for premature ventricular contractions

In one of the first prognostic studies of depression following acute MI, Frasure-Smith et al reported an interaction between depression and premature ventricular contractions (VPCs) on subsequent mortality.6 Specifically, they found that depressed patients who had 10 or more VPCs per hour after an MI were at considerably higher risk of death than were either depressed post-MI patients without VPCs or nondepressed post-MI patients with 10 or more VPCs per hour. One interpretation of these data is that depressed patients may be at greater risk for death due to an abnormal response to VPCs or other arrhythmias.

HR turbulence analysis is a method for quantifying HR response to VPCs. In most individuals, when a VPC occurs, HR first accelerates and then decelerates. HR responses that differ from this pattern have been found to be even better predictors of post-MI mortality than more traditional measures of HRV in these patients.54,55

A total of 498 patients from the study reported above53 were found to have VPCs during 24-hour ambulatory monitoring.34 Of these patients, 260 had normal HR turbulence, 152 had equivocal HR turbulence, and 86 had abnormal HR turbulence. The depressed patients were more likely than their nondepressed counterparts to have abnormal HR turbulence (risk factor–adjusted odds ratio [OR] = 1.8; 95% CI, 1.0 to 3.0; P = .03). The patients were followed for a median of 24 months. Consistent with earlier studies, depressed patients had worse survival (OR for death = 2.4; 95% CI, 1.2 to 4.6; P = .02) than the nondepressed patients. When HR turbulence was added to the statistical model, the adjusted hazard ratio for depression decreased to 1.9 (95% CI, 0.9 to 3.8; P = .08). When the LnVLF was added to this model, the adjusted hazard ratio decreased further, to 1.6 (95% CI, 0.8 to 3.4; P = .18). Thus, the combination of VLF and HR response to VPCs explained about half of the effect of depression on survival in these patients.

Causality not proven, but further study warranted

Obviously, these results do not prove that there is a causal relationship between depression, low HRV, and mortality. However, they are consistent with the interpretation that HRV, especially when combined with measures of HR response to VPCs, may account for a significant proportion of depression’s association with mortality following an MI. Future studies of these risk markers should explore their potential interrelationships to clarify how they may jointly contribute to the risk of death in patients with depression.

RELATIONSHIP AMONG HRV AND OTHER POSSIBLE BIOLOGICAL PATHWAYS

As discussed earlier, other biological pathways that may link depression to increased mortality have been reported. The two that have received the most support are proinflammatory and procoagulant processes.18,19 Studies of medically healthy depressed psychiatric patients and of depressed CHD patients have found depression to be associated with higher levels of the inflammatory risk markers interleukin-6 (IL-6), C-reactive protein (CRP), and tumor necrosis factor– alpha (TNF-α) and with inflammatory-procoagulant markers such as fibrinogen,56–60 as well as with platelet activation. Low HRV and elevations in proinflammatory or procoagulant markers generally have been described as though they are independent pathways. However, both inflammatory and coagulant responses can be modulated by ANS activity,61,62 and a cholinergic anti-inflammatory pathway was recently proposed in which there is vagal efferent inhibition of proinflammatory cytokine release, thereby reducing systemic inflammation.62,63 Low HRV, reflecting reduced vagal activity, should therefore be associated with higher levels of both proinflammatory and procoagulant markers. Recent studies have found a relationship between HRV activity and increased markers of inflammation in other high-risk patients, including those with heart failure64,65 and with acute coronary syndrome.66

In a recent study of 44 patients with major depression, moderate negative correlations were found between fibrinogen and four measures of HRV.67 IL-6 was also negatively correlated with one measure of HRV (total power) and was marginally related to two others (VLF and LF power). On the other hand, neither CRP nor TNF-α was significantly related to any measure of HRV. The finding that fibrinogen and IL-6 are moderately related to HRV suggests a link between these factors in depressed CHD patients. Thus, these risk markers, which are commonly found in patients with depression, may be related and contribute to the increased mortality associated with depression. This possibility should be investigated in larger mechanistic studies of depression and cardiac morbidity and mortality.

SUMMARY AND FUTURE DIRECTIONS

Low HRV and other markers of cardiac ANS dysfunction in depressed patients are likely to contribute to the elevated risk associated with depression in patients with CHD. More work is needed to clarify the physiologic and behavioral mechanisms underlying depression’s role as a risk factor for mortality in patients with CHD. Work is also needed to identify treatments that improve both depression and HRV, and to determine whether such treatments might also improve survival in these patients.68

Acknowledgments

This manuscript was supported in part by grant RO1 HL76808 from the National Heart, Lung, and Blood Institute and by the Lewis and Jean Sachs Charitable Lead Trust.

Footnotes

Both authors reported that they have no fientricular financial interests or relationships that pose a potential conflict of interest with this article.

Contributor Information

ROBERT M. CARNEY, Department of Psychiatry, Washington University School of Medicine, St. Louis, MO.

KENNETH E. FREEDLAND, Department of Psychiatry, Washington University School of Medicine, St. Louis, MO.

REFERENCES

  • 1.Kessler RC, Berglund P, Demler O, et al. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R) JAMA. 2003;289:3095–3105. doi: 10.1001/jama.289.23.3095. [DOI] [PubMed] [Google Scholar]
  • 2.Carney RM, Rich MW, teVelde A, et al. Major depressive disorder in coronary artery disease. Am J Cardiol. 1987;60:1273–1275. doi: 10.1016/0002-9149(87)90607-2. [DOI] [PubMed] [Google Scholar]
  • 3.Hance M, Carney RM, Freedland KE, Skala J. Depression in patients with coronary heart disease: a 12-month follow-up. Gen Hosp Psychiatry. 1996;18:61–65. doi: 10.1016/0163-8343(95)00100-x. [DOI] [PubMed] [Google Scholar]
  • 4.Rudisch B, Nemeroff CB. Epidemiology of comorbid coronary artery disease and depression. Biol Psychiatry. 2003;54:227–240. doi: 10.1016/s0006-3223(03)00587-0. [DOI] [PubMed] [Google Scholar]
  • 5.Thombs BD, Bass EB, Ford DE, et al. Prevalence of depression in survivors of acute myocardial infarction. J Gen Intern Med. 2006;21:30–38. doi: 10.1111/j.1525-1497.2005.00269.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Frasure-Smith N, Lespérance F, Talajic M. Depression and 18-month prognosis after myocardial infarction. Circulation. 1995;91:999–1005. doi: 10.1161/01.cir.91.4.999. [DOI] [PubMed] [Google Scholar]
  • 7.Carney RM, Rich MW, Freedland KE, et al. Major depressive disorder predicts cardiac events in patients with coronary artery disease. Psychosom Med. 1988;50:627–633. doi: 10.1097/00006842-198811000-00009. [DOI] [PubMed] [Google Scholar]
  • 8.Herrmann C, Brand-Driehorst S, Buss U, Rüger U. Effects of anxiety and depression on 5-year mortality in 5,057 patients referred for exercise testing. J Psychosom Res. 2000;48:455–462. doi: 10.1016/s0022-3999(99)00086-0. [DOI] [PubMed] [Google Scholar]
  • 9.Bush DE, Ziegelstein RC, Tayback M, et al. Even minimal symptoms of depression increase mortality risk after acute myocardial infarction. Am J Cardiol. 2001;88:337–341. doi: 10.1016/s0002-9149(01)01675-7. [DOI] [PubMed] [Google Scholar]
  • 10.Carney RM, Blumenthal JA, Catellier D, et al. Depression as a risk factor for mortality after acute myocardial infarction. Am J Cardiol. 2003;92:1277–1281. doi: 10.1016/j.amjcard.2003.08.007. [DOI] [PubMed] [Google Scholar]
  • 11.Ladwig KH, Kieser M, König J, Breithardt G, Borggrefe M. Affective disorders and survival after acute myocardial infarction: results from the post-infarction late potential study. Eur Heart J. 1991;12:959–964. [PubMed] [Google Scholar]
  • 12.Lespérance F, Frasure-Smith N, Juneau M, Théroux P. Depression and 1-year prognosis in unstable angina. Arch Intern Med. 2000;160:1354–1360. doi: 10.1001/archinte.160.9.1354. [DOI] [PubMed] [Google Scholar]
  • 13.Blumenthal JA, Lett HS, Babyak MA, et al. Depression as a risk factor for mortality after coronary artery bypass surgery. Lancet. 2003;362:604–609. doi: 10.1016/S0140-6736(03)14190-6. [DOI] [PubMed] [Google Scholar]
  • 14.Burg MM, Benedetto C, Rosenberg R, Soufer R. Depression prior to CABG predicts 6-month and 2-year morbidity and mortality. Psychosom Med. 2001;63:103. Abstract 1175. [Google Scholar]
  • 15.Connerney I, Shapiro PA, McLaughlin JS, Sloan RP. In-hospital depression after CABG surgery predicts 12-month outcome. Psychosom Med. 2000;62:106. Abstract 1195. [Google Scholar]
  • 16.van Melle JP, de Jonge P, Spijkerman TA, et al. Prognostic association of depression following myocardial infarction with mortality and cardio-vascular events: a meta-analysis. Psychosom Med. 2004;66:814–822. doi: 10.1097/01.psy.0000146294.82810.9c. [DOI] [PubMed] [Google Scholar]
  • 17.Barth J, Schumacher M, Herrmann-Lingen C. Depression as a risk factor for mortality in patients with coronary heart disease: a meta-analysis. Psychosom Med. 2004;66:802–813. doi: 10.1097/01.psy.0000146332.53619.b2. [DOI] [PubMed] [Google Scholar]
  • 18.Carney RM, Freedland KE, Miller GE, Jaffe AS. Depression as a risk factor for cardiac mortality and morbidity: a review of potential mechanisms. J Psychosom Res. 2002;53:897–902. doi: 10.1016/s0022-3999(02)00311-2. [DOI] [PubMed] [Google Scholar]
  • 19.Carney RM, Freedland KE. Depression, mortality, and medical morbidity in patients with coronary heart disease. Biol Psychiatry. 2003;54:241–247. doi: 10.1016/s0006-3223(03)00111-2. [DOI] [PubMed] [Google Scholar]
  • 20.Carney RM, Freedland KE, Veith RC. Depression, the autonomic nervous system, and coronary heart disease. Psychosom Med. 2005;67(suppl 1):S29–S33. doi: 10.1097/01.psy.0000162254.61556.d5. [DOI] [PubMed] [Google Scholar]
  • 21.Kliks BR, Burgess MJ, Abildskov JA. Influence of sympathetic tone on ventricular fibrillation threshold during experimental coronary occlusion. Am J Cardiol. 1975;36:45–49. doi: 10.1016/0002-9149(75)90866-8. [DOI] [PubMed] [Google Scholar]
  • 22.Podrid PJ, Fuchs T, Candinas R. Role of the sympathetic nervous system in the genesis of ventricular arrhythmia. Circulation. 1990;82(2 suppl):I103–I113. [PubMed] [Google Scholar]
  • 23.Schwartz PJ, Vanoli E. Cardiac arrhythmias elicited by interaction between acute myocardial ischemia and sympathetic hyperactivity: a new experimental model for the study of antiarrhythmic drugs. J Cardiovasc Pharmacol. 1981;3:1251–1259. doi: 10.1097/00005344-198111000-00012. [DOI] [PubMed] [Google Scholar]
  • 24.Esler M, Turbott J, Schwarz R, et al. The peripheral kinetics of norepinephrine in depressive illness. Arch Gen Psychiatry. 1982;39:295–300. doi: 10.1001/archpsyc.1982.04290030035006. [DOI] [PubMed] [Google Scholar]
  • 25.Lake CR, Pickar D, Ziegler MG, Lipper S, Slater S, Murphy DL. High plasma norepinephrine levels in patients with major affective disorder. Am J Psychiatry. 1982;139:1315–1318. doi: 10.1176/ajp.139.10.1315. [DOI] [PubMed] [Google Scholar]
  • 26.Roy A, Pickar D, De Jong J, Karoum F, Linnoila M. Norepinephrine and its metabolites in cerebrospinal fluid, plasma, and urine. Relationship to hypothalamic-pituitary-adrenal axis function in depression. Arch Gen Psychiatry. 1988;45:849–857. doi: 10.1001/archpsyc.1988.01800330081010. [DOI] [PubMed] [Google Scholar]
  • 27.Veith RC, Lewis N, Linares OA, et al. Sympathetic nervous system activity in major depression: basal and desipramine-induced alterations in plasma norepinephrine kinetics. Arch Gen Psychiatry. 1994;51:411–422. doi: 10.1001/archpsyc.1994.03950050071008. [DOI] [PubMed] [Google Scholar]
  • 28.Dawson ME, Schell AM, Catania JJ. Autonomic correlates of depression and clinical improvement following electroconvulsive shock therapy. Psychophysiology. 1977;14:569–578. doi: 10.1111/j.1469-8986.1977.tb01201.x. [DOI] [PubMed] [Google Scholar]
  • 29.Lahmeyer HW, Bellur SN. Cardiac regulation and depression. J Psychiatr Res. 1987;21:1–6. doi: 10.1016/0022-3956(87)90004-5. [DOI] [PubMed] [Google Scholar]
  • 30.Wyatt RJ, Portnoy B, Kupfer DJ, Snyder F, Engelman K. Resting plasma catecholamine concentrations in patients with depression and anxiety. Arch Gen Psychiatry. 1971;24:65–70. doi: 10.1001/archpsyc.1971.01750070067009. [DOI] [PubMed] [Google Scholar]
  • 31.Carney RM, Rich MW, teVelde A, et al. The relationship between heart rate, heart rate variability and depression in patients with coronary artery disease. J Psychosom Res. 1988;32:159–164. doi: 10.1016/0022-3999(88)90050-5. [DOI] [PubMed] [Google Scholar]
  • 32.Carney RM, Freedland KE, Veith RC, et al. Major depression, heart rate, and plasma norepinephrine in patients with coronary heart disease. Biol Psychiatry. 1999;45:458–463. doi: 10.1016/s0006-3223(98)00049-3. [DOI] [PubMed] [Google Scholar]
  • 33.Carney RM, Freedland KE, Stein PK, et al. Effects of depression on QT interval variability after myocardial infarction. Psychosom Med. 2003;65:177–180. doi: 10.1097/01.psy.0000033129.21715.4b. [DOI] [PubMed] [Google Scholar]
  • 34.Carney RM, Howells WB, Blumenthal JA, et al. Heart rate turbulence, depression, and survival after acute myocardial infarction. Psychosom Med. 2007;69:4–9. doi: 10.1097/01.psy.0000249733.33811.00. [DOI] [PubMed] [Google Scholar]
  • 35.Carney RM, Freedland KE, Rich MW, Smith LJ, Jaffe AS. Ventricular tachycardia and psychiatric depression in patients with coronary artery disease. Am J Med. 1993;95:23–28. doi: 10.1016/0002-9343(93)90228-h. [DOI] [PubMed] [Google Scholar]
  • 36.Task Force of the European Society of Cardiology and the North American Society of Pacing Electrophysiology. Heart rate variability: standards of measurement, physiological interpretation, and clinical use. Circulation. 1996;93:1043–1065. [PubMed] [Google Scholar]
  • 37.Bigger JT, Jr, Fleiss JL, Steinman RC, Rolnitzky LM, Kleiger RE, Rottman JN. Frequency domain measures of heart period variability and mortality after myocardial infarction. Circulation. 1992;85:164–171. doi: 10.1161/01.cir.85.1.164. [DOI] [PubMed] [Google Scholar]
  • 38.Kleiger RE, Miller JP, Bigger JT, Jr, Moss AJ. Decreased heart rate variability and its association with increased mortality after acute myocardial infarction. Am J Cardiol. 1987;59:256–262. doi: 10.1016/0002-9149(87)90795-8. [DOI] [PubMed] [Google Scholar]
  • 39.Vaishnav S, Stevenson R, Marchant B, Lagi K, Ranjadayalan K, Timmis AD. Relation between heart rate variability early after acute myocardial infarction and long-term mortality. Am J Cardiol. 1994;73:653–657. doi: 10.1016/0002-9149(94)90928-8. [DOI] [PubMed] [Google Scholar]
  • 40.Taylor JA, Carr DL, Myers CW, Eckberg DL. Mechanisms underlying very-low-frequency RR-interval oscillations in humans. Circulation. 1998;98:547–555. doi: 10.1161/01.cir.98.6.547. [DOI] [PubMed] [Google Scholar]
  • 41.Carney RM, Blumenthal JA, Stein PK, et al. Depression, heart rate variability, and acute myocardial infarction. Circulation. 2001;104:2024–2028. doi: 10.1161/hc4201.097834. [DOI] [PubMed] [Google Scholar]
  • 42.Guinjoan SM, de Guevara MS, Correa C, et al. Cardiac parasympathetic dysfunction related to depression in older adults with acute coronary syndromes. J Psychosom Res. 2004;56:83–88. doi: 10.1016/S0022-3999(03)00043-6. [DOI] [PubMed] [Google Scholar]
  • 43.Pitzalis MV, Iacoviello M, Todarello O, et al. Depression but not anxiety influences the autonomic control of heart rate after myocardial infarction. Am Heart J. 2001;141:765–771. doi: 10.1067/mhj.2001.114806. [DOI] [PubMed] [Google Scholar]
  • 44.van den Berg MP, Spijkerman TA, van Melle JP, et al. Depression as an independent determinant of decreased heart rate variability in patinets post myocardial infarction. Neth Heart J. 2005;13:1365–1369. [PMC free article] [PubMed] [Google Scholar]
  • 45.Vigo DE, Siri L Nicola, Guevara MS Ladrón De, et al. Relation of depression to heart rate nonlinear dynamics in patients ≥ 60 years of age with recent unstable angina pectoris or acute myocardial infarction. Am J Cardiol. 2004;93:756–760. doi: 10.1016/j.amjcard.2003.11.056. [DOI] [PubMed] [Google Scholar]
  • 46.Carney RM, Saunders RD, Freedland KE, Stein P, Rich MW, Jaffe AS. Association of depression with reduced heart rate variability in coronary artery disease. Am J Cardiol. 1995;76:562–564. doi: 10.1016/s0002-9149(99)80155-6. [DOI] [PubMed] [Google Scholar]
  • 47.Krittayaphong R, Cascio WE, Light KC, et al. Heart rate variability in patients with coronary artery disease: differences in patients with higher and lower depression scores. Psychosom Med. 1997;59:231–235. doi: 10.1097/00006842-199705000-00004. [DOI] [PubMed] [Google Scholar]
  • 48.Stein PK, Carney RM, Freedland KE, et al. Severe depression is associated with markedly reduced heart rate variability in patients with stable coronary heart disease. J Psychosom Res. 2000;48:493–500. doi: 10.1016/s0022-3999(99)00085-9. [DOI] [PubMed] [Google Scholar]
  • 49.Gehi A, Mangano D, Pipkin S, Browner WS, Whooley MA. Depression and heart rate variability in patients with stable coronary heart disease: findings from the Heart and Soul Study. Arch Gen Psychiatry. 2005;62:661–666. doi: 10.1001/archpsyc.62.6.661. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50.Gehi A, Whooley M. Heart rate variability and depression [reply to letter] Arch Gen Psychiatry. 2006;63:1052. doi: 10.1001/archpsyc.63.9.1052-a. [DOI] [PubMed] [Google Scholar]
  • 51.Bigger JT, Jr, Fleiss JL, Rolnitzky LM, Steinman RC. Frequency domain measures of heart period variability to assess risk late after myocardial infarction. J Am Coll Cardiol. 1993;21:729–736. doi: 10.1016/0735-1097(93)90106-b. [DOI] [PubMed] [Google Scholar]
  • 52.Berkman LF, Blumenthal J, Burg M, et al. Effects of treating depression and low perceived social support on clinical events after myocardial infarction: the Enhancing Recovery in Coronary Heart Disease Patients (ENRICHD) Randomized Trial. JAMA. 2003;289:3106–3116. doi: 10.1001/jama.289.23.3106. [DOI] [PubMed] [Google Scholar]
  • 53.Carney RM, Blumenthal JA, Freedland KE, et al. Low heart rate variability and the effect of depression on post-myocardial infarction mortality. Arch Intern Med. 2005;165:1486–1491. doi: 10.1001/archinte.165.13.1486. [DOI] [PubMed] [Google Scholar]
  • 54.Ghuran A, Reid F, La Rovere MT, et al. Heart rate turbulence-based predictors of fatal and nonfatal cardiac arrest (The Autonomic Tone and Reflexes After Myocardial Infarction substudy) Am J Cardiol. 2002;89:184–190. doi: 10.1016/s0002-9149(01)02198-1. [DOI] [PubMed] [Google Scholar]
  • 55.Schmidt G, Malik M, Barthel P, et al. Heart-rate turbulence after ventricular premature beats as a predictor of mortality after acute myocardial infarction. Lancet. 1999;353:1390–1396. doi: 10.1016/S0140-6736(98)08428-1. [DOI] [PubMed] [Google Scholar]
  • 56.Dentino AN, Pieper CF, Rao MK, et al. Association of interleukin-6 and other biologic variables with depression in older people living in the community. J Am Geriatr Soc. 1999;47:6–11. doi: 10.1111/j.1532-5415.1999.tb01894.x. [DOI] [PubMed] [Google Scholar]
  • 57.Maes M, Meltzer HY, Bosmans E, et al. Increased plasma concentrations of interleukin-6, soluble interleukin-6, soluble interleukin-2 and transferrin receptor in major depression. J Affect Disord. 1995;34:301–309. doi: 10.1016/0165-0327(95)00028-l. [DOI] [PubMed] [Google Scholar]
  • 58.Maes M, Bosmans E, De Jongh R, et al. Increased serum IL-6 and IL-1 receptor antagonist concentrations in major depression and treatment resistant depression. Cytokine. 1997;9:853–858. doi: 10.1006/cyto.1997.0238. [DOI] [PubMed] [Google Scholar]
  • 59.Miller GE, Stetler CA, Carney RM, Freedland KE, Banks WA. Clinical depression and inflammatory risk markers for coronary heart disease. Am J Cardiol. 2002;90:1279–1283. doi: 10.1016/s0002-9149(02)02863-1. [DOI] [PubMed] [Google Scholar]
  • 60.von Känel R, Mills PJ, Fainman C, Dimsdale JE. Effects of psychological stress and psychiatric disorders on blood coagulation and fibrinolysis: a biobehavioral pathway to coronary artery disease? Psychosom Med. 2001;63:531–544. doi: 10.1097/00006842-200107000-00003. [DOI] [PubMed] [Google Scholar]
  • 61.März P, Cheng JG, Gadient RA, et al. Sympathetic neurons can produce and respond to interleukin 6. Proc Natl Acad Sci USA. 1998;95:3251–3256. doi: 10.1073/pnas.95.6.3251. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 62.Tracey KJ. The inflammatory reflex. Nature. 2002;420:853–859. doi: 10.1038/nature01321. [DOI] [PubMed] [Google Scholar]
  • 63.Pavlov VA, Tracey KJ. The cholinergic anti-inflammatory pathway. Brain Behav Immun. 2005;19:493–499. doi: 10.1016/j.bbi.2005.03.015. [DOI] [PubMed] [Google Scholar]
  • 64.Aronson D, Mittleman MA, Burger AJ. Interleukin-6 levels are inversely correlated with heart rate variability in patients with decompensated heart failure. J Cardiovasc Electrophysiol. 2001;12:294–300. doi: 10.1046/j.1540-8167.2001.00294.x. [DOI] [PubMed] [Google Scholar]
  • 65.Malave HA, Taylor AA, Nattama J, Deswal A, Mann DL. Circulating levels of tumor necrosis factor correlate with indexes of depressed heart rate variability: a study in patients with mild-to-moderate heart failure. Chest. 2003;123:716–724. doi: 10.1378/chest.123.3.716. [DOI] [PubMed] [Google Scholar]
  • 66.Lanza GA, Sgueglia GA, Cianflone D, et al. Relation of heart rate variability to serum levels of C-reactive protein in patients with un-stable angina pectoris. Am J Cardiol. 2006;97:1702–1706. doi: 10.1016/j.amjcard.2006.01.029. [DOI] [PubMed] [Google Scholar]
  • 67.Carney RM, Freedland KE, Stein PK, et al. Heart rate variability and markers of inflammation and coagulation in depressed patients with coronary heart disease. J Psychosom Res. 2007;62:463–467. doi: 10.1016/j.jpsychores.2006.12.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 68.Carney RM, Freedland KE, Stein PK, et al. Change in heart rate and heart rate variability during treatment for depression in patients with coronary heart disease. Psychosom Med. 2000;62:639–647. doi: 10.1097/00006842-200009000-00007. [DOI] [PubMed] [Google Scholar]

RESOURCES