Templin C, Hänggi J, Klein C, et al. Altered limbic and autonomic processing supports brain-heart axis in Takotsubo syndrome. Eur Heart J. 2019 14;40(15):1183-1187.
Functional MRI brain scans of people who survived Takotsubo Syndrome (TTS) in the past were compared with scans from healthy controls
The present analysis included 54 subjects. Of these, 15 had survived TTS within the past few years (median time between the TTS event and the MRI scans: 378 days). The TTS patients were enrolled from the InterTAK Registry, established at the University Hospital Zurich.15 The remaining 39 subjects were age- and gender-matched, healthy controls.
For statistical analyses of the MRI data, the researchers defined 4 different sets of brain regions that could allow analysis of how and to what extent different areas of the brain were simultaneously activated and communicating with each other. These networks were compared in the Takotsubo Survivors and healthy controls.
In the healthy volunteers, the parts of the brain associated with the emotions and the sympathetic and parasympathetic nervous systems lit up synchronously. The communication among those areas was relatively slight in the TTS survivors. Parasympathetic- and sympathetic-associated subnetworks both showed reduced resting state functional connectivity in TTS survivors compared with controls. The dimmed neuronal activity was most notable between the brain regions that control the sympathetic and parasympathetic nervous systems; the physiological calming that should occur after stress was apparently less likely to take place.
This study is a major step forward that brings us closer toward an explanation of how emotions affect health—in particular cardiovascular health—so it is worth our sweating through some of the details and complexities of what these researchers did in order to get a glimpse of the larger picture.
It’s long been believed that emotions and cardiac function are linked. This is reflected linguistically in most languages. Just consider how our very choice of words reflects the idea that emotions are felt in the heart and that the heart is a person’s emotional center. We do not suffer from distress secondary to ending a relationship with a loved one; we suffer from a broken heart.
TTS is perhaps the most critical physical expression of this phenomenon. Takotsubo is a life-threatening reaction to intensely strong emotions. When someone dies of a broken heart, it may not be just a figure of speech, it may be from TTS.
TTS was first described in 1991 by Japanese doctors who reported 5 cases of transient multivessel coronary spasm. The disease manifests predominantly in postmenopausal females. “In about 75% of cases there are emotional triggers such as severe physical or emotional stress, natural disasters such as earthquakes, unexpected death of relatives, acute medical illnesses, etc.”
The common scenario is that the stress or grief is the sort experienced after a romantic breakup or the death of a spouse. The symptoms mimic a heart attack: chest pain, shortness of breath, even congestive heart failure. This association with intense emotions has earned TTS the nickname “broken heart syndrome.”1 The heart muscle balloons into a distinctive shape resembling, at least to the Japanese doctors who came up with the name, the clay pots used in Japan to trap octopus. Takotsubo pots have a wide base and narrow necks, and apparently once the octopus enters it can’t figure out how to exit the pot.2
This syndrome usually resolves on its own within a few weeks, but the acute period can be severe enough to cause heart failure, arrhythmia, and even death. People literally do die of a broken heart.
The etiology of TTS is still unclear, but the most plausible explanation is that the sudden release of stress hormones such as norepinephrine, epinephrine, and dopamine stuns the heart. This triggers changes in the cardiac myocytes and hinders coronary perfusion. Stress hormone levels in TTS patients can be double or triple the normal range.3 High catecholamine levels lead to negative inotropy and results in left ventricular contractile dysfunction.4 Because the beta-adrenergic receptors are the most concentrated in the apical region of the heart, this may explain the heart’s changes in shape. Many of the features of TTS can be triggered by giving high doses of catecholamines and beta-adrenergic agonists.5 Following this line of thinking, betablockers are used in managing TTS.
Estrogen provides protection to the heart, and since more than 90% of TTS patients are postmenopausal women, this suggests that estrogen may provide some protection against TTS.6,7 Studies have shown that lack of estrogen replacement therapy may predispose women to TTS.8,9
Does a weakened parasympathetic system leave these patients vulnerable to heartbreak? Or did the heart episode cause the problem in function?
Templin et al’s findings suggest that TTS may begin in the brain, the result of an uncontained reaction to emotions and an inability to dampen them. Whether it is the stress that changes the brain or whether the brains of people who develop TTS started out predisposed to handle stress differently is not clear. Earlier, somewhat simpler studies have also suggested that TTS survivors possess a weakened parasympathetic ability to moderate the stress brought on by intense emotions.
Back in 2016, writing in the American Journal of Cardiology, Norcliffe-Kaufmann et al reported they had characterized autonomic function in 10 women with a history of TTS, comparing them with an equal number of healthy controls. These researchers used more traditional assessment tools including baroreflex stimulation (Valsalva maneuver and tilt testing), cognitive stimulation (Stroop test), and emotional stimulation (event recall, patients). Ambulatory blood pressure monitoring and measurement of brachial artery flow-mediated vasodilation were also performed. The testing was performed an average of 37 months after the Takotsubo event. Even 3 years later, those TTS survivors had excessive sympathetic responsiveness and reduced parasympathetic modulation of heart rate.10
A second paper published in 2016 used functional MRIs to monitor 4 TTS survivors, comparing them with 8 healthy volunteers while they underwent various autonomic challenges. Similar conclusions were reached: “The central autonomic response to autonomic challenges is altered in patients with Takotsubo cardiomyopathy, thus suggesting a dysregulation of the central autonomic nervous system network … whether these alterations are causal or predisposing factors to Takotsubo cardiomyopathy.”11
Lazzeroni et al reported similar findings in 2017 after comparing autonomic function in 24 Takotsubo patients, 25 healthy subjects, and 22 post-myocardial infarction (MI) patients. Once again, Takotsubo survivors “showed a blunted parasympathetic reactivation after exercise, similar to that observed in post-MI patients, thereby suggesting that vagal control of heart rate after exercise is abnormal long after the acute presentation of TS.”
Thus, although “exaggerated sympathetic stimulation plays a role in the development of [TTS] during the acute phase,” parasympathetic function continues to be weak long after the episode.12
The question remains: Is this weakened parasympathetic response the result of the Takotsubo episode or is it causal? Was it there before the episode? Does a weakened parasympathetic system leave these patients vulnerable to heartbreak? Or did the heart episode cause the problem in function?
This raises a somewhat parallel question about depression and cardiac disease.
Symptoms of depression are about 3 times more common in patients after an acute heart attack than in the general population, according to the American Heart Association, which strongly suggests a link between depression and heart disease.
For their 2017 report, May et al followed 24,137 patients with coronary artery disease (CAD). At follow-up, 3,646 of this group (15%) were diagnosed as depressed. During the next decade about 40% of the larger cohort died. In those diagnosed with depression, 50% had died while only 38% of those who were not depressed had died. A depression diagnosis at any time following CAD diagnosis was associated with a two-fold higher risk of death. Being depressed was the strongest predictor of death in those diagnosed with CAD, doubling risk of death.13
An April 2019 study by Liu et al examined data from 32,345 people in the United States and evaluated how depression and anxiety affect risk of coronary artery disease (CAD). Here too, depression or anxiety were associated with double the risk of developing CAD. Treating and reducing the severity of either psychological disorder was associated with lower risk of CAD.14
There are hints that depressed cardiovascular patients differ deeply from those who aren’t depressed. Williams et al reported in March 2019 that, “depressed cardiovascular patients had higher serotonin receptor density, and significantly higher incidence of major and minor cardiac adverse events” than non-depressed cardiac patients.15
Something appears to shift in the very biology of these patients. This may be why treating these depressed patients with serotonin reuptake inhibitors (SSRIs) is more effective at reducing major cardiovascular events than antidepressants that do not target serotonin pathways.16
Depressed cardiac patients may also look and feel depressed for another reason. “Patients with depressive symptoms directly after MI have a flattened diurnal serum cortisol profile. This is particularly expressed in patients with longer lasting symptoms.”17
It is a challenge even for an experienced practitioner to differentiate cortisol-associated depression and general depression. Few cardiologists will probably even think to make the distinction between the 2 conditions.
These associations between cardiac disease and depression highlight the question: Will treating the depression improve the cardiac prognosis? Rahmani et al reported in 2018 that it might help. They found that taking part in cardiac rehabilitation programs following coronary angiography is associated with less depression. Patients who do not take part in rehab are nearly 11 times more likely to be depressed.18 One might reasonably argue though that the more depressed someone is, the less likely they will attend these sessions.
There’s another new paper suggesting that post-cardiac disease depression is deep in the physiology. Bremner et al reported that there are specific changes in brain function in depressed cardiac patients. Depressed CAD patients had “increased parietal cortex activation and a relative failure of medial prefrontal/anterior cingulate activation during mental stress compared to CAD patients without depression.”
The authors of this study consider their findings to be “consistent with a role for brain areas implicated in stress and depression in the mechanism of increased risk for CAD morbidity and mortality in CAD patients with the diagnosis of major depression.”19 In other words, they posit that depression may lead to CAD.
A year earlier in 2018, the same authors, Bremner et, al described a situation reminiscent of Takotsubo: “Mental stress-induced myocardial ischemia is associated with activation in brain areas involved in the stress response and autonomic regulation of the cardiovascular system. Altered brain reactivity to stress could possibly represent a mechanism through which stress leads to increased risk of CAD-related morbidity and mortality.”20
A decade or so back this association between stress and heart disease was used to justify interventions aimed at increasing resilience in patients in order to reduce the impact of heart disease.
Dimsdale wrote in 2008, “There is nonetheless overwhelming evidence both for the deleterious effects of stress on the heart and for the fact that vulnerability and resilience factors play a role in amplifying or dampening those effects. Numerous approaches are available for stress management that can decrease patients’ suffering and enhance their quality of life.”21
Sadly, these attempts at stress management and other psychological interventions have not proven to be terribly fruitful in preventing heart disease. In an umbrella study (a meta-analysis of prior meta-analyses) published in 2018, Machado et al stated, “A causal effect of depression on all-cause and cause-specific mortality remains unproven, and thus interventions targeting depression are not expected to result in lower mortality rates at least based on current evidence from observational studies.”22
A 2017 Cochrane review was even less supportive of this approach. The reviewers report that for people with coronary heart disease, there was no evidence that psychological treatments had an effect on total mortality, the risk of revascularization procedures, or the rate of nonfatal myocardial infarction. However, there was some positive news: The rate of cardiac mortality was reduced and psychological symptoms (depression, anxiety, or stress) were alleviated.23
There is one additional 2016 study on TTS patients that is worth mention.
Marfella and colleagues treated 48 people diagnosed with TTS by giving them 600 mg per day of alpha lipoic acid or placebo after they were discharged. The patients were followed for 12 months. As in other studies, changes in heart function persisted long after the initial episode. However, treatment with alpha lipoic acid improved the adrenergic cardiac innervation.24 If alpha lipoic acid helps prevent heart damage in Takotsubo, might it also ameliorate depression in CAD patients? This supplement is already suggested for treating CVD and for depression in general.25,26
Depression in cardiac patients is common and is not a good sign. This is one of those chicken-and-egg situations. Which came first? Does injury to the heart release chemicals that make people feel depressed, or does depression release chemicals that promote heart injury? Or is it a two-way street that the poor chicken is trying to cross? At this point the science is unclear so we might as well look both ways.
If we treat depression and improve heart function, it’s not the end of the world. And if we treat cardiac disease and accidentally cheer people up, once again not the end of the world. Though if you talk to people with heart disease, some of them will believe it is the end of the world. Those are the ones we need to worry the most about.
- Dote K, Sato H, Tateishi H, Uchida T, Ishihara M. [Myocardial stunning due to simultaneous multivessel coronary spasms: a review of 5 cases]. J Cardiol. 1991;21(2):203-214.
- Gianni M, Dentali F, Grandi AM, Sumner G, Hiralal R, Lonn E. Apical ballooning syndrome or takotsubo cardiomyopathy: a systematic review. Eur Heart J. 2006;27(13):1523-1529.
- Wittstein IS, Thiemann DR, Lima JA, et al. Neurohumoral features of myocardial stunning due to sudden emotional stress. N Engl J Med. 2005;352(6):539-548
- Lyon AR, Rees PS, Prasad S, Poole-Wilson PA, Harding SE. Stress (Takotsubo) cardiomyopathy--a novel pathophysiological hypothesis to explain catecholamine-induced acute myocardial stunning. Nat Clin Pract Cardiovasc Med. 2008;5(1):22-29.
- Paur H, Wright PT, Sikkel MB, et al. High levels of circulating epinephrine trigger apical cardiodepression in a β2-adrenergic receptor/Gi-dependent manner: a new model of Takotsubo cardiomyopathy. Circulation. 2012;126(6):697-706.
- Moolman JA. Unravelling the cardioprotective mechanism of action of estrogens. Cardiovasc Res. 2006;69(4):777-780.
- Khalid N, Ahmad SA, Shlofmitz E, Chhabra L. Racial and gender disparities among patients with Takotsubo syndrome. Clin Cardiol. 2019;42(1):19.
- Kuo BT, Choubey R, Novaro GM. Reduced estrogen in menopause may predispose women to takotsubo cardiomyopathy. Gend Med. 2010;7(1):71-77.
- Khalid N, Chhabra L. Pathophysiology of Takotsubo Syndrome. [Updated 2019 Feb 5]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2019 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK538160/.
- Norcliffe-Kaufmann L, Kaufmann H, Martinez J, Katz SD, Tully L, Reynolds HR. Autonomic findings in Takotsubo cardiomyopathy. Am J Cardiol. 2016;117(2):206-213.
- Pereira VH, Marques P, Magalhães R, et al. Central autonomic nervous system response to autonomic challenges is altered in patients with a previous episode of Takotsubo cardiomyopathy. Eur Heart J Acute Cardiovasc Care. 2016;5(2):152-163.
- Lazzeroni D, Bini M, Castiglioni P, et al. Autonomic function in Takotsubo syndrome long after the acute phase. Int J Cardiol. 2017;231:222-224.
- May HT, Horne BD, Knight S, et al. The association of depression at any time to the risk of death following coronary artery disease diagnosis. Eur Heart J Qual Care Clin Outcomes. 2017;3(4):296-302.
- Liu H, Tian Y, Liu Y, Nigatu YT, Wang J. Relationship between major depressive disorder, generalized anxiety disorder and coronary artery disease in the US general population. J Psychosom Res. 2019;119:8-13.
- Williams MS, Ziegelstein RC, McCann UD, Gould NF, Ashvetiya T, Vaidya D. Platelet serotonin signaling in patients with cardiovascular disease and comorbid depression. Psychosom Med. 2019;81(4):352-362.
- Iasella CJ, Kreider MS, Huang L, Coons JC, Stevenson JM. Effect of selective serotonin reuptake inhibitors on cardiovascular outcomes after percutaneous coronary intervention: a retrospective cohort study. Clin Drug Investig. 2019 Jun;39(6):543-551.
- Wilkowska A, Rynkiewicz A, Wdowczyk J, Landowski J. Morning and afternoon serum cortisol level in patients with post-myocardial infarction depression. Cardiol J. 2019;26(5):550-554.
- Rahmani R, Rahimi L, Shafiee A. Effect of cardiac rehabilitation programme following elective percutaneous coronary angiography on depressive symptoms: A cohort study. Indian Heart J. 2018;70(6):783-787.
- Bremner JD, Campanella C, Khan Z, et al. Brain mechanisms of stress and depression in coronary artery disease. J Psychiatr Res. 2019;109:76-88.
- Bremner JD, Campanella C, Khan Z, et al. Brain correlates of mental stress-induced myocardial ischemia. Psychosom Med. 2018;80(6):515-525.
- Dimsdale JE. Psychological stress and cardiovascular disease. J Am Coll Cardiol. 2008; 51(13):1237-1246.
- Machado MO, Veronese N, Sanches M, et al. The association of depression and all-cause and cause-specific mortality: an umbrella review of systematic reviews and meta-analyses. BMC Med. 2018;16(1):112.
- Richards SH, Anderson L, Jenkinson CE, et al. Psychological interventions for coronary heart disease. Cochrane Database Syst Rev. 2017;4:CD002902.
- Marfella R, Barbieri M, Sardu C, et al. Effects of α-lipoic acid therapy on sympathetic heart innervation in patients with previous experience of transient takotsubo cardiomyopathy. J Cardiol. 2016;67(2):153-161.
- Skibska B, Goraca A. The protective effect of lipoic acid on selected cardiovascular diseases caused by age-related oxidative stress. Oxid Med Cell Longev. 2015;2015:313021.
- Salazar MR. Alpha lipoic acid: a novel treatment for depression. Med Hypotheses. 2000;55(6):510-512.