Sakurada K, Konta T, Watanabe M, et al. Associations of frequency of laughter with risk of all-cause mortality and cardiovascular disease incidence in a general population: findings from the Yamagata Study. J Epidemiol. 2020;30(4):188-193.
To determine whether associations exist between frequency of laughter and incidence of cardiovascular disease (CVD) and all-cause mortality.
Researchers analyzed the self-reported frequency of laughter by subjects who participated in annual health checkups for associations with all-cause mortality and CVD incidence using Kaplan-Meier and Cox proportional hazards modeling.
All subjects were part of the Yamagata Study, a large, community-based, prospective cohort that recruited subjects in 7 cities in the Yamagata Prefecture, Japan, starting in 2009. Participants were aged 40 years or more at study onset. There were no exclusion criteria. Over the following 6 years, 20,969 subjects enrolled. Adequate data allowed 17,152 (10,149 females) participants, with a mean age of 62.8 years and a median follow-up of 5.4 years, to be included in this analysis.
The study investigated associations between frequency of laughter and all-cause mortality and CVD incidence.
Researchers used a self-administered questionnaire to document subjects’ medical history, current medications, clinical symptoms, blood pressure, frequency of laughter, alcohol-drinking status, smoking status, physical activity, education level, marital status, level of perceived mental stress, and social participation.
They assessed frequency of laughter via the single question: “How often do you laugh out loud?” The question allowed for 4 possible answers: almost every day, 1–5 times/week, 1–3 times/month, and <1 time/month. The researchers grouped the responses into 3 categories (≥1/week; ≥1/month but <1/week; or <1/month) because the Kaplan-Meier curves for laughter almost every day and laughter 1–5 times/week were similar.
Researchers confirmed mortality through death certificates and incidence of CVD through official registries.
Low frequency of laughter was significantly associated with all-cause mortality and CVD incidence in an older Japanese population. In short, those who rarely laughed were more likely to die during the span of the study.
During the course of the study, 257 (1.5%) of the subjects died and 138 (0.8%) had CVD incidents. Kaplan-Meier analysis showed all-cause mortality to be significantly higher in subjects with a low frequency of laughter (log-rank test, P=0.003). A similar curve was observed for CVD incidence (log-rank test, P<0.001).
Cox proportional analysis showed similar independent associations between frequency of laughter and both all-cause death and CVD. In an unadjusted model, all-cause mortality was significantly higher among individuals who laughed <1/month (HR 2.38; 95% CI, 1.42–3.74) than in those who laughed ≥1/ week. After adjusting for age, gender, hypertension, diabetes, smoking status, and alcohol-drinking status, researchers found that the risk of all-cause mortality remained significantly higher in subjects who laughed <1/month than in subjects who laughed ≥1/week (HR 1.95; 95% CI, 1.16–3.09). Risk of CVD incidence was significantly higher in subjects who laughed ≥1/month but <1/week than in subjects who laughed ≥1/week (HR 2.06; 95% CI, 1.38–3.00) in the unadjusted model. After adjusting for the above-mentioned potential confounders, researchers found that CVD incidence was significantly higher in subjects who laughed ≥1/month and <1/week than in subjects who laughed ≥1/week (HR 1.62; 95% CI, 1.07–2.40).
We should pay attention to how often our patients laugh. Such knowledge can be a clue to their risk for both CVD and all-cause mortality. A simple intake-form question, such as the authors of this study used, appears to be adequate, but perhaps paying attention when sitting with patients will work even better. Do they laugh or not? Interestingly, the authors report no clear correlation between the participants’ stress level and how often the study participants laugh.
This is not the first study to report an inverse association between CVD incidence and laughter frequency. In 2016 Hayashi et al reported that among 20,394 individuals, higher frequency of laughter was associated with significantly lower risk of CVD and stroke incidence among older Japanese adults.1
The authors of this current study note that low frequency of laughter was more common in men, current drinkers, diabetics, those with low physical activity, and those who lived without a spouse. Other studies have reported similar associations.2 Low frequency of laughing may simply be an indicator of other risk factors for CVD, similar to how not using a seatbelt is predictive of other risky driving behaviors.3
Proving an association does not prove causation, and it is conceivable that those with comorbid disease and impending cardiovascular events might via some still unknown mechanism lose their sense of humor. Infrequent laughter might be a sign of disease rather than an etiology for disease. CVD is positively associated with depression, and so we might assume those suffering from CVD might find that fewer things trigger laughter.4 Assuming that this association is causative leads us to conclude that increasing laughter frequency will be protective against disease onset. This has yet to be proven. While it is easy for us to accept the idea that laughter could be used as prophylactic medicine, we do not have a controlled intervention trial to hold up as proof.
This current study is a step in the direction of proving that laughter may be therapeutic, in that it is a large, long-term, prospective cohort that looks at laughter frequency years prior to disease onset. This study also takes into account the other major known risk factors for CVD and analyzed them for effect to show that laughter frequency was an independent predictor.
An October 2020 paper by Li et al suggests that the relationship between cardiac morbidity and depression is genetic in nature, a bidirectional expression of phenotypes. Knowing that depression and CVD are associated with each other, Li’s team determined that the genetic predisposition to depression was causally linked to CVD, myocardial infarction (MI), stroke, and atrial fibrillation (AF); they determined this by analyzing data from the largest genome-wide association studies (GWAS) and correlating 2 depression phenotypes with CVD. They report that depression phenotypes are genetically correlated with MI and AF. While the connection was there, the effect did not seem large. Doubling the risk of depression genetically increased risk of cardiac arterial disease (CAD) by about 10% (OR=1.099; 95% CI, 1.031–1.170; P=0.004) and MI by 15% (OR=1.146; 95% CI, 1.070–1.228; P=1.05 × 10−4).
While it is easy for us to accept the idea that laughter could be used as prophylactic medicine, we do not have a controlled intervention trial to hold up as proof.
In other words, those prone to depression are genetically slightly more prone to have heart disease.5 Infrequent laughing might simply be a signal that alerts us to the presence of this genetic phenotype, a sign that risk for both depression and cardiac disease could coexist in a patient. It might not be a cause or a solution. On the other hand, this information might also argue that increasing frequency of laughter could be a way to change phenotypical expression.
Angelman syndrome, a rare neurologic condition characterized by paroxysmal laughter and ataxic jerking movements, is now understood to be genetic in origin.6 (As a side note, recent trials using betaine and folic acid to treat this syndrome have so far failed to show benefit.7) Our tendency or susceptibility toward laughter is clearly controlled to some degree by genetics.
Laughter also clearly affects genetic expression. Takashi Hayashi and Kazuo Murakami reported in 2009 that laughter improved blood sugar levels in diabetic patients through changing genetic expression. Their research identified specific genes that changed in response to laughter and also “revealed that laughter decreased the levels of prorenin in blood; prorenin is involved in the onset of diabetic complications.”8,9 In particular, “prorenin and the (pro)renin receptor play a pivotal role in the pathophysiology of diabetic nephropathy.”10 Could prorenin, which may help regulate the angiotensin pathway, affect cardiac disease risk? This is hypothetical, and just 1 of many plausible connections between laughter and the cardiovascular system.
Results from research by Claudia Haase and colleagues published in 2013 suggest that the short allele of 5HTTLPR polymorphism in the serotonin transporter gene has a significant impact on emotional expression, increasing the likelihood a person will laugh out loud.11 Short 5HTTLPR alleles also appear to increase the influence environmental cues have on emotional development and on behavior.12 This gene is associated with post-stroke depression13,14 and depression associated with coronary artery disease.15 These relationships between depression and heart disease appear to be bidirectional.16
A February 2020 study by Ikeda et al correlated laughter frequency with blood pressure; it was conducted in Japan and reported that men who laughed infrequently (1–3 times per month) had significantly higher systolic and diastolic blood pressure than those who laughed more often. In women, blood pressure did not vary with laughter frequency. Of note, though, is that in this study, only 13% of the male participants (72/554) fell into this infrequent laughter category.17
The other peculiar thing reported in the Sakurada results is that the associations between laughter, CVD, and mortality were only significant in women. When data from men and women were combined, the associations were all significant, but when data from men were separated out, the association disappeared. This stands in contrast to the Ikeda results related to blood pressure, where laughter improved blood pressure in men but not women.
While the authors of the current study write that their “findings suggest that increasing the frequency of laughter might reduce the risk of cardiovascular disease and increase longevity,” it may be premature to call this evidence-based medicine. We hope that this proves to be true, but until a prospective intervention study confirms that making people laugh lowers their risk of becoming heart-disease patients, uncertainty remains. At the same time, the suggested or implied intervention of increasing frequency of laughing out loud certainly seems safe enough that we should ask, why not encourage it? Our patients certainly engage in other activities and make choices in their lives that are based on far weaker evidence, believing that doing so will promote better health.
- Hayashi K, Kawachi I, Ohira T, Kondo K, Shirai K, Kondo N. Laughter is the best medicine? A cross-sectional study of cardiovascular disease among older Japanese adults. J Epidemiol. 2016;26(10):546-552.
- Imai Y, Nagai M, Ohira T, Shirai K, Kondo N, Kondo K. Impact of social relationships on income-laughter relationships among older people: the JAGES cross-sectional study. BMJ Open. 2018;8(7):e019104.
- Kizer KW, Trent RB. Safety belts and public health. The role of medical practitioners. West J Med. 1991;154(3):303-306.
- Hare DL, Toukhsati SR, Johansson P, Jaarsma T. Depression and cardiovascular disease: a clinical review. Eur Heart J. 2014;35(21):1365-1372.
- Li GH, Cheung CL, Chung AK, et al. Evaluation of bi-directional causal association between depression and cardiovascular diseases: a Mendelian randomization study. Psychol Med. Published online October 9, 2020:1-12.
- Bonello D, Camilleri F, Calleja-Agius J. Angelman syndrome: identification and management. Neonatal Netw. 2017;36(3):142-151.
- Han J, Bichell TJ, Golden S, et al. A placebo-controlled trial of folic acid and betaine in identical twins with Angelman syndrome. Orphanet J Rare Dis. 2019;14(1):232.
- Hayashi T, Murakami K. The effects of laughter on post-prandial glucose levels and gene expression in type 2 diabetic patients. Life Sci. 2009;85(5-6):185-187.
- Hayashi T, Urayama O, Hori M, et al. Laughter modulates prorenin receptor gene expression in patients with type 2 diabetes. J Psychosom Res. 2007;62(6):703-706.
- Ichihara A, Sakoda M, Mito-Kurauchi A, Itoh H. Activated prorenin as a therapeutic target for diabetic nephropathy. Diabetes Res Clin Pract. 2008;82 Suppl 1:S63-S66.
- Haase CM, Saslow LR, Bloch L, et al. The 5-HTTLPR polymorphism in the serotonin transporter gene moderates the association between emotional behavior and changes in marital satisfaction over time. Emotion. 2013;13(6):1068-1079.
- Sawano E, Doi H, Nagai T, Ikeda S, Shinohara K. Interactive effects of 5-HTTLPR genotype and rearing environment on affective attitude towards own infant in Japanese mothers. Behav Brain Res. 2017;325(Pt B):173-180.
- Guo WY, Zhang ZH, Mu JL, et al. Relationship between 5-HTTLPR polymorphism and post-stroke depression. Genet Mol Res. 2016;15(1).
- Mak KK, Kong WY, Mak A, Sharma VK, Ho RC. Polymorphisms of the serotonin transporter gene and post-stroke depression: a meta-analysis. J Neurol Neurosurg Psychiatry. 2013;84(3):322-328.
- Golimbet VE, Volel’ BA, Dolzhikov AV, Isaeva MI. [The role of the 5-HTTLPR polymorphism of the serotonin transporter gene in the development of depression in patients with coronary heart disease.] [Article in Russian.] Zh Nevrol Psikhiatr Im S S Korsakova. 2012;112(8):63-69. Russian.
- Wium-Andersen MK, Wium-Andersen IK, Prescott EIB, Overvad K, Jørgensen MB, Osler M. An attempt to explain the bidirectional association between ischaemic heart disease, stroke and depression: a cohort and meta-analytic approach. Br J Psychiatry. 2020;217(2):434-441.
- Ikeda S, Ikeda A, Yamagishi K, et al. Longitudinal trends in blood pressure associated with the frequency of laughter: longitudinal study of Japanese general population: the Circulatory Risk in Communities Study (CIRCS). J Epidemiol. Published online February 22, 2020. doi: 10.2188/jea.JE20190140.