In this two-sample MR study, we found that genetically predicted dark chocolate intake was associated with a lower risk of EH, but not with HF, CHD, MI, AF, non-rheumatic valvular heart disease, non-ischemic cardiomyopathy, DVT of the lower extremities, stroke, ischemic stroke, and TIA. Limited evidence supports a suggested inverse association between dark chocolate intake and the risk of VTE, but the analysis results show mild horizontal pleiotropy.
Dark chocolate is rich in substances such as flavanols, methylxanthines, and caffeine, among which flavanols are the main reason for the beneficial effects of dark chocolate on the cardiovascular system. Studies have shown that flavanols can activate the NO synthase in endothelial cells, leading to the release of NO, which then activates the guanylate cyclase in smooth muscle cells, increasing the levels of cyclic guanosine monophosphate, and subsequently causing a decrease in intracellular calcium ion concentration, resulting in vasodilation 40. A RCT involving 45 participants showed that acute ingestion of dark chocolate compared to placebo can improve endothelial function (measured as flow-mediated dilation) 41. In another RCT involving 22 heart transplant recipients, intake of dark chocolate significantly increased coronary artery diameter and endothelium-dependent coronary vasodilate on 6. Previous studies have shown that flavanols has physiological effects similar to aspirin in inhibiting cyclooxygenase 42. Additionally, flavanols can inhibit platelet aggregation by promoting the release of NO 40. Two small-sample RCTs indicate that dark chocolate can significantly reduce shear stress-dependent platelet adhesion and platelet aggregation 6,7. In addition, flavanols can regulate the production of pro-inflammatory cytokines. The NO released by flavanols can also inhibit the recruitment of white blood cells and the aggregation of platelets to the site of inflammation, thereby exerting local anti-inflammatory activity 43, which is particularly important for delaying the development of atherosclerosis. Previous studies have found that inflammation is an important risk factor for CVDs, especially atherosclerosis-related diseases 44,45. Regarding the lipid-lowering effects of dark chocolate, meta-analyses have shown that consumption of dark chocolate and cocoa products can lower levels of low-density lipoprotein cholesterol and total cholesterol, while increasing high-density lipoprotein cholesterol levels 8,46. However, in this MR study, we did not find any evidence for the reduction of the risk of 11 outcomes excluding EH, which is not contradictory to previous findings. Based on the evidence from intervention studies mentioned above, dark chocolate indeed provides some cardiovascular benefits. However, the pathophysiological mechanisms underlying the development and progression of CVDs are highly complex, and these studies only revealed individual risk factors and certain aspects of the pathogenesis of CVDs affected by dark chocolate intake. It cannot be concluded that dark chocolate intake reduces the risk of CVDs. The cardiovascular benefits of dark chocolate intake may not be sufficient to reduce the risk of these diseases. Moreover, most of these small-sample controlled trials have some limitations, which lead to a low level of reliability of their conclusions.
The research results on the relationship between dark chocolate and blood pressure were controversial 10 years ago 47. A recent meta-analysis involving 31 studies showed that consuming cocoa beverages or chocolate for more than 2 weeks was associated with a reduction in systolic and diastolic blood pressure. However, the overall effect size of blood pressure reduction was too small to be clinically significant 48. A cross-sectional study involving 14,310 Jordanian adults also showed that dark chocolate intake has a significant beneficial effect on the blood pressure of healthy adults 49. The mechanism of blood pressure reduction by dark chocolate may be related to the increase of NO 40, and there is also evidence that flavanols have an inhibitory effect on angiotensin-converting enzyme activity in vitro 50. In this study, we have established a clear association between dark chocolate intake and a reduced risk of EH, which is consistent with most previous research. However, it is important to note that lowering blood pressure does not necessarily equate to reducing the risk of EH, as many risk factors for hypertension may lead to physiological and histological changes in the body that cannot be reversed by simply lowering blood pressure.
In this MR study, we used data on EH from the FinnGen consortium, rather than data on hypertension in general. As the sample of hypertension data includes cases of secondary hypertension, which is essentially the manifestation of kidney disease, renal vascular disease, and some endocrine diseases (such as pheochromocytoma, Cushing's syndrome, and aldosteronism) in the cardiovascular system, our study does not investigate the causality between dark chocolate intake and these diseases. In addition, some methodological researchers of MR oppose interpreting causal effect estimates as expected effects of intervening on the exposure factor in a clinical setting, and even recommend against making causal effect estimates 51. Therefore, we do not recommend that everyone prevent EH by consuming dark chocolate, but rather suggest that individuals at risk for EH can replace their usual unhealthy snacks with dark chocolate.
This study has several significant strengths. First, there have been no MR studies or clinical studies analyzing the causality between dark chocolate intake and the risk of CVDs in the past. Second, this MR analysis utilized the latest exposure and outcome GWAS summary-level data, comprehensively analyzed the causality between dark chocolate intake and multiple CVDs, maximally avoided the influence of confounders and reverse causation, and used multiple sensitivity analysis methods to verify the causality. Third, MR studies reveal the total effect, which in this study refers to the overall impact of all components (including potentially harmful sugar and fat for health) in dark chocolate on CVDs. However, many controlled trials use placebos with similar components to dark chocolate, some of which only differ in their flavanols content 48, which to some extent reduces the credibility of previous research conclusions.
This study also has several limitations. First, the sample size of the exposure data is not large enough, and the screened SNPs did not reach the traditional genome-wide significance threshold (P < 5×10− 8). But all of the IVs have an F-statistic greater than 10, indicating that these SNPs can be considered as effective IVs. The results of sensitivity analysis also demonstrate the robustness of the estimated causal effect. Second, a considerable number of SNPs were lost in the summary-level data for HF and stroke, which may have some impact on the analysis results. Third, the sample populations in the summary-level data for the exposure and outcome are of European ancestry, which makes it difficult to generalize the study results to other populations. Fourth, the summary-level data we used did not stratify for certain factors, which only allowed for general analysis and could not investigate the relationship between the risk of CVDs and age and gender of the population, as well as the amount of dark chocolate intake.