Introduction

There is a deep relationship between cardiovascular disease and periodontitis; however, the detailed mechanisms between myocardial hypertrophy and periodontitis have not yet been elucidated.1 Recently, we demonstrated that periodontal bacteria infection accelerated myocardial hypertrophy.2, 3, 4 Chronic inflammation induced by periodontitis may have a key role in the development of myocardial hypertrophy. In this article, we review the pathophysiological mechanism between myocardial hypertrophy and periodontitis.

Myocardial hypertrophy and chronic inflammation

Among the various cardiovascular diseases, myocardial hypertrophy is the most common manifestation because hypertension and other systemic diseases induce the condition.5 It is recognized that chronic inflammation induced by infection could be a cause of myocardial hypertrophy. HIV infection is the most well-known pathogenesis of myocardial hypertrophy. Kearney et al.6 revealed that more than half of the children with HIV infection had myocardial hypertrophy. This was proved by echocardiogram and postmortem cardiac pathology. Similarly, Georgescu et al.7 showed that 25.6% of child patients with HIV infection had left ventricular (LV) myocardial hypertrophy judged by echocardiogram. Breuckmann et al.8 also revealed that a quarter of patients with HIV infection had myocardial hypertrophy. This evaluation was performed by MRI. At this moment, there is no clinical report to show the direct relationship between myocardial hypertrophy and chronic inflammation induced by bacterial infection. However, Kita et al.9 showed that Escherichia coli endotoxin enhanced myocardial hypertrophy in rats with chronic alcohol consumption. Thus, chronic inflammation induced by bacterial infection may be a cause of myocardial hypertrophy. Persistent inflammation has a pathogenic role in chronic heart failure by influencing heart contractility, inducing hypertrophy and promoting apoptosis, which contributes to myocardial remodeling.10, 11 It was also reported that the heart failure with preserved ejection fraction paradigm shifted from LV afterload excess to coronary microvascular inflammation. The new paradigm consists of a systemic proinflammatory state that causes coronary microvascular endothelial inflammation that reduces nitric oxide bioavailability, cyclic guanosine monophosphate content and protein kinase G (PKG). Low PKG activity enhances myocardial hypertrophy development because of hypophosphorylation of titin.12 Biwer et al.13 showed the temporal response to nitric oxide synthase (NOS) and renin-angiotensin system inhibition with respect to cardiac hypertrophy in rats. They demonstrated that L-NAME with enalapril accelerated a significant increase in cardiac mass in the spontaneously hypertensive rat (SHR). Thus, NOS and renin-angiotensin system also has critical roles in cardiac hypertrophy. Nakashima et al.14 showed that reactive oxygen species are critical in angiotensin II-induced vascular remodeling. Taken together, several factors are involved in pressure overload-induced cardiovascular remodeling.

Periodontitis is a major cause of chronic inflammation

Many researchers have studied the relationship between periodontitis and systemic diseases, because periodontitis is a major cause of systemic and chronic inflammation.15, 16 Because a relationship between periodontal disease and cardiovascular disease has been broadly recognized,17 we investigated the pathophysiological relationship between periodontitis and cardiovascular disease.18, 19 Periodontitis is an infectious disease induced by many species of periodontal bacteria, such as Porphyromonas gingivalis (P.g.), Aggregatibacter actinomycetemcomitans (A.a.) and Prevotella intermedia.20 It was reported that each periodontal pathogen influenced the progression of abdominal aortic aneurysm.21, 22, 23 We also reported that P.g. accelerated the progression of abdominal aortic aneurysm through Toll-like receptors (TLRs) and matrix metalloproteinases (MMPs) using experimental murine models.24, 25, 26 On the other hand, there are limited clinical and experimental reports revealing the relationship between periodontitis and myocardial hypertrophy at this point. Moreover, the clinical influence of specific periodontal bacterium on myocardial hypertrophy has not been clarified epidemiologically.

Myocardial hypertrophy may be affected by periodontitis in clinical settings

Clinical observations revealed a relationship between myocardial hypertrophy and periodontitis. The Hisayama study showed that mean probing depth, mean attachment loss, number of teeth and plaque index were associated with LV hypertrophy. In multivariate analysis, the subjects with deep pocket depth had an increased risk of LV hypertrophy compared with the subjects without deep pocket depth. Subjects with severe attachment loss also had significant risk of LV hypertrophy. Although this observation clearly showed the relationship between LV hypertrophy and periodontitis, it has a study limitation because they only judged LV hypertrophy using electrocardiogram (ECG).27 Angeli et al.28 showed a clinical association between periodontitis and LV mass in subjects with essential hypertension. LV mass progression was dependent on the severity of periodontitis. Body surface area, systolic and diastolic blood pressure, and LV mass were determinants of a composite of severe periodontitis. In a multivariate logistic analysis, LV mass was the only determinant of severe periodontitis. Their findings suggested a direct association between the severity of periodontitis and increased LV mass in subjects with essential hypertension. Although they measured LV mass using echocardiogram, this paper has a study limitation in the diagnosis of periodontitis. They evaluated periodontitis using only the community periodontal index of treatment needs (CPITN). CPITN is a convenient methodology to diagnose the severity of periodontits, for example, CPITN 0 (periodontal health), CPITN 1 (gingival bleeding), CPITN 2 (calculus), CPITN 3 (pockets 4–5 mm) and CPITN 4 (pockets ⩾6 mm), it lacks other periodontal information such as attachment loss, number of teeth, and plaque index.28 Franek et al.29 also demonstrated an association between chronic periodontitis and increased LV mass in subjects with Type 2 diabetes mellitus. They clarified that subjects with periodontitis had larger LV mass compared with non-periodontitis subjects. They concluded that periodontitis was associated with increased LV mass and elevated central and systemic blood pressure in subjects with Type 2 diabetes. This study clearly demonstrated the relationship between precisely measured LV mass and periodontitis. However, periodontitis was judged as three biofilm-gingival interface groups; healthy, gingivitis and periodontitis using semi-quantitative methods. Thus, lacking enough information of periodontitis and patients enrollment only from Type 2 diabetes are the study limitation of this paper.29 Although these clinical observations had some study limitations, they strongly suggest a direct association between severity of periodontitis and LV hypertrophy. (Table 1)

Table 1 Clinical observations which revealed a relationship between myocardial hypertrophy and periodontitis
Full size table

Specific periodontal pathogens deteriorate load-induced myocardial hypertrophy

We demonstrated that some specific periodontal pathogens accelerated myocardial hypertrophy. First, we showed that a major periodontal pathogen deteriorated pressure overload-induced myocardial hypertrophy in mice. To establish myocardial hypertrophy in an animal model, transverse aortic constriction (TAC) was performed in mice. We injected a periodontal pathogen, A.a. in the infected group and phosphate buffered saline (PBS) in the control group. We showed that heart per body weight ratio increased in the A.a. infected group compared with the control group. Histopathologically, A.a.-infected mice showed markedly enhanced cardiac hypertrophy, fibrosis and arteriosclerosis 4 weeks after TAC operation. Immunohistochemistry revealed that expression of MMP-2 in the interstitial tissue was enhanced in the A.a.-infected group.2 Pressure overload-induced myocardial hypertrophy is known to be caused by changes in cardiac myocytes and abnormalities in the extracellular matrix network. Progressive LV remodeling and extracellular matrix degradation is associated with increased MMP activity. It is also well recognized that periodontal pathogens increase the activity of MMPs. The activation of MMP-2 was also induced by the lipopolysaccharides of A.a.30 MMP-2 is involved in physiological tissue remodeling and pathological extracellular matrix degradation in the pathogenesis of periodontal diseases.31 Thus, our results suggest that a periodontal pathogen causes a deterioration of pressure overload-induced myocardial hypertrophy through MMP-2 activation. We also evaluated the effect of another periodontal pathogen, P.g. on TAC-induced myocardial hypertrophy. Interestingly, P.g. worsened area of myocardial fibrosis, while the degree of hypertrophy was comparable between the P.g.-infected group and the control group.3 At this moment, the reason why the different pathogens showed different results is to be clarified. It is known that A.a. secretes leukotoxin, which affects polymorphonuclear leukocytes, lymphocytes and macrophages via TLR2 and TLR4. If these cells are activated, proinflammatory cytokines are produced, and it results in enhanced inflammation. On the other hand, P.g. secretes gingipine which works to degrade cytokines, thereby downregulating the host response in the form of reduced inflammation through TLR2 signaling.32, 33, 34, 35 Therefore, the effect of periodontal pathogens is varied on the progression of myocardial hypertrophy induced by pressure overload.

A periodontal pathogen accelerates isoproterenol-induced myocardial hypertrophy

Next, we observed the effect of a periodontal pathogen on catecholamine induced myocardial hypertrophy. To make the model, we subcutaneously implanted a coil-shaped chamber into the back of a mouse and P.g. was injected into the chamber. Following this, an osmotic pump was implanted to infuse isoproterenol systemically. Four weeks after the isoproterenol infusion, we performed an echocardiography and harvested the hearts and blood. Microscopically, we found stronger cardiomyocyte hypertrophy in P.g.-infected mice compared with the control mice. We also detected a higher level of mRNA expression in TLR2 and NADPH oxidase 4 (Nox4) in P.g.-infected mice compared with the control mice.4 It is well known that P.g. enhanced the expression of TLR2 in various kinds of cells. Because we detected a higher expression of TLR2 in P.g.-injected mice, it implied that P.g. enhanced the expression of TLR2 in the hearts. Regarding cardiac hypertrophy, a study using the TAC model reported that the hypertrophy was suppressed in TLR2-deficient mice.36 These results and our observation suggest that TLR2 may have a critical role in cardiomyocyte hypertrophy induced by periodontal pathogens. It was also reported that P.g. enhanced the expression of Nox4 in some cells. Nox4 is known to have an important role in cardiomyocyte hypertrophy. Upregulation of Nox4 in the myocardium causes cardiac remodeling through the activation of Akt-mTOR and NF-κB signaling pathways.37 Therefore, P.g. infection enhances Nox4, resulting in cardiomyocyte hypertrophy. These results suggest that a periodontal pathogen effects isoproterenol-induced cardiac hypertrophy via oxidative stress.

Possible pathophysiological mechanisms between periodontitis and myocardial hypertrophy

The systemic inflammatory state induced by periodontal pathogens affects the human coronary endothelium.38, 39 Proinflammatory cytokines (for example, interleukin-6, tumor necrosis factor-alpha) induce vascular cell adhesion molecule-1 and E-selectin expression on the endothelium.40 Their expression leads to activation and subendothelial migration of circulating leukocytes.41 These cytokines also induce endothelial production of reactive oxygen species through activation of nicotinamide adenine dinucleotide phosphate oxidases.42 Production of reactive oxygen species leads to formation of peroxynitrite (ONOO-) and reduced nitric oxide (NO) bioavailability, both suppress soluble guanylate cyclase activity in adjacent cardiomyocytes. NO is also known to contribute to pathological effects of periodontitis in the heart.43 Lower soluble guanylate cyclase activity decreases cyclic guanosine monophosphate concentration and PKG activity. Low PKG activity increases resting tension of cardiomyocytes because of hypophosphorylation of titin and removes the brake on prohypertrophic stimuli, inducing cardiomyocyte hypertrophy.12 The PKG function as a brake on myocardial hypertrophy has been observed in a wide variety of experimental and clinical settings. In cardiomyocytes cultured from neonatal rat hearts, NO or a cyclic guanosine monophosphate analog attenuated the norepinephrine-induced hypertrophic response.44 Ruiz-Hurtado et al.45 showed that LA-419, which protected NO from degradation, has been found to restore the complete NO signaling cascade and reduce LV remodeling in a model of aortic stenosis-induced pressure overload. Because LA-419 did not restore the original pressure gradient, the increasing NO bioavailability has a possible direct anti-proliferative effect on cardiac myocytes. In mice subjected to TAC, sildenafil, which increases myocardial PKG activity through inhibited breakdown of cyclic guanosine monophosphate by phosphodiesterase 5 (PDE5), prevented or reversed cardiomyocyte hypertrophy by deactivating multiple prohypertrophic pathways.46 In patients with diabetic cardiomyopathy and concentric LV remodeling, sildenafil treatment reduced the LV mass/volume ratio.47 In line with these experimental and clinical findings, lower myocardial PKG activity was shown to correlate with a larger cardiomyocyte diameter. A similar relationship between myocardial PKG activity and cardiomyocyte hypertrophy was also present in aortic stenosis patients who had less myocardial PKG activity and more cardiomyocyte hypertrophy.48 We demonstrated the hypothetical idea with representative factors which have a relationship between periodontal pathogen-induced chronic inflammation and cardiomyocyte hypertrophy (Figure 1).

Figure 1
figure 1

Possible mechanisms between periodontitis and myocardial hypertrophy. cGMP, cyclic guanosine monophosphate; IL, interleukin; MMPs, matrix metalloproteinases; NF-κB, nuclear factor-kappa B; NO, nitric oxide; Nox, nicotinamide adenine dinucleotide phosphate oxidase; ONOO, peroxynitrite; PKG, protein kinase G; ROS, reactive oxygen species; sGC, soluble guanylate cyclase; TNF, tumor necrosis factor; TLRs, Toll-like receptors; VCAMs, vascular cell adhesion molecules.

Full size image

In conculsion, periodontitis contributes to a systemic inflammatory state, which induces oxidative stress in the coronary microvascular endothelium. This reduces myocardial NO bioavailability and leads to reduced PKG activity in cardiomyocytes, which enhances myocardial hypertrophy. The new paradigm between periodontitis and myocardial hypertrophy has important diagnostic and therapeutic implications.