Global obesity rates have nearly tripled since 1975. This obesity rate increase is mirrored by increases in atrial fibrillation (AF) that now impacts nearly 10% of Americans over the age of 65. Numerous epidemiologic studies have linked incidence of AF and obesity and other obesity-related diseases, including hypertension and diabetes. Due to the wealth of epidemiologic data linking AF with obesity-related disease, mechanisms of AF pathogenesis in the context of obesity are an area of ongoing investigation. However, progress has been somewhat slowed by the complex phenotype of obesity; separating the effects of obesity from those of related sequelae is problematic. While the initiation of pathogenic pathways leading to AF varies with disease (including increased glycosylation in diabetes, increased renin angiotensin aldosterone system activation in hypertension, atrial ischemia in coronary artery disease, and sleep apnea) the pathogenesis of AF is united by shared mediators of altered conduction in the atria. We suggest focusing on these downstream mediators of AF in obesity is likely to yield more broadly applicable data. In the context of obesity, AF is driven by the interrelated processes of inflammation, atrial remodeling, and oxidative stress. Obesity is characterized by a constant low-grade inflammation that leads to increased expression of pro-inflammatory cytokines. These cytokines contribute to changes in cardiomyocyte excitability. Atrial structural remodeling, including fibrosis, enlargement, and fatty infiltration is a prominent feature of AF and contributes to the altered conduction. Finally, obesity impacts oxidative stress. Within the cardiomyocyte, oxidative stress is increased through both increased production of reactive oxygen species and by downregulation of scavenging enzymes. This increased oxidative stress modulates of cardiomyocyte excitability, increasing susceptibility to AF. Although the initiating insults vary, inflammation, atrial remodeling, and oxidative stress are conserved mechanisms in the pathophysiology of AF in the obese patients. In this review, we highlight mechanisms that have been shown to be relevant in the pathogenesis of AF across obesity-related disease.

Calcium-dependent cardiac muscle contraction is regulated by the protein complex troponin. Calcium binds to the N-terminal domain of troponin C (cNTnC) which initiates the process of contraction. Heart failure is a consequence of a disruption of this process. With the prevalence of this condition, a strong need exists to find novel compounds to increase the calcium sensitivity of cNTnC. Desirable are small chemical molecules that bind to the interface between cTnC and the cTnI switch peptide and exhibit calcium sensitizing properties by possibly stabilizing cTnC in an open conformation. To identify novel drug candidates, we employed a structure-based drug discovery protocol that incorporated the use of a relaxed complex scheme (RCS). In preparation for the virtual screening, cNTnC conformations were identified based on their ability to correctly predict known cNTnC binders using a receiver operating characteristics analysis. Following a virtual screen of the National Cancer Institute's Developmental Therapeutic Program database, a small number of molecules were experimentally tested using stopped-flow kinetics and steady-state fluorescence titrations. We identified two novel compounds, 3-(4-methoxyphenyl)-6,7-chromanediol (NSC600285) and 3-(4-methylphenyl)-7,8-chromanediol (NSC611817), that show increased calcium sensitivity of cTnC in the presence of the regulatory domain of cTnI. The effects of NSC600285 and NSC611817 on the calcium dissociation rate was stronger than that of the known calcium sensitizer bepridil. Thus, we identified a 3-phenylchromane group as a possible key pharmacophore in the sensitization of cardiac muscle contraction. Building on this finding is of interest to researchers working on development of drugs for calcium sensitization.

Despite extensive efforts spanning multiple decades, the development of highly effective Ca2+ sensitizers for the heart remains an elusive goal. Existing Ca2+ sensitizers have other targets in addition to cardiac troponin (cTn), which can lead to adverse side effects, such as hypotension or arrhythmias. Thus, there is a need to design Ca2+-sensitizing drugs with higher affinity and selectivity for cTn. Previously, we determined that many compounds based on diphenylamine (DPA) were able to bind to a cTnC–cTnI chimera with moderate affinity (Kd ∼10–120 µM). Of these compounds, 3-chlorodiphenylamine (3-Cl-DPA) bound most tightly (Kd of 10 µM). Here, we investigate 3-Cl-DPA further and find that it increases the Ca2+ sensitivity of force development in skinned cardiac muscle. Using NMR, we show that, like the known Ca2+ sensitizers, trifluoperazine (TFP) and bepridil, 3-Cl-DPA is able to bind to the isolated N-terminal domain (N-domain) of cTnC (Kd of 6 µM). However, while the bulky molecules of TFP and bepridil stabilize the open state of the N-domain of cTnC, the small and flexible 3-Cl-DPA molecule is able to bind without stabilizing this open state. Thus, unlike TFP, which drastically slows the rate of Ca2+ dissociation from the N-domain of isolated cTnC in a dose-dependent manner, 3-Cl-DPA has no effect on the rate of Ca2+ dissociation. On the other hand, the affinity of 3-Cl-DPA for a cTnC–TnI chimera is at least an order of magnitude higher than that of TFP or bepridil, likely because 3-Cl-DPA is less disruptive of cTnI binding to cTnC. Therefore, 3-Cl-DPA has a bigger effect on the rate of Ca2+ dissociation from the entire cTn complex than TFP and bepridil. Our data suggest that 3-Cl-DPA activates the cTn complex via a unique mechanism and could be a suitable scaffold for the development of novel treatments for systolic heart failure.

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