Congestive heart failure is a progressive disease that causes ischemia and congestion in peripheral tissues and may result in function loss in many organs such as the kidney, liver, stomach and intestine. Nausea and lack of appetite may also occur as blood is shifted from the GI tract to the more vital organs. Susceptibility of the pancreas to ischemic injury in shock, malignant hypertension and after cardiac surgery is well known[22-25]. The splanchnic circulation normally receives ap-proximately 20%-30% of the cardiac output[26,27]. In patients with CHF, the splanchnic circulation is decreased, and if this state is prolonged, tissue damage to the splanchnic organs is possible, especially in pancreas that are highly vascularized organs[22,28].
Pancreatic exocrine insufficiency in patients with heart failure
Appetite loss and malnutrition are well known and highly prevalent in patients with CHF and an important risk factor for morbidity and mortality[29,30]. PEI refers to an insufficient secretion of pancreatic enzymes (acinar function) and/or sodium bicarbonate (ductal function), mostly associated with various pancreatic illnesses but could be associated even with extra pancreatic diseases.
Earlier, we performed a prospective study on 87 patients with CHF, using fecal elastase-1 (FE-1) as a diagnostic tool for diagnosis of PEI. The mean time from the confirmation of chronic heart failure to inclusion in the study was 4 years and PEI was diagnosed in 6.9% of patients suggesting a possibility that PEI occurred because of decreased splanchnic circulation in CHF patients. Additionally, the clinical significance of PEI was assessed in this study by using a complete laboratory serum nutritional panel showing decreased levels in one or more nutritional serum markers (vitamin D, selenium, phosphorus, zinc, folic acid, and prealbumin) in all of the patients tested with PEI.
Özcan et al investigated FE-1 levels (as an indicator of pancreatic exocrine function) and blood ghrelin levels (which affect eating, sleeping, cell proliferation, the cardiovascular system, and carbohydrate energy metabolism in patients with CHF as well as the pancreatic exocrine function) in 52 patients with acute decompensated heart failure and compared them with 31 healthy patients in the control group. The authors reported significant difference in FE-1 levels between the control and NYHA I/II patients vs NYHA III/IV group. In patients with advanced heart failure, ten patients (50%) had severe, and four patients (20%) moderate PEI, whereas two- thirds of the controls and patients with mild heart failure had normal pancreatic function. However, there was no statistically significant difference for ghrelin levels.
Xia et al attempted to detect the association between PEI (measured by FE-1 levels) and CHF-induced appetite, which was tested by the simplified nutritional appetite questionnaire. PEI was diagnosed in 56.7% of 104 patients with CHF and in none within the control group (n = 20) of patients with normal heart function. In the very important second part of this study, patients with CHF and PEI were treated with pancreatic enzyme replacement therapy (PERT) in the form of pancreatin (30000 units per day) and compared with the CHF and PEI patients treated with a placebo. After a 4-wk treatment, pancreatin significantly improved the appetite loss in the treatment group, indicating that PERT can attenuate the appetite loss in CHF and give the strongest evidence so far in the association of PEI with appetite loss in patients with CHF.
Cardiovascular risk in patients with CP
The association between CP and CVD has received little attention in the past. In 1975, Tuzhilin et al reported a study on cardiovascular lesions in 98 patients with CP and 32 control subjects, analyzing serum amylase, trypsin, trypsin inhibitor, elastase, plasma recalcification time, plasma heparin tolerance, blood fibrinogen level, fibrinolysis activity and capillary permeability to protein and water. They observed a marked correlation between the clinical symptoms in CP and chronic coronary insufficiency, probably because of pancreatic enzymes and their inhibitors that profoundly affected blood coagulability and appear to influence the course of pancreatic inflammation.
In 1982, Gullo et al prospectively investigated 54 consecutive CP patients and 54 control subjects for the presence of cardiovascular lesions. Clinical and laboratory evidence of arterial involvement was found in 18 patients (33%) and in 5 controls (9%) (P < 0.01), concluding that patients with CP have more frequent cardiovascular lesions that tend to develop at an earlier age, compared to the general population (there were no differences between the two groups for major risk factors like arterial hypertension, smoking habits, or blood lipid abnormalities).
Lee et al recently performed an interesting retrospective observational study on 32 patients with alcohol related CP and type 3 c diabetes mellitus (diabetes secondary to pancreatic disease) in whom panoramic (dental) images were taken and compared to a historical cohort of healthy patients. The prevalence rate of calcified carotid artery plaques (25%) was significantly higher than the rate (3%) in the control group.
Although DM is common in CP and is a well-known risk factor for arteriosclerosis, the link between CP and CVD seems to depend on other mechanisms. Chronic inflammation has been found to be associated with accelerated atherosclerosis and increased risk of CVDs. The pancreatic changes at an advanced age are considered to be related to atherosclerosis (of small vessels). This concept of “senile pancreatitis” was first described by Ammann et al and in most cases has a silent and mild course.
In a prospective, longitudinal cohort study, Spanish colleagues evaluated the risk of cardiovascular events and the impact of PEI in a cohort of 430 CP patients with the mean follow-up of 8.6 years. The study demonstrated, for the first time, that PEI is an independent risk factor significantly associated with an increased risk of cardiovascular events.
Hsu et al conducted a nationwide retrospective cohort study in Taiwan to determine the risk of acute coronary syndrome (ACS) in patients with CP. In total, 17405 patients with CP and 69620 individuals without CP were followed for 84430 and 417426 person-years showing that overall ACS incidence was 2.15-fold higher in the CP cohort than in the non-CP cohort. Interestingly, the highest risk of ACS was observed in patients aged ≤ 39 years. Here the increased risk was thought to be caused by inflammation leading to endothelial dysfunction and progress of unstable plaque. In the similarly conducted retrospective population-based cohort study from Taiwan, Wong et al reported association of CP with increased risk of subsequent cerebrovascular disease. The overall incidence of cerebrovascular disease among 16672 patients with CP was 1.24-fold greater than in the non-CP patients.
In conclusion, so far, research on association between heart and pancreas disease has received little attention and its role in pathogenesis is not fully elucidated. However, studies presented in this article indicate an important association that should be further investigated. Patients with CP/pancreatic exocrine insufficiency and chronic heart failure (especially right ventricular dysfunction) share similar clinical symptoms like abdominal pain, anorexia, nausea and bloating[1,2]. Interplay between malnutrition (intake driven) and cachexia (disease driven) can also be seen in both cardiac and pancreatic patients, as well as in sarcopenia (muscle wasting)[1,10,11,16,35]. Current evidence implicates possible association between PEI and malnutrition in patients with CHF. Chronic pancreatic tissue hypoxia and consequent injury is likely to contribute to malnutrition and cachexia in patients with CHF; however, too simplistic of an explanation should be avoided. Future prospective studies on this topic are necessary, especially using diagnostic methods for PEI other than FE-1, like the 13C-trygliceride breath test, secretin enhanced magnetic resonance cholangiopancreatography and serum nutritional markers.
On the other side, besides well-known risk factors, CP and PEI seem to be independent risk factors associated with an increased risk of CVD. However, most of the studies so far have been performed on patients with alcohol related CP, and in males. Future studies on CP patients with other etiologies and female patients would be of interest.