Medical Hypotheses I Medial f&ohm# (1992) 1). 58-62 QbqumGmpUKLtd1992
Relationship Between Dietary Fatty Acid, Selenium, and Degenerative Cardiomyopathy M.L. BIERENBAUM, Y. CHEN, H. LEI and T WATKINS Kenneth L. Jordan Heart Fund, Montclair, NJ, USA, and First Hospital, Sciences, Chongqing, Sichuan Province, People’s Republic of China
Chongqing
University of Medical
Abstract-With the finding of an increasing number of cases of degenerative cardiomyopathy (DCM) amongst patients in Chongqing, Sichuan, People’s Republic of China, an attempt has been made to delineate possible etiological factors. In this province endemic for Keshan disease and with considerable consumption of oils high in erucic acid, the latter does not appear to be an operative noxious agent in DCM. Additionally, it does not appear to be caused by excessive oxygen radicals, low levels of antioxidants or low selenium levels. However, lower omega-3 fatty acid levels along with higher serum lipids may be the mechanism, via higher thromboxane levels, of the production of the myocardial degeneration seen in DCM.
Introduction In 1987 when joint work first started on the problem of idiopathic cardiomyopathy in Chongqing, it was noted on medical rounds that there were a number of such cases with no apparent viral etiology as the explanation. In 1989, on a repeat survey, it was quite clear that the number of cases found on the ward had about doubled and once again, no evidence of a viral epidemic or viral disease could be found to explain the unusual occurrence. Several other possibilities of etiology were then entertained, the first being that this was some variant of Keshan disease. Keshan disease still has a significant morbidity rate in Sichuan Province, particularly in Mianning and Xichang Counties where the content of soil selenium is very low. Congestive heart failure is a significant part of this disease picture suggesting Date received 26 November 1991 Date accepted 23 December 1991
similarity to the DCM noted in Chongqing. However, despite the many epidemiological studies done trying to chart the cause of Keshan disease, at best selenium deficiency was found to be only a co-factor with no success in clearly delineating the other etiological factor or factors (1). Discussion then led to some of the more remote possibilities as to the causative agent of DCM and excessive erucic acid intake was offered as a possibility. It was quite clear from innumerable studies during the 1970s (2,3,4) that high levels of intake of erucic acid were related to the development of degenerative changes of the myocardium in many animal species. The mechanism of its action was far less clear but there appeared to be an initial deposition process followed by a degenerative one. Also it was unclear if the same relationship held in humans, but since many
58
DIETARY FATl-Y ACID, SELENIUM AND DEGENERATIVE CARDIOMYOPATHY
Sichuan residents consumed large amounts of mustard seed oil (5), it seemed worthy of testing. It was the purpose of this study 1) to evaluate the fatty acid composition of the tissue of 10 subjects diagnosed as having idiopathic cardiomyopathy and study the relationships and 2) also to attempt delineation of any additional associated toxic factors such as excessive oxygen radicals perhaps related to low levels of antioxidants or excessive production of noxious prostaglandins. Design
In this pilot study, 10 subjects admitted to Chongqing University of Medical Sciences First Hospital with a working diagnosis of congestive cardiomyopathy of unknown etiology were studied. Standard evaluation and treatment were followed but a nutritionist did a diet history of food consumed for the 72 h prior to hospital admission. If the usual oil regularly utilized was either rapeseed or mustard seed oil, they were included in the study. The figure shows the fatty acid composition of mustard seed oil. As can be seen, over 50% of this oil is erucic acid, but there is also considerable N-3 and N-6 fatty acid present. Linoleate
Saturate (B-24)
Eruaxie 51.4
59
rheumatic, congenital or arteriosclerotic heart disease were also excluded. Additionally, diabetics and those consuming over two alcoholic drinks per day were not eligible. Utilization of other forms of medication including traditional therapy were not the basis of exclusion. Protocol Protocol subjects were recruited from successive admissions to the hospital with a working diagnosis of congestive cardiomyopathy of unknown etiology. A nutritionist or dietitian reviewed a diet history of the 72 h prior to the patient’s admission to ascertain whether either rapeseed or mustard seed oil was consumed on a regular basis, and if positive, notified the director of cardiology. Borderline positive cases were included. Standard diagnostic and therapeutic procedures were instituted but until the diagnostic studies were completed, vitamin and mineral supplements were not added to the treatment program. For the purpose of the study, the following data were required: 1) History (a) where had the volunteer resided during his life and for how long at each place; (b) what kind of cooking oil had been used and how much for how long; (c) pertinent past family and social history. 2) Blood samples provided serum and red blood cells for fatty acid analysis, lipid profile, vitamin and mineral content. 3) A sample of frozen cardiac tissue was obtained by myocardial biopsy for fatty acid analysis when possible. 4) A copy of the pathological slide prepared by the pathology department on the myocardial biopsy section. 5) A copy of the hospital summary. 6) 5 age- and sex-matched healthy controls from Chongqing consuming the same type and amount of oil and 6 healthy hyperlipemic age- and sex-matched controls from Montclair, New Jersey, served as the basis of comparison to the study group.
Fig.
Results The subjects aged 12-65 years of age, men or women who were selected once their diet history revealed that they had consumed regularly 500 ml/month of either rapeseed or mustard seed oil for the year prior to admission. Only those agreeing to comply with the protocol were accepted; they had the option to withdraw at any time during the study. The Scientific Committee of the Jordan Research Group had reviewed and approved the protocol. Persons coming from outside Sichuan Province and those consuming vitamin and minera supplements on a regular basis were excluded. Those with known
In order to evaluate the possibilities that higher levels of oxygen radicals related to low levels of antioxidants such as vitamin E and glutathione peroxidase via low selenium intake might be responsible for the syndrome of DCM, serum thiobarbituric reactive substances (TBARS) and selenium levels were measured (6) and compared. In regard to the TBARS, Table 1 shows that those of the study group were low normal and, although not significantly so, were lower than that of the control group, removing this from the possible list of etiological factors. Serum vitamin E levels were assayed
60
MEDIcALHYpoTHEsEs
(7) and were almost identical in the China study and control groups and were in the high normal range for adult humans. This is probably a reflection of high vegetable intake and adds further argument against the oxygen radical being of importance in DCM. Additionally, and further against the oxygen radical proposal, the serum selenium level (8) in the study was almost 50% higher (RO.05) than in the control group, suggesting that glutathione peroxidase activity should have been adequate in this model.
Table 1 Serum lhrs and antioxidant levels (Mean f SEM)
=sCIM E MG/DL Selenium R P. B.
study gmlp (IO)
Control group (5)
1.64 f 0.19 2.08 f 0.08 360 f 30.4
2.04 f 0.92’ 2.06 f 0.3@ 264 f 26.5b
1 - Not significant, b - PcO.05
Table 2 presents the results of the erucic acid and oleic acid content of the study and both control groups. As expected from the differing oil intake, both China groups were significantly higher in erucic acid content than the Montclair control. Somewhat disappointing to the erucic acid toxicity theory, however, was the finding that the China study and control groups had virtually the same intake. Additionally, it had been shown earlier in rat studies (9) that high erucic acid intake might interfere with the formation of oleic acid, a major component of the cardiac fat pattern and thus lead to degeneration. As had been found with the selenium levels, diametrically opposite findings were measured for oleate in that the study group had significantly higher levels of oleic acid than the China control. Table 3 examines the serum lipid levels found in both the China study and control groups. As can be noted, the serum cholesterol and LDL cholesterol levels were significantly higher in the study group than in the control and raised the possibility that lipid metabolism might be important or even responsible
for the changes found in DCM. This was further supported by the adverse trends found in the HDL cholesterol and triglycerides, although these were not statistically significant. Table 3 Serum lipid levels MG/DL (SEM) srudy CHOL HDL LDL TRI
group (10)
Control group (S)
197 f 12 39 f 2.4 130 f 7.9 183 f 26
166 f 9.4b 48 f 4.5. 96 f 6.9 14of3@
’ - Not significant, b PcO.05
Further, exploring the possibility of abnormal lipid metabolism as an etiological factor, the omega-3 fatty acid content of the rbc was next measured and is shown in Table 4. As can be noted, the 18: 3W3 and 22:6W3 content added together were significantly higher in the China control than the study group. They were also higher than in the Montclair control. This finding appeared to be of even greater importance when viewed from the content of omega-6 fatty acids shown in Table 5. Here the palmitic acid was higher in the China study than in the China control with the stearic acid almost identical and the linoleic acid significantly lower. This is certainly in keeping with the serum lipid levels shown earlier. Of particular note is the finding of no significant difference in arachidonic acid levels between the China study and control groups. In view of the high omega-3 levels in the control group and the preventive effect of such as noted by Lands (10) against the formation of potentially noxious thromboxanes, it is entirely possible that this may be an important mechanism in the process of degeneration as seen in DCM. Lagarde (11) has demonstrated that as the n3/n6 fatty acid ratio decreased in rat platelets and lung homogenates, TXA2 and TXB2 levels increased. The reduced tissue n3/n6 fatty acids measured in these DCM patients compared with controls suggest that such competition of n3 and n6 fatty acids may
Table 2 RBC erucic and oleic acid content (Mean f SEM) China sludy group (10)
hucic acid Oleic acid * - Not significant, b - P co.01
1.04 f 0.10 25.5 f 1.0
China coNrol(5)
1.07 f 0.41. 22.2 f 0.64b
MoNdoir
CoNrol (6)
0.39 f O.t?7b 21.9 f 0.89.
61
DIETARY FAlTY ACID. SELFNUM AND DEGENERATIVE CARDIOMYOPATHY
Table 4 RJX omega-3
fatty acid content (Mean f SEM) China sl*
0.82 f 0.06 2.82 f 0.17 3.36 f 0.35
Linolenic acid Docosohexanoic acid 18:3W3 and 22:6W3 1 - Not significant,
conlrol (10)
Monlclair control (6)
1.48 f 0.45’ 3.24 f 0.45. 4.72 f 0.57b
0.28 f 0.m 3.24 f 0.42. 3.46 f 0.45.
b PcO.05
Table 5 RBC omega-6
saturated
fatty content (Mean f SEM) China study group (10)
Palmitic acid Stearic acid Linoleic acid Arachidonic acid a - Not significant,
China confrol (5)
25.6 f 0.62 10.3 f 0.47 19.9 It 0.78 7.3 f 0.33
China control (S) 20.4 9.63 25.2 8.74
f f i f
1.03c 0.56. 1.04~ 0.551
Monlclair control (6) 24.4 13.1 17.6 10.9
f f * f
1.36b 0.6oc 0.86~ 1.02
b - P
Relationship Between Dietary Fatty Acid, Selenium, and Degenerative Cardiomyopathy M.L. BIERENBAUM, Y. CHEN, H. LEI and T WATKINS Kenneth L. Jordan Heart Fund, Montclair, NJ, USA, and First Hospital, Sciences, Chongqing, Sichuan Province, People’s Republic of China
Chongqing
University of Medical
Abstract-With the finding of an increasing number of cases of degenerative cardiomyopathy (DCM) amongst patients in Chongqing, Sichuan, People’s Republic of China, an attempt has been made to delineate possible etiological factors. In this province endemic for Keshan disease and with considerable consumption of oils high in erucic acid, the latter does not appear to be an operative noxious agent in DCM. Additionally, it does not appear to be caused by excessive oxygen radicals, low levels of antioxidants or low selenium levels. However, lower omega-3 fatty acid levels along with higher serum lipids may be the mechanism, via higher thromboxane levels, of the production of the myocardial degeneration seen in DCM.
Introduction In 1987 when joint work first started on the problem of idiopathic cardiomyopathy in Chongqing, it was noted on medical rounds that there were a number of such cases with no apparent viral etiology as the explanation. In 1989, on a repeat survey, it was quite clear that the number of cases found on the ward had about doubled and once again, no evidence of a viral epidemic or viral disease could be found to explain the unusual occurrence. Several other possibilities of etiology were then entertained, the first being that this was some variant of Keshan disease. Keshan disease still has a significant morbidity rate in Sichuan Province, particularly in Mianning and Xichang Counties where the content of soil selenium is very low. Congestive heart failure is a significant part of this disease picture suggesting Date received 26 November 1991 Date accepted 23 December 1991
similarity to the DCM noted in Chongqing. However, despite the many epidemiological studies done trying to chart the cause of Keshan disease, at best selenium deficiency was found to be only a co-factor with no success in clearly delineating the other etiological factor or factors (1). Discussion then led to some of the more remote possibilities as to the causative agent of DCM and excessive erucic acid intake was offered as a possibility. It was quite clear from innumerable studies during the 1970s (2,3,4) that high levels of intake of erucic acid were related to the development of degenerative changes of the myocardium in many animal species. The mechanism of its action was far less clear but there appeared to be an initial deposition process followed by a degenerative one. Also it was unclear if the same relationship held in humans, but since many
58
DIETARY FATl-Y ACID, SELENIUM AND DEGENERATIVE CARDIOMYOPATHY
Sichuan residents consumed large amounts of mustard seed oil (5), it seemed worthy of testing. It was the purpose of this study 1) to evaluate the fatty acid composition of the tissue of 10 subjects diagnosed as having idiopathic cardiomyopathy and study the relationships and 2) also to attempt delineation of any additional associated toxic factors such as excessive oxygen radicals perhaps related to low levels of antioxidants or excessive production of noxious prostaglandins. Design
In this pilot study, 10 subjects admitted to Chongqing University of Medical Sciences First Hospital with a working diagnosis of congestive cardiomyopathy of unknown etiology were studied. Standard evaluation and treatment were followed but a nutritionist did a diet history of food consumed for the 72 h prior to hospital admission. If the usual oil regularly utilized was either rapeseed or mustard seed oil, they were included in the study. The figure shows the fatty acid composition of mustard seed oil. As can be seen, over 50% of this oil is erucic acid, but there is also considerable N-3 and N-6 fatty acid present. Linoleate
Saturate (B-24)
Eruaxie 51.4
59
rheumatic, congenital or arteriosclerotic heart disease were also excluded. Additionally, diabetics and those consuming over two alcoholic drinks per day were not eligible. Utilization of other forms of medication including traditional therapy were not the basis of exclusion. Protocol Protocol subjects were recruited from successive admissions to the hospital with a working diagnosis of congestive cardiomyopathy of unknown etiology. A nutritionist or dietitian reviewed a diet history of the 72 h prior to the patient’s admission to ascertain whether either rapeseed or mustard seed oil was consumed on a regular basis, and if positive, notified the director of cardiology. Borderline positive cases were included. Standard diagnostic and therapeutic procedures were instituted but until the diagnostic studies were completed, vitamin and mineral supplements were not added to the treatment program. For the purpose of the study, the following data were required: 1) History (a) where had the volunteer resided during his life and for how long at each place; (b) what kind of cooking oil had been used and how much for how long; (c) pertinent past family and social history. 2) Blood samples provided serum and red blood cells for fatty acid analysis, lipid profile, vitamin and mineral content. 3) A sample of frozen cardiac tissue was obtained by myocardial biopsy for fatty acid analysis when possible. 4) A copy of the pathological slide prepared by the pathology department on the myocardial biopsy section. 5) A copy of the hospital summary. 6) 5 age- and sex-matched healthy controls from Chongqing consuming the same type and amount of oil and 6 healthy hyperlipemic age- and sex-matched controls from Montclair, New Jersey, served as the basis of comparison to the study group.
Fig.
Results The subjects aged 12-65 years of age, men or women who were selected once their diet history revealed that they had consumed regularly 500 ml/month of either rapeseed or mustard seed oil for the year prior to admission. Only those agreeing to comply with the protocol were accepted; they had the option to withdraw at any time during the study. The Scientific Committee of the Jordan Research Group had reviewed and approved the protocol. Persons coming from outside Sichuan Province and those consuming vitamin and minera supplements on a regular basis were excluded. Those with known
In order to evaluate the possibilities that higher levels of oxygen radicals related to low levels of antioxidants such as vitamin E and glutathione peroxidase via low selenium intake might be responsible for the syndrome of DCM, serum thiobarbituric reactive substances (TBARS) and selenium levels were measured (6) and compared. In regard to the TBARS, Table 1 shows that those of the study group were low normal and, although not significantly so, were lower than that of the control group, removing this from the possible list of etiological factors. Serum vitamin E levels were assayed
60
MEDIcALHYpoTHEsEs
(7) and were almost identical in the China study and control groups and were in the high normal range for adult humans. This is probably a reflection of high vegetable intake and adds further argument against the oxygen radical being of importance in DCM. Additionally, and further against the oxygen radical proposal, the serum selenium level (8) in the study was almost 50% higher (RO.05) than in the control group, suggesting that glutathione peroxidase activity should have been adequate in this model.
Table 1 Serum lhrs and antioxidant levels (Mean f SEM)
=sCIM E MG/DL Selenium R P. B.
study gmlp (IO)
Control group (5)
1.64 f 0.19 2.08 f 0.08 360 f 30.4
2.04 f 0.92’ 2.06 f 0.3@ 264 f 26.5b
1 - Not significant, b - PcO.05
Table 2 presents the results of the erucic acid and oleic acid content of the study and both control groups. As expected from the differing oil intake, both China groups were significantly higher in erucic acid content than the Montclair control. Somewhat disappointing to the erucic acid toxicity theory, however, was the finding that the China study and control groups had virtually the same intake. Additionally, it had been shown earlier in rat studies (9) that high erucic acid intake might interfere with the formation of oleic acid, a major component of the cardiac fat pattern and thus lead to degeneration. As had been found with the selenium levels, diametrically opposite findings were measured for oleate in that the study group had significantly higher levels of oleic acid than the China control. Table 3 examines the serum lipid levels found in both the China study and control groups. As can be noted, the serum cholesterol and LDL cholesterol levels were significantly higher in the study group than in the control and raised the possibility that lipid metabolism might be important or even responsible
for the changes found in DCM. This was further supported by the adverse trends found in the HDL cholesterol and triglycerides, although these were not statistically significant. Table 3 Serum lipid levels MG/DL (SEM) srudy CHOL HDL LDL TRI
group (10)
Control group (S)
197 f 12 39 f 2.4 130 f 7.9 183 f 26
166 f 9.4b 48 f 4.5. 96 f 6.9 14of3@
’ - Not significant, b PcO.05
Further, exploring the possibility of abnormal lipid metabolism as an etiological factor, the omega-3 fatty acid content of the rbc was next measured and is shown in Table 4. As can be noted, the 18: 3W3 and 22:6W3 content added together were significantly higher in the China control than the study group. They were also higher than in the Montclair control. This finding appeared to be of even greater importance when viewed from the content of omega-6 fatty acids shown in Table 5. Here the palmitic acid was higher in the China study than in the China control with the stearic acid almost identical and the linoleic acid significantly lower. This is certainly in keeping with the serum lipid levels shown earlier. Of particular note is the finding of no significant difference in arachidonic acid levels between the China study and control groups. In view of the high omega-3 levels in the control group and the preventive effect of such as noted by Lands (10) against the formation of potentially noxious thromboxanes, it is entirely possible that this may be an important mechanism in the process of degeneration as seen in DCM. Lagarde (11) has demonstrated that as the n3/n6 fatty acid ratio decreased in rat platelets and lung homogenates, TXA2 and TXB2 levels increased. The reduced tissue n3/n6 fatty acids measured in these DCM patients compared with controls suggest that such competition of n3 and n6 fatty acids may
Table 2 RBC erucic and oleic acid content (Mean f SEM) China sludy group (10)
hucic acid Oleic acid * - Not significant, b - P co.01
1.04 f 0.10 25.5 f 1.0
China coNrol(5)
1.07 f 0.41. 22.2 f 0.64b
MoNdoir
CoNrol (6)
0.39 f O.t?7b 21.9 f 0.89.
61
DIETARY FAlTY ACID. SELFNUM AND DEGENERATIVE CARDIOMYOPATHY
Table 4 RJX omega-3
fatty acid content (Mean f SEM) China sl*
0.82 f 0.06 2.82 f 0.17 3.36 f 0.35
Linolenic acid Docosohexanoic acid 18:3W3 and 22:6W3 1 - Not significant,
conlrol (10)
Monlclair control (6)
1.48 f 0.45’ 3.24 f 0.45. 4.72 f 0.57b
0.28 f 0.m 3.24 f 0.42. 3.46 f 0.45.
b PcO.05
Table 5 RBC omega-6
saturated
fatty content (Mean f SEM) China study group (10)
Palmitic acid Stearic acid Linoleic acid Arachidonic acid a - Not significant,
China confrol (5)
25.6 f 0.62 10.3 f 0.47 19.9 It 0.78 7.3 f 0.33
China control (S) 20.4 9.63 25.2 8.74
f f i f
1.03c 0.56. 1.04~ 0.551
Monlclair control (6) 24.4 13.1 17.6 10.9
f f * f
1.36b 0.6oc 0.86~ 1.02
b - P
