Nigella sativa: A potential natural protective agent against cardiac dysfunction in patients with type 2 diabetes mellitus.

OBJECTIVES: To study the effect of Nigella sativa supplementation on cardiac functions in Type 2 diabetic patients treated with oral hypoglycemic agents.
BACKGROUND: Diabetes mellitus is associated with a high risk of cardiovascular morbidity and mortality. A number of reported beneficial effects of N. sativa on cardiovascular function were the inspiration for this study.
MATERIALS AND METHODS: Sixty patients with uncontrolled diabetes (hemoglobin A1c [HbA1c] >7%) and with no known cardiovascular complications were recruited from the outpatient diabetes clinic. They were assigned, by convenience, to two groups; the control group received activated charcoal as placebo while the test group received 2 g/day of powdered N. sativa for 1-year. All patients continued with their standard oral hypoglycemic agents. Echocardiography was used to evaluate the diastolic function, systolic function, and left ventricular mass (LVM) before the intervention and after 6 and 12 months of the treatment.
RESULTS: HbA1c decreased significantly in the N. sativa group but did not change in the control group. Echocardiographic assessment in the control group showed impairment in diastolic function after 12 months, but there were no significant changes in fractional shortening (FS) or ejection fraction (EF). Furthermore, left ventricular (LV) dimensions at diastole and systole, LVM, and LVM index were significantly increased. In N. sativa group, no significant changes were found in diastolic function or LVM. LV dimension at systole was decreased while FS and EF were significantly increased after 6 and 12 months.
CONCLUSION: N. sativa supplementation may protect the hearts of type 2 diabetic patients from diastolic dysfunction while improving LV systolic function.

RCT Entities:   Population Interventions Outcomes

INTRODUCTION

Diabetes mellitus (DM) is a chronic metabolic disorder caused by a defect in insulin secretion, insulin action, or both. The prevalence of DM is growing rapidly. According to the latest International Diabetes Federation (IDF) data, the worldwide prevalence of DM in 2012 was 371 million, and it is projected to reach 552 million by the year 2030. Studies have also indicated that the current prevalence of diabetes in the Arab world is among the 10 highest in the world.[12] Patients with diabetes are at an increased risk of cardiovascular disease, and DM adds to the impact of other atherosclerosis risk factors such as dyslipidemia and hypertension for the prediction of cardiovascular manifestations.[3] It was estimated that 4.8 million people died as a result of diabetes in 2012, and cardiovascular complications were the most common cause of the death of those patients.[145] Cardiomyopathy characterized by an early diastolic and late systolic dysfunction is another manifestation of cardiac complications in patients with diabetes.[67]

Nigella sativa (N. sativa) has been reported to possess hypoglycemic,[89] hypolipidemic,[10] and antioxidant properties.[11] Hypotensive and diuretic effects of N. sativa have been reported in spontaneously hypertensive rats.[12] It was also reported to induce homogenous physiologic cardiac hypertrophy with increased inotropic effect in rats.[1314] Despite several published studies, there is still a gap in the information on the effect of N. sativa on human hearts and specifically the hearts of diabetics. With this background, the objective of this study was to explore the effects of a 1-year supplementation with N. sativa on cardiac function, evaluated by echocardiography, in uncontrolled type 2 diabetic patients treated with oral hypoglycemic agents.

MATERIALS AND METHODS

This was a phase 2 participant blinded placebo-controlled clinical trial, carried out at the College of Medicine, University of Dammam, Kingdom of Saudi Arabia, from May 2009 to December 2011. The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki. The study was approved by the local ethical research committee of the University of Dammam and registered in the clinical trial registry– India, under the reference no. CTRI/2013/06/003781.

We calculated a sample size of 24 for each group assuming the probability of Type I error (α) to be 0.05, Power (1-β) to be 0.8, paired difference to be detected as 0.6 and expected standard deviation (SD) of difference to be 1.00. However, assuming from previous experience that there would be about 15% dropout or failure to follow-up, we increased the sample size to 30 for each group.

Sixty patients with type 2 diabetes of both genders were recruited from the outpatient diabetes clinic of King Fahd Hospital of the University-Al Khobar and its affiliated primary health care center. The inclusion criteria were uncontrolled type 2 DM (based on two consecutive readings 3 months apart of hemoglobin A1c [HbA1c] of >7%), aged between 18 and 60 years, using standard oral hypoglycemic drugs regularly and consenting for intervention and regular follow-up. Patients with HbA1c >9%, treated with insulin therapy, with a body mass index (BMI) of ≥40 kg/m2 or with known cardiovascular diseases (coronary artery disease, valvular heart diseases, and heart failure), uncontrolled hypertension or nephropathy were excluded from the study.

For convenience, based on patients with lower HbA1c assigned to the placebo group, the patients were divided into two equal groups (n = 30 each), the control group (received placebo) and the test group (received N. sativa). The rationale for this division was to minimize the number of patients in the placebo group exceeding HbA1c of 9, in the 1-year treatment period, which would increase the dropout from the study.

Two visits at the 6th and 12th months were scheduled for a general follow-up after the initial visit. Patients were also contacted by phone every month in between the scheduled visits to check for compliance to their medications and any untoward effects.

N. sativa seed powder in the form of 500 mg capsules (BioExtract [Pvt.] Ltd., Srilanka) was used in a dose of 2 g/day in two divided doses. Dose selection was based on a previous study by our group[8]

Activated charcoal capsules (260 mg) similar in size and color to the capsules of N. sativa (Arkopharma Pharmaceutical Laboratories Carros, France) were used as placebo and given 2 h before the standard oral hypoglycemic drugs, in two divided doses/day. In addition, the patients in both groups continued to use their regular standard oral hypoglycemic drugs.

Baseline data including age, gender, and duration of diabetes were recorded during the initial visit. Blood pressure, radial pulse rate, BMI, and HbA1c were measured prior to treatment and in each follow-up visit.

Echocardiogram was done at baseline and repeated at 6th and 12th months of follow-up. These measurements were performed in the same cardiac laboratory and interpreted by the same cardiologist. All patients underwent routine echocardiography using commercially available cardiac ultrasound diagnostic equipment (Toshiba Xario) with a 3 MHz transducer. Echocardiograms were obtained in the left lateral position at the end of expiration.[15] The following measurements were obtained in two-dimensional guided M-mode, and at the end of both diastole and systole: End-diastolic left ventricular internal dimension (LVIDd), end-systolic left ventricular internal dimensions (LVIDs), end-diastolic interventricular septal wall thickness (IVSd), end-diastolic left ventricular posterior wall thickness (LVPWd).

Left ventricular mass (LVM) and corrected LVM (LVMc) were calculated according to the following:[16]

LVM = 1.04 {(LVIDd + IVSd + LVPWd)3−(LVIDd)3} (g).

LVMc = 0.8 (LVM) +0.6 (g)

This was indexed to body surface area (BSA) as follows: Left ventricle mass index (LVMI) = Corrected ventricle mass/BSA (g/m2).[17]

For LV diastolic function, pulse wave Doppler was used to measure E/A ratio (the ratio of left ventricle early filling phase velocity, E, to late filling phase velocity, A, at the tip of mitral valve leaflets). Left atrial volume indexed to BSA (LAVI) was used to confirm the changes in E/A ratio and to differentiate between type 2 diastolic dysfunction and the pseudo normalization pattern of E/A ratio.

LAVI was calculated as based on cube method[18] as follows:

Left atrial volume = π (constant) × (atrial dimension in cm)3/ 6

LAV = 3.14159265 × D3/ 6

LAVI = LAV/BSA= (cm3/m2)

LV systolic function was assessed by end-systolic LV internal dimension and by both fractional shorting (FS) and ejection fraction (EF) of the left ventricle.

Statistical analysis was performed using the Statistical Package of Social Science (SPSS) version 16 (SPSS Inc. Released 2007. SPSS for Windows, Version 16.0. Chicago, SPSS Inc). Data are presented as means ± SD. In each group, readings were compared to their corresponding baseline values using Student's t-test for paired data. Results in the two groups were compared using Student's t-test for unpaired data. P <0.05 was considered as significant.

RESULTS

Table 1 shows the comparison of baseline data between the placebo (control) and N. sativa Groups. The demographic and pretreatment baseline data of all patients in the two groups did not differ significantly, except for HbA1c, which was higher in the N. sativa group than the controls. All patients in the N. sativa group tolerated the treatment and showed no adverse effects throughout the study period.

Table 1

Comparison of baseline data between the placebo group (control) and N. sativa groups

Table 2 shows changes in echocardiographic measurements of diastolic and systolic functions. E/A ratio was decreased in the placebo group in both readings. This decrease was only significant at 12th month reading (P < 0.05). However, the N. sativa group did not show any decrease in E/A ratio. On the contrary, the ratio insignificantly increased. There was no significant change in LAVI in both the groups. As regards the parameters of systolic function, LVIDs at 6th month was significantly increased in the placebo group (P < 0.05), while it was significantly decreased in N. sativa group at both 6th (P < 0.05) and 12th (P < 0.01) months. Interestingly, there was a significant improvement in both FS% and EF% in N. sativa group, unlike the placebo group.

Table 2

Comparison of echocardiographic parameters of cardiac diastolic and systolic function at 6 months and 12 months after treatment with their corresponding baseline values in the control and Nigella sativa groups

Table 3 illustrates changes in echocardiographic measurements of left ventricular (LV) internal dimensions and mass at different treatment durations in both the groups. LVIDd increased significantly (P < 0.05) in the control group both at 6th and 12th months. This increase was, however, not seen in the N. sativa group. There was no significant change in LVPWd or IVSd in any reading in both groups. However, the reading at 6 months for both LVMc and LVMI were significantly (P < 0.05) increased in the Control group, but not in the N. sativa group.

Table 3

Changes in echocardiographic measurements of LV internal dimensions at different treatment durations in the control group and N. sativa group compared to their corresponding baseline values

Table 4 demonstrates a comparison of all the echocardiographic parameters between the control group and N. sativa group at the baseline, 6 months and 12 months after initiation of treatment. There was no significant difference in any baseline reading for all echocardiographic parameters evaluated. LVIDs at 6th month were significantly (P < 0.05) less in the N. sativa group. FS(%) was significantly more in the N. sativa group both at 6th (P < 0.01) and 12th (P < 0.05) months while EF(%) was significantly (P < 0.01) higher in the N. sativa group at the 6th month reading only.

Table 4

Comparison of echocardiographic measurements of diastolic function, systolic function, and LV internal dimensions

Table 5 shows a comparison of BMI, HbA1c, pulse rate and mean arterial pressure (MAP) between baseline, 6 months and 12 months for both the groups. HbA1c was reduced in the N. sativa group at both follow-ups; but, this reduction was only significant at 12 months (P < 0.05). Pulse rate was significantly (P < 0.05) reduced at 12 months follow-up in the N. sativa group. MAP was significantly (P < 0.05) reduced at both the 6th month and 12th month follow-up in the N. sativa group.

Table 5

Changes in baseline measurements at different treatment durations in the placebo and N. sativa group compared to their corresponding baseline values

DISCUSSION

A review of the literature shows that the current study is the first to examine the effects of N. sativa on cardiac functions in patients with type 2 DM. The results indicated potential protective effects of N. sativa on cardiac diastolic and systolic functions and LVM in diabetic patients. N. sativa supplementation tended to prevent diastolic dysfunction as well as improve systolic function. In addition, it showed a trend of preventing an increase in the LVM.

Cardiac dysfunction in patients with DM manifests as diabetic cardiomyopathy that is characterized by an early diastolic and late systolic dysfunction.[67] Diastolic dysfunction has been reported in diabetic animals[19] as well as diabetic patients.[2021] Transmitral flow (E/A) ratio as a marker of diastolic dysfunction has been found to be impaired in diabetic patients without overt cardiovascular disease.[2223] In this study, the placebo group showed a trend towards diastolic dysfunction, as E/A ratio was significantly decreased at the end of the study, while in N. sativa group, the diastolic function was preserved. This may imply a protective role of N. sativa against diastolic dysfunction in diabetic patients.

Left ventricular systolic dysfunction has been linked to DM as a late manifestation of diabetic cardiomyopathy.[2425] Interestingly, in the current study, N. sativa supplementation for 1-year improved systolic function manifested by a significant decrease in LVIDs, and a significant increase in both FS% and EF% compared to their baseline readings and to the corresponding control group values. Studies on cardiac contractility in experimental rat models fed with N. sativa for 2 months resulted in a positive inotropic effect manifested as better contractility,[1314] which supports our findings in the N. sativa treated group. In contrast to our results, Boskabady et al.[26] reported a potent inhibitory effect on the muscle contractility of guinea pig isolated heart produced by perfusing the myocardium with N. sativa extract. However, since we have investigated the effect of N. sativa supplementation on cardiac parameters, our study is closer to that of the first group of researchers[1314] who reported enhanced cardiac performance than the Boskabady group. Therefore, it is likely that the direct effect of N. sativa on cardiac muscle fibers is inhibitory, while long-term ingestion of N. sativa may lead to structural and/or functional myocardial modifications that enhance cardiac performance.

Previous studies have demonstrated that LV hypertrophy occurs in patients with type 2 DM independent of hypertension or coronary artery disease.[27] In diabetic rats, LV hypertrophy was found to be associated with increased left ventricle internal dimensions in both diastole and systole.[28] Likewise, in the current study, both LVID in systole and diastole were increased significantly in the placebo group compared to their baseline values. LVMc was also increased in this group. However, this increment in LVMc was not associated with a parallel increment in the posterior wall thickness (LVPWd) or interventricular septum thickness (IVSd), which indicates that this increase may be due to the increase in LV internal dimensions. In contrast, a previous study on elderly individuals (≥65 years) reported that increased LVM in diabetics was associated with a greater interventricular septum and left posterior wall thicknesses rather than in dimensions when compared to nondiabetic patients.[29] However, the age of the patients in that study was much higher (≥65 years) than our patients age (mean age 46.9), which might explain this difference. Indeed, it has been reported that LVM age coefficient in diabetic women was significantly higher than the estimate for nondiabetics.[30] Interestingly, in the test group, N. sativa supplementation tended to prevent such an increase in ventricular mass and ventricular dimensions.

Felicio et al.[31] reported reductions in LVM index associated with a fall in blood glucose while the mass index increased in those who did not achieve glycemic control. In addition, a close relationship was found between glycemic control and improvement in LV diastolic[32] and systolic[33] functions. Therefore, the beneficial effects of N. sativa on cardiac parameters, encountered in our study, might be partly due to the improvement in glycemic control in these diabetic patients. Indeed, a study on newly diagnosed diabetic patients showed a significant improvement in cardiac functions after 15 months of better glycemic control in these patients.[34]

The improvement in blood pressure observed in the N. sativa group, compared to their baseline values, is consistent with our recent report on the short-term effect of N. sativa in diabetic patients.[35] Other human studies have also demonstrated the hypotensive effect of N. sativa in patients with mild hypertension[36] and those with central obesity.[37]

Limitations of this study include small sample size, aggravated by the loss of some patients who did not turn up for follow-up, and the relatively short duration of the intervention. Further studies on a larger sample size in a longer duration utilizing advanced echocardiography techniques such as tissue Doppler, might confirm these promising effects of N. sativa on the heart and explore possible mechanisms.

CONCLUSION

The present study indicates the potential beneficial effects of a 1-year supplementation of N. sativa in protecting the hearts of type 2 diabetic patients against diastolic dysfunction and left ventricle mass increment, and improving systolic function.