CLINICAL STUDIES
Maternally transmitted susceptibility to non–insulin-dependent diabetes mellitus and left ventricular hypertrophy
Yukihiko Momiyama, MD*,
Yoshihiko Suzuki, MD*,
Fumitaka Ohsuzu, MD ,
Yoshihito Atsumi, MD*,
Kempei Matsuoka, MD* and
Mitsuru Kimura, MD*
* Division of Internal Medicine, Tokyo Saiseikai Central Hospital, Tokyo, Japan
Division of Medicine I, National Defense Medical College, Saitama, Japan
Manuscript received May 29, 1998;
revised manuscript received November 10, 1998,
accepted December 23, 1998.
Reprint requests and correspondence: Dr. Yukihiko Momiyama, Division of Internal Medicine, Tokyo Saiseikai Central Hospital, 1-4-17 Mita, Minato-ku, Tokyo 108-0073, Japan
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Abstract
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OBJECTIVES
We studied the association of diabetes transmission with left ventricular hypertrophy (LVH) in patients with non–insulin-dependent diabetes mellitus (NIDDM).
BACKGROUND
It is suggested that NIDDM has a strong genetic basis and that maternally transmitted NIDDM is associated with mitochondrial deoxyribonucleic acid (DNA) mutations. However, genetic factors for LVH in NIDDM are unknown.
METHODS
We investigated the family history of diabetes and the prevalence of LVH using electrocardiography in 834 patients with NIDDM, of whom 199 also underwent echocardiography.
RESULTS
Of the 834 patients, 121 had diabetic mothers, 122 had diabetic fathers and 30 had both. The LVH criterion of SV1 + RV5 or RV6 >35 mm was met in 148 patients. The percentage of patients having diabetic mothers was higher in those with LVH criterion (29%) than without it (16%) (p < 0.001), but the percentage of patients having diabetic fathers was similar in those with LVH (18%) and without it (18%). Compared with the 683 patients with nondiabetic mothers, the 151 patients with diabetic mothers were younger and had earlier onset of diabetes. The percentage of patients having diabetic siblings was also higher in those with diabetic mothers (31%) than in those with nondiabetic mothers (18%) (p < 0.001). On electrocardiograms, the prevalence of LVH was higher in patients with diabetic mothers (28%) than in those with nondiabetic mothers (15%) (p < 0.001). Echocardiograms showed that patients with diabetic mothers had greater left ventricular wall thickness and mass than those with nondiabetic mothers. In multivariate analysis, the family history of diabetes in mothers was an independent factor to LVH, but the family history of diabetes in fathers was not.
CONCLUSIONS
Maternal transmission of diabetes was associated with LVH in patients with NIDDM. Some genetic factors of diabetes, such as mitochondrial DNA abnormalities, may contribute to the development of LVH in maternally transmitted NIDDM.
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Abbreviations and Acronyms
| | DNA | = deoxyribonucleic acid | | ECG | = electrocardiogram | | HCM | = hypertrophic cardiomyopathy | | IVS | = interventricular septum | | LV | = left ventricular | | LVH | = left ventricular hypertrophy | | LVIDd | = LV end diastolic internal dimension | | LVIDs | = LV end systolic internal dimension | | MELAS | = mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes | | NIDDM | = non–insulin-dependent diabetes mellitus | | PWT | = posterior wall thickness |
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Several clinical studies have demonstrated that diabetic patients have greater left ventricular (LV) mass and LV wall thickness than healthy subjects (1–4). The Framingham Heart Study reported that hypertension and obesity often coexist in diabetic patients (5). Because hypertension and obesity are strong contributing factors to LV hypertrophy (LVH) (6–8), LVH in diabetes could be attributed to those concomitant factors. However, Lonn et al. (9) and Lee et al. (10) recently documented that diabetes mellitus is associated with LVH independent of hypertension and obesity.
Non–insulin-dependent diabetes mellitus (NIDDM) is a disease strongly associated with genetic factors. A strong genetic basis in NIDDM has been suggested by the high concordance in monozygotic twins and the high incidence of diabetes among the first-degree relatives of NIDDM patients (11–13). We hypothesized that LVH in NIDDM may be related to the genetic factors of diabetes. To know the effect of diabetes transmission on LVH in NIDDM, we investigated the family history of diabetes and the prevalence of LVH using 12-lead electrocardiography in patients with NIDDM.
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Methods
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Study subjects.
We examined 834 consecutive patients with NIDDM (mean age 58 ± 9 years, range 40 to 79 years) who were admitted to a two-week educational program for diabetic patients at Tokyo Saiseikai Central Hospital from January 1995 to December 1996. The diagnosis of NIDDM had been made by diabetologists according to the World Health Organization criteria. On the first day of the admission, blood samples were taken. On the second day, all patients had 12-lead electrocardiography and the measurements of blood pressures at rest. They were investigated by the questionnaire as to whether their parents or siblings had diabetes. Patients with secondary diabetes or bundle branch blocks were excluded from this study.
Electrocardiography.
Standard 12-lead electrocardiograms (ECGs) were recorded at rest in a supine position at 25 mm/s and 1 mV/cm using a Mac PC electrocardiograph (Marquette, Milwaukee, Wisconsin) and were interpreted blindly to all clinical data. For each lead, R-wave and S-wave voltages were measured from the PR segment to the top of the R wave and the bottom of the S wave, respectively. The precordial voltage combination of Sokolow and Lyon (14) was measured as SV1 + higher RV5 or RV6. We considered the ECG to inscribe LVH if SV1 + RV5 or RV6 was >35 mm. In addition, the Romhilt–Estes point score for LVH was calculated, based on the presence or absence of QRS amplitude criteria (3 points), ST-T abnormalities typical of LVH (3 points with no digitalis or 1 with digitalis), left atrial abnormality (3 points), left axis deviation  –30 (2 points) and QRS duration 0.09 s or intrinsicoid deflection 0.05 s (1 point each) (15). Q waves were considered to be abnormal if their duration was 0.04 s or if their depth was 1/4 of the height of the ensuing R wave.
Echocardiography.
Of the 834 study patients, 199 also underwent echocardiography because of suspected or proven coronary artery disease (93 patients), the long duration or poor control of diabetes (81 patients), arrhythmias (14 patients) and suspected LVH (13 patients). M-mode and two-dimensional echocardiography were performed using a Sonos 1500 or 2500 ultrasonograph (Hewlett-Packard, Andover, Massachusetts). On M-mode echocardiograms, interventricular septum (IVS), posterior wall thickness (PWT) and LV end-diastolic (LVIDd) and end-systolic (LVIDs) internal dimensions were measured blindly to all clinical data, according to the recommendations of the American Society of Echocardiography. Fractional shortening and LV mass were calculated as follows:  ; and  (16). On two-dimensional echocardiograms, we paid attention to the presence of any wall motion abnormalities. Three cardiac cycles were measured and averaged.
Statistical analysis.
Differences between the groups of patients were evaluated by the unpaired t test for continuous variables and by the chi-square test for categorical variables. Forward stepwise multiple logistic regression analysis was used to elucidate the association of LVH with diabetes transmission and other variables. A p value of <0.05 was considered to be statistically significant. Results are presented as mean value ±SD.
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Results
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Clinical characteristics and electrocardiographic findings.
Of the 834 patients, 121 (15%) had diabetic mothers, 122 (15%) had diabetic fathers and 30 (4%) had both (Table 1). On ECGs, 148 patients fulfilled the LVH criterion of SV1 + RV5 or RV6 >35 mm. As a result, the percentage of patients who had diabetic mothers was significantly higher in those with the LVH criterion (29%) than in those without it (16%) (p < 0.001), whereas the percentage of patients having diabetic fathers was similar in those with LVH (18%) and in those without it (18%) (p = NS).
To clarify the association of LVH with maternal transmission of diabetes, 151 patients with diabetic mothers (group M+) were compared with the other 683 who had nondiabetic mothers (group M–). As shown in Table 2, patients in group M+ were younger (56 ± 8 vs. 59 ± 9 years, p < 0.001) and had earlier onset of diabetes (46 ± 9 vs. 49 ± 10 years, p < 0.001) than those in group M–. The percentage of patients who had diabetic siblings was higher in group M+ (31%) than in group M– (18%) (p < 0.001). However, gender, body mass index, diabetes duration and blood glycemic levels were not different between the two groups. Hypertension (blood pressures >140/90 mm Hg and/or on antihypertensive medication) was present in 38% of group M+ and in 46% of group M– (p = NS), and blood pressures were not different between the two groups. Coronary artery disease had been angiographically proven before this study in 3% of group M+ and in 6% of group M– (p = NS).
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Table 2 Clinical Characteristics of Patients Having Diabetic Mothers (M+) and Those Having Nondiabetic Mothers (M–)
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On ECGs, abnormal Q waves were seen in 2% of group M+ and in 4% of group M– (p = NS) (Table 3). The voltage combination of SV1 + RV5 or RV6 was greater in group M+ than in group M– (29.3 ± 9.1 vs. 27.5 ± 8.2 mm, p < 0.02). The LVH criterion of SV1 + RV5 or RV6 >35 mm was fulfilled in 28% of group M+ compared with 15% of group M– (p < 0.001). The other LVH criterion of Romhilt–Estes point score 4 was also found in 15% of group M+ versus 6% of group M– (p < 0.001). In multivariate analysis, the family history of diabetes in mothers, hypertension, blood pressure, gender and body weight were each significantly associated with the LVH criterion of SV1 + RV5 or RV6 >35 mm, but the family history of diabetes in fathers, age, body mass index, diabetes duration and blood glycemic levels were not (Table 4). The family history of diabetes in mothers, hypertension and gender were also significantly associated with the other LVH criterion of Romhilt–Estes point score  4 (Table 5).
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Table 3 Electrocardiographic Findings of Patients Having Diabetic Mothers (M+) and Those Having Nondiabetic Mothers (M–)
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Echocardiographic findings.
Of the 199 patients who underwent echocardiography, 42 (21%) had diabetic mothers (group M+), and the other 157 had nondiabetic mothers (group M–) (Table 6). No difference was found in the reasons for undergoing echocardiography between the two groups. Patients were younger in group M+ than in group M– (58 ± 8 vs. 62 ± 8 years, p < 0.002), but gender, body mass index, diabetes duration and blood glycemic levels were not different. Hypertension was present in 52% of group M+ and in 66% of group M– (p = NS), and blood pressures were not different between the two groups.
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Table 6 Echocardiographic Findings of Patients With Diabetic Mothers (M+) and Those With Nondiabetic Mothers (M–)
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On two-dimensional echocardiograms, LV wall motion abnormalities were present in 14% of group M+ and in 13% of group M– (p = NS). On M-mode echocardiograms, LV internal dimensions and fractional shortening were not different between the two groups. However, patients in group M+ had significantly thicker interventricular septum (9.4 ± 1.7 vs. 9.0 ± 1.0 mm, p < 0.05) and posterior wall (9.5 ± 1.3 vs. 9.2 ± 1.0 mm, p < 0.05) than those in group M–. Left ventricular mass was also greater in group M+ than in group M– (158 ± 53 vs. 144 ± 37 g, p < 0.05). Left ventricular hypertrophy of wall thickness >12 mm was found in 17% of group M+ compared with 7% of group M– (p = NS).
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Discussion
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On ECGs, the voltage criterion of SV1 + RV5 or RV6 >35 mm is widely used and highly specific for detecting LVH (14,17). Using this ECG LVH criterion, we investigated the association of diabetes transmission with LVH in NIDDM. In patients with NIDDM, LVH was significantly more prevalent in those with diabetic mothers than in those with nondiabetic mothers. In multivariate analysis, maternal transmission of diabetes was associated with LVH independent of hypertension, obesity and the duration and control of diabetes. The fact that patients with diabetic mothers were younger than those with nondiabetic mothers was noteworthy, because LVH increases with age. Despite the younger age, the higher prevalence of LVH in patients with diabetic mothers suggests the further association of maternal transmission of diabetes with LVH. Moreover, patients with diabetic mothers had earlier onset of diabetes and higher prevalence of diabetes in siblings than those with nondiabetic mothers, suggesting a strong genetic basis in maternally transmitted NIDDM. These results suggest that some genetic factors of diabetes could be contributing to the development of LVH in maternally transmitted NIDDM. However, the increased prevalence of LVH was not found in paternally transmitted NIDDM.
Because falsely high QRS voltages are often seen in young people (18) and extracardiac factors, such as obesity, attenuate QRS voltages (19), patients with diabetic mothers may have had more false positive LVH on ECGs. Grubschmidt and Sokolow (20) reported that LVH voltage criteria are reliable in adults over the age of 25 years, although 13% of people between the ages of 20 and 25 years show false positive. To reduce false positive, we excluded patients younger than 40 years. The higher prevalence of LVH in patients with diabetic mothers was also shown by Romhilt–Estes point score, which incorporates nonvoltage criteria. In multivariate analysis, the association of maternal transmission of diabetes with LVH was independent of age and obesity. Hence, the possibility of more false positive LVH in patients with diabetic mothers is slim. Although echocardiography was not performed in all our study subjects, it showed greater LV wall thickness and mass in patients with diabetic mothers than in those with nondiabetic mothers. It suggests that the higher prevalence of LVH on ECGs in patients with diabetic mothers reflects more hypertrophied LV associated with more thickened LV wall.
Left ventricular hypertrophy in diabetes.
It is well known that LVH is often seen in diabetic patients (1–4). Autopsy studies reported marked LVH in diabetic patients who died of heart failure in the absence of coronary artery disease (21–23). Although LVH in diabetes could be attributed to coexisting hypertension and obesity (5–8), recent studies documented that diabetes is associated with LVH independent of hypertension and obesity (9,10). Moreover, Grossman et al. (24) showed that in patients with hypertension, diabetes accelerates the development of LVH. Clinical and experimental studies demonstrated interstitial myocardial accumulation of collagen and glycoprotein (25–27) and metabolic alterations of myocardium in diabetes (27–29). However, the pathogenesis of LVH in diabetes has not been fully clarified.
Left ventricular hypertrophy and mitochondrial deoxyribonucleic acid (DNA) mutations.
Hypertrophic cardiomyopathy (HCM) characteristic of marked LVH is one of the most common forms of genetic heart disease. Watkins et al. (30,31) showed that about 50% of familial HCM is caused by nuclear DNA mutations in cardiac beta myosin heavy-chain or troponin T genes. Because these nuclear DNA mutations are transmitted as an autosomal dominant trait, they cannot account for LVH in maternally transmitted diabetes.
Mitochondrial DNA mutations have been reported in some patients with HCM (32,33). Obayashi et al. (34) detected mitochondrial DNA mutations in seven patients with non–autosomal dominant HCM and suggested that these mutations are one of the causes of non–autosomal dominant HCM. The theory is based on the fact that mitochondrial DNA genes are exclusively maternally transmitted. Recently, in patients with maternally transmitted HCM, mitochondrial DNA mutations were reported as the cause of their HCM (35–38). On the other hand, the syndrome mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) are known to be caused by a mitochondrial DNA mutation at position 3243 (39). In MELAS, LVH is considered to be the clinical feature of cardiac involvement (40–43). Ito et al. (43) reviewed 21 patients with MELAS and found LVH in eight patients. Marked LVH as seen in HCM was reported in some patients with MELAS (44,45). Ultrastructure of their myocardium showed markedly increased mitochondria. Hence, it is reasonable to think that maternally transmitted LVH may be related to mitochondrial DNA mutations.
Maternally transmitted diabetes.
Recently, it has been suggested that maternally transmitted diabetes is associated with mitochondrial DNA mutations (46–53). Katagiri et al. (48) reported that 1.3% of maternally transmitted diabetes is caused by a mitochondrial DNA mutation at position 3243 and that this mutation manifests a wide range of diabetic phenotypes from NIDDM to IDDM. Kishimoto et al. (49) detected this mutation in 5.1% of patients with maternally transmitted NIDDM. Other mutations at position 3256, 3260, 3264, 3271 or 8344 were also documented to cause diabetes (35,50–53). Because maternally transmitted diabetes could be associated with mitochondrial DNA mutations and because mitochondrial DNA mutations can be a cause of LVH, it is reasonable to think that latent mitochondrial DNA mutations could contribute to LVH in maternally transmitted NIDDM. Moreover, Poulton et al. (54) recently documented that 17% of patients with NIDDM have a mitochondrial DNA variant at position 16189. This variant was shown to be associated with insulin resistance, and it was suggested to be a premutation for pathogenic mutations. In addition to the mutations, such mitochondrial DNA variants may contribute to the development of LVH as well as NIDDM.
The intrauterine environment of diabetes is also recognized to play a role in maternally transmitted NIDDM. Pettitt et al. (55) reported the higher prevalence of NIDDM in offspring of diabetic mothers than in those of mothers who became diabetic after pregnancy. They also showed that diabetic intrauterine environment has a long-term effect on glucose tolerance in offspring, so-called "programming" (56). It can be speculated that the fetal programming of the diabetic intrauterine environment may change susceptibility to LVH and that this effect may be additional to those of genetic factors. However, there is no report to support this speculation, and the onset of NIDDM is usually after childbearing age (57).
Conclusions.
Maternal transmission of diabetes was associated with LVH in patients with NIDDM. This suggests that some genetic factors of diabetes, such as mitochondrial DNA abnormalities, may contribute to the development of LVH in maternally transmitted NIDDM.
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[Abstract]
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Abstract
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