Ilkka Kantola

Myocardial Oxygen Consumption Is Unchanged but Efficiency Is Reduced in Patients With Essential Hypertension and Left Ventricular Hypertrophy

BACKGROUND Patients with hypertension and left ventricular hypertrophy (LVH) are prone to develop heart failure. We tested the hypothesis that compensatory LVH is associated with normalization of myocardial oxygen consumption and that this occurs at the expense of a decrease in the ratio between cardiac work and oxygen consumption (efficiency). METHODS AND RESULTS Nine hypertensive men with LVH (LVH+) (age 42+/-2 years), left ventricular mass index (LVMI) 161+/-8 g/m(2), blood pressure (BP) 145+/-16/88+/-10 mm Hg (mean+/-SD); 8 hypertensive men without LVH (LVH-) (age 39+/-5 years, LVMI 107+/-15 g/m(2), BP 140+/-15/90+/-11 mm Hg); and 10 normotensive men (CONT) were studied. Myocardial blood flow, oxygen consumption, and glucose uptake were measured during euglycemic hyperinsulinemia using PET techniques. LV dimensions, volumes, and workload were determined by echocardiography, and efficiency was calculated. Myocardial workload (2.5+/-0.8 versus 3.0+/-0.6 versus 2. 3+/-0.5 mm Hg. mL. min(-1). g(-1) for CONT versus LVH- versus LVH+; P<0.05, LVH- versus LVH+), myocardial blood flow (0.84+/-0.16 versus 1.06+/-0.22 versus 0.81+/-0.09 mL. g(-1). min, respectively; P<0.05, LVH- versus other groups) and oxygen consumption (0.09+/-0.02 versus 0.14+/-0.03 versus 0.11+/-0.01 ml. g(-1). min(-1), respectively; P<0. 05, LVH- versus other groups) were increased in the LVH- group. Myocardial efficiency was reduced in the LVH+ group (18.1+/-4.1% versus 15.1+/-2.3% versus 13.5+/-1.9%, respectively; P<0.05, LVH+ versus CONT). CONCLUSIONS Myocardial oxygen consumption per unit weight is increased in hypertensive patients without LVH but is normal in those with LVH. The normalization of oxygen consumption via hypertrophy occurs at the expense of efficiency, which may predispose hypertensive patients with LVH to heart failure.

Cardiovascular Events in Patients With Fabry Disease: Natural History Data From the Fabry Registry

OBJECTIVES These analyses were designed to determine the incidence of major cardiovascular (CV) events and the natural history of CV complications in patients with Fabry disease. BACKGROUND Fabry disease, a genetic disorder caused by deficiency of alpha-galactosidase A activity, is associated with CV dysfunction. METHODS Major CV events (myocardial infarction, heart failure, or cardiac-related death) were analyzed in 2,869 Fabry Registry patients during the natural history period (i.e., before enzyme replacement therapy or among patients who never received therapy). Multivariate logistic regression analyses were performed to identify significant predictors of CV events. RESULTS Eighty-three of 1,424 men (5.8%) and 54 of 1,445 women (3.7%) experienced CV events at mean ages of 45 and 54 years, respectively. Heart failure was the most common first CV event, reported by 50 men (3.5%) and 33 women (2.3%). Hypertension and left ventricular hypertrophy were the risk factors most strongly associated with CV events. When these parameters were used as covariates in logistic regression analyses, the odds ratio (OR) for hypertension in men was 7.8 (95% confidence interval [CI]: 2.1 to 28.6, p = 0.0019), and the OR for hypertension in women was 4.5 (95% CI: 1.6 to 12.3, p = 0.0037). The OR for left ventricular hypertrophy was 4.8 in men (95% CI: 1.03 to 22.2, p = 0.0463) and 8.2 in women (95% CI: 2.6 to 26.0, p = 0.0003). CONCLUSIONS Major CV events occurred in approximately 5% of Fabry Registry patients during the natural history period. All patients with Fabry disease should be monitored for possible CV risk factors, particularly hypertension and left ventricular hypertrophy.

The effect of 12-month enzyme replacement therapy on myocardial perfusion in patients with Fabry disease.

SummaryFabry disease (McKusick 301500) is an X-linked lysosomal storage disorder secondary to deficient α-galactosidase A activity which leads to the widespread accumulation of globotriaosylceramide (Gb3) and related glycosphingolipids, especially in vascular smooth-muscle and endothelial cells. We have recently shown that the myocardial perfusion reserve of Fabry patients is significantly decreased. Thus, in the present study we investigated, whether it can be improved with enzyme replacement therapy (ERT). Ten patients (7 male, 3 female; mean age 34, range 19–49 years) with confirmed Fabry disease were approved for this uncontrolled, open-label study. Myocardial perfusion was measured at rest and during dipyridamole-induced hyperaemia by positron emission tomography and radiowater. Myocardial perfusion reserve was calculated as the ratio between maximal and resting perfusion. Perfusion measurements were performed before and after 6 and 12 months of ERT by recombinant human α-galactosidase A (Fabrazyme, Genzyme). Plasma Gb3 concentration decreased significantly and the patients reported that they felt better and suffered less pain after the ERT. However, neither resting or dipyridamole-stimulated myocardial perfusion nor myocardial perfusion reserve changed during the ERT. Pretreatment relative wall thickness correlated negatively with posttreatment changes in flow reserve (r = −0.76, p = 0.05) and positively with posttreatment changes in minimal coronary resistance (r = 0.80, p = 0.03). This study shows that 12 months of ERT does not improve myocardial perfusion reserve, although the plasma Gb3 concentration decreases. However, individual variation in the response to therapy was large and the results suggest that the success of the therapy may depend on the degree of cardiac hypertrophy.

Upper airway obstruction in hypothyroidism

Abstract. Objectives. To determine the occurrence and frequency of nocturnal upper airway obstruction in hypothyroidism.

Diabetic complications are associated with liver enzyme activities in people with type 1 diabetes

This study was performed to clarify if diabetic complications are associated with liver enzyme activities in type 1 diabetic outpatients. Elevated activities of serum aminotransferases are a common sign of liver disease and are observed more frequently among people with diabetes than in the general population. Many studies have shown an association between specific diabetic complications and disturbances in various tissues, such as diabetic nephropathy and cardiovascular diseases, but only limited data are available on the possible association between diabetic complications and liver function. We studied 28 patients with type 1 diabetes. Mean age was 43.4+/-9.5 (S.D.), and duration of diabetes 25.2+/-9.7. Limited joint mobility (LJM) was assessed by the Rosenblooms method. Background and proliferative retinopathy, and peripheral symmetrical polyneuropathy were also assessed. Activities of alanine amino transferase (ALT), gamma-glutamyl transferase (GGT) and alkaline phosphatase (ALP) in serum were determined. The metabolic control of the diabetes was evaluated by the glycosylated haemoglobin A(1c) (HbA(1c)) level and lipid values were also measured. ALT activity was associated with LJM (P<0.01) and with neuropathy (P<0.01). Association between GGT activity and LJM (P<0.01) and neuropathy (P<0.01) were also found. GGT activity was also associated with the severity of retinopathy (P<0.01). None of these associations was explained by confounding effects of diabetes duration, age, body mass index (BMI), HbA(1c) or alcohol consumption. In conclusion, diabetic complications such as LJM, retinopathy and neuropathy are associated with liver enzyme activities independent of alcohol consumption, BMI and metabolic control of diabetes.

Neuropathic symptoms and findings in women with Fabry disease

OBJECTIVE To examine the neurologic and neurophysiologic findings and neurologic symptoms in 12 women with Fabry disease and to study the relationship between the subjective symptoms and the findings on the various tests done. METHODS Neurography, vibratory and thermal quantitative sensory testing (QST), skin biopsy for measuring intraepidermal nerve fiber density (IENFD). Heart rate variability (HRV) and sympathetic skin response (SSR) tests for detecting autonomic dysfunction, pain-, depression- and somatic symptom questionnaires and clinical examination. RESULTS Only two women had no persistent symptoms or signs of polyneuropathy, 10 had symptoms of small fiber neuropathy. Neurological examination was normal in most patients. Five patients had decreased IENFD or thermal hypoesthesia in QST. In QST, Adelta-fiber function for innocuous cold was more often impaired than C-fiber function. Conventional nerve conduction studies were mostly normal. Carpal tunnel syndrome (CTS) incidence was increased, 25% had symptomatic CTS. CONCLUSIONS Heterozygous women carrying the gene for Fabry disease have symptoms and findings of small-fiber polyneuropathy more often than has previously been considered. The prevalence of CTS is also increased. SIGNIFICANCE While the clinical diagnosis of small-fiber neuropathy is difficult, the diagnostic yield can be increased using a combination of thermal QST and IENFD measurements.

Little Effect of Ordinary Antihypertensive Therapy on Nocturnal High Blood Pressure in Patients with Sleep Disordered Breathing

The antihypertensive effects of four different antihypertensive medications (beta-blocking agent, atenolol 50 mg; calcium-antagonist, isradipine SRO [slow release] 2.5 mg; diuretic, hydrochlorothiazide [HCTZ] 25 mg; and angiotension converting enzyme-inhibitor, spirapril 6 mg) on obese patients with sleep disordered breathing and hypertension were compared by the ambulatory blood pressure measurement (ABPM). Eighteen patients were randomized in a double-blind, crossover fashion to receive each of the four different medications for 8 weeks. ABPM was performed at baseline and after an 8-week treatment with these medications. A 2- to 3-week washout period occurred both at baseline and between each of the four medications. Three patients were omitted from statistical analysis because of technical problems of ABPM. Atenolol, isradipine SRO, and spirapril decreased significantly (P < .01) the mean 24-h systolic blood pressure, whereas HCTZ did not. The mean 24-h diastolic blood pressure decreased significantly after all four medications: 12 (SD+/-14) mm Hg with atenolol, 7 (SD+/-10) mm Hg with isradipine SRO, 3 mm Hg (SD+/-14) with HCTZ, and 6 (SD+/-15) mm Hg with spirapril (P < .01). During nighttime none of the medications reduced the mean diastolic or systolic blood pressure significantly. According to the 24-h blood pressure curve the influence of these four medications during the whole measurement period was not similar. Atenolol and spirapril lost their antihypertensive effect during the early morning hours. The antihypertensive effect of HCTZ varied markedly from hour to hour. The trough-to-peak ratio of no medication was >0.50. Negative correlation was observed between the apnea time and the mean systolic 24-h (r = -0.604, P = NS) and the mean systolic nocturnal blood pressure change (r = -0.590, P = NS). Our study revealed that the daytime high blood pressure was quite easily controlled by the ordinary monotherapy in these patients with partial upper airway obstruction and hypertension. Instead none of the medications used decreased nocturnal high blood pressure markedly.

Home-measured blood pressure is more strongly associated with atherosclerosis than clinic blood pressure: the Finn-HOME Study

Background The aim of this study was to assess whether carotid intima–media thickness (IMT) is more strongly associated with home-measured blood pressure (BP) than clinic BP. Other risk factors associated with carotid atherosclerosis were also investigated. Methods We studied a representative unselected sample of the Finnish adult population (758 subjects aged 45–74 years). Subjects included in the study underwent a clinical interview, carotid ultrasonography, and measurement of clinic BP (mean of two measurements using a mercury sphygmomanometer) and home BP (mean of 14 duplicate measurements during 1 week using a validated, automatic device). Fasting blood samples for serum lipids and glucose were drawn. Results The Pearson correlation coefficients for carotid IMT and home/clinic BP differed significantly in favour of home measurement for systolic BP (0.34 versus 0.25, P < 0.001), diastolic BP (0.20 versus 0.07, P < 0.001) and pulse pressure (0.37 versus 0.27, P < 0.001). In a linear regression model (R2 = 0.32, P < 0.001), age (P < 0.001), home systolic BP (P = 0.002), serum triglycerides (P = 0.006), male sex (P = 0.009), smoking (P = 0.017), diabetes (P = 0.035), and low-density lipoprotein cholesterol (P = 0.041) were independently associated with increased IMT. The association between home BP and carotid IMT did not increase with the number of home measurements. Conclusion BP is one of the most important factors in the pathogenesis of atherosclerosis. Home-measured BP is more strongly associated with carotid atherosclerosis than clinic BP, even for a low number of measurements. These data support the application of home BP measurement in clinical practice.

Limited Joint Mobility in Non-Insulin- Dependent Diabetic (NIDDM) Patients: Correlation to Control of Diabetes, Atherosclerotic Vascular Disease, and Other Diabetic Complications

This study examined the association between limited joint mobility (LJM) and diabetic control, atherosclerotic vascular disease and other diabetic complications in non-insulin-dependent diabetic (NIDDM) patients. LJM was studied in 139 [age (mean +/- SD) 61.3 +/- 12.3 years] NIDDM patients. Limitation of several joints was examined with a goniometer and LJM was classified by the Rosenbloom method. The NIDDM patients were examined for the following diseases: history of myocardial infarction, coronary heart, cerebrovascular and peripheral vascular diseases. The diabetic complications, background and proliferative retinopathy, nephropathy, and neuropathy, were also assessed. The metabolic control of the diabetes was evaluated by the average glycosylated hemoglobin Alc (GHbA kappa) concentration and lipid values were also measured. Mean levels of GHbAlc were 8.9 vs. 8.2% (p < 0.05) in NIDDM patients with and without LJM. NIDDM patients with LJM had a 3.1- (95% confidence interval, 1.2-7.7) and a 4.0-fold risk (95% confidence interval, 1.2-13.0) for coronary heart and cerebrovascular disease respectively, when the confounding effects of age, duration of diabetes and control of diabetes were controlled using stepwise logistic regression analysis. Patients with LJM had a 9.3- (95% confidence interval, 1.1-79.0) and a 3.3-fold risk (95% confidence interval, 1.0-10.5) of proliferative retinopathy and nephropathy respectively, when the confounding effects of age and duration of diabetes were controlled, but the correlation disappeared when control of diabetes was included in the model. In conclusion, the presence of LJM is associated with the control of diabetes and with the presence of coronary heart and cerebrovascular diseases in NIDDM patients.

Structural and functional changes in peripheral vasculature of Fabry patients

SummaryObjective: Fabry disease is a lysosomal storage disorder due to deficient α-galactosidase A activity, which leads to glycosphingolipid accumulation especially in vascular smooth-muscle and endothelial cells. Little is known about the effects of Fabry disease on peripheral artery function and structure. Therefore, we aimed to further characterize the peripheral vascular structural and functional changes in Fabry disease. Methods and results: We measured structural and functional vascular parameters, including intima-media thickness (IMT) of brachial and carotid arteries and abdominal aorta, carotid and aortic compliance, and brachial artery flow-mediated dilatation (FMD) in 17 Fabry patients and 34 healthy controls matched for age, sex and smoking. Carotid IMT (0.64 ± 0.15 vs 0.57 ± 0.12 mm), brachial IMT (1.02 ± 0.25 vs 0.74 ± 0.18 mm), and aortic IMT (0.31 ± 0.09 vs 0.26 ± 0.04 mm) were significantly increased, and brachial FMD was significantly impaired (6.3 ± 5.0 vs 9.7 ± 3.9%) in Fabry patients compared to healthy controls (p < 0.05 in all comparisons after adjustments for age, LDL-cholesterol, and systolic blood pressure). No differences were observed in arterial compliance between the groups. Conclusions: These data suggest that Fabry disease affects arterial function and structure by disturbing peripheral endothelial function and promoting intima-media thickening.