Jan Sundell

Effects of Low and High Plasma Concentrations of Dexmedetomidine on Myocardial Perfusion and Cardiac Function in Healthy Male Subjects

Background:Dexmedetomidine, a selective &agr;2-adrenoceptor agonist, has counteracting effects on the cardiovascular system. It mediates sympatholysis by activating &agr;2 adrenoceptors in the central and peripheral nervous system, and vasoconstriction and vasorelaxation by activating postsynaptic &agr;2 adrenoceptors in blood vessels. The goal of this study was to determine the effects of therapeutic and high concentrations of dexmedetomidine on myocardial perfusion and cardiac function in healthy subjects. Methods:The authors studied 12 healthy young men. Myocardial blood flow (assessed with positron emission tomography), myocardial function (by echocardiography), and hemodynamic data were collected before and during low (measured mean plasma concentration, 0.5 ng/ml) and high (5 ng/ml) plasma concentrations of dexmedetomidine. Results:The low concentration of dexmedetomidine reduced myocardial perfusion (mean difference, −27% from baseline [95% confidence interval, −31 to −23%], P < 0.001) in parallel with a reduction in myocardial oxygen demand (estimated by the rate–pressure product (−23% [−28 to −18%], P < 0.001). The high dexmedetomidine plasma concentration did not further attenuate myocardial perfusion (−3% [−12 to +6%] from low dexmedetomidine, P > 0.05; −29% [−39 to −18%] from baseline, P < 0.001) or statistically significantly affect the rate–pressure product (+5% [0 to +10%], P > 0.05). Systolic myocardial function was attenuated by sympatholysis during the low infusion rate and was further attenuated by a combination of the sustained sympatholysis and increased afterload during the high infusion rate. Conclusions:In healthy subjects, plasma concentrations of dexmedetomidine that significantly exceed the recommended therapeutic level do not seriously attenuate myocardial perfusion below the level that is observed with usual therapeutic concentrations and do not induce evident myocardial ischemia.

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.

Insulin and myocardial blood flow

The renaissance of glucose-insulin-potassium infusion (GIK) as a treatment of acute myocardial infarction both in diabetic and nondiabetic subjects has raised new interests to clarify the effects and mechanisms of insulin on myocardium. Although the action of insulin on substrate metabolism is quite well studied in heart, the cardiovascular effects were until recent years poorly known. Insulin induces skeletal muscle vasodilation mainly via the endothelium-dependent mechanism and appears to have an important role in normal vascular function. There is increasing amount of evidence that insulin acts as a vasodilatory hormone also in coronary arteries. Insulin enhances myocardial blood flow and decreases coronary vascular resistance in a dose-dependent manner in healthy subjects. Moreover, insulin is able to increase myocardial blood flow also in subjects who are characterized by coronary dysfunction such as subjects with obesity, type 1 diabetes and coronary artery disease. However, vasodilatory effect of insulin may be blunted in these patients. Since already very small increase in myocardial blood flow can reduce significantly myocardial ischemia, these vasodilatory actions of insulin in coronary arteries might partly contribute to beneficial effects of GIK therapy. On the other hand, in contrast to these acute beneficial effect of insulin, epidemiological studies have indentified chronic hyperinsulinemia, a common feature in subjects with insulin resistance to glucose uptake, as an independent risk factor for coronary artery disease. The present article review the physiological and pathophysiological role of insulin in cardiac vasculature and its clinical importance during myocardial ischemia and development of coronary artery disease.

Resistance Training Is an Effective Tool against Metabolic and Frailty Syndromes

Metabolic syndrome is a set of risk factors (abdominal obesity, insulin resistance, hypertension, and dyslipidemia) which increases markedly the risk of arteriosclerotic vascular disease. In subjects with frailty syndrome, aging-related loss of muscle (sarcopenia) and bone (osteoporosis) might progress to the extent that an older person loses his or her ability to live independently. Due to ongoing obesity pandemic and growing elderly population, metabolic and frailty syndromes are major emerging concerns in healthcare system. Recent studies show that resistance training has remarkable beneficial effects on the musculoskeletal system including prevention and treatment of these syndromes. Resistance training has favourable effect on metabolic syndrome since it decreases fat mass including abdominal fat. It also enhances insulin sensitivity, improves glucose tolerance, and reduces blood pressure values. The combination of sarcopenia and osteoporosis is often seen in the frailty syndrome. Resistance training is probably the most effective measure to prevent and treat sarcopenia. In addition, many studies show that resistance training can maintain or even increase bone mineral density. Optimal nutrition enhances the anabolic effect of resistance training. Resistance training should be a central component of public health promotion programs along with an aerobic exercise.

Impaired myocardial perfusion reserve but preserved peripheral endothelial function in patients with Fabry disease

SummaryFabry disease (McKusick 301500) is an X-linked lysosomal storage disorder due to deficient α-galactosidase A activity, which leads to accumulation of glycosphingolipids, especially in vascular smooth-muscle and endothelial cells. The effect of this accumulation on peripheral and cardiac vascular function is poorly known. We studied 15 Fabry patients (mean age 35 years and mean BMI 24.8 kg/m2) and 30 age- and BMI-matched healthy controls to examine whether myocardial perfusion reserve and peripheral artery endothelial function are altered. Myocardial perfusion was measured at rest and during dipyridamole-induced hyperaemia by positron emission tomography and H215O. Myocardial blood flow reserve was calculated as the ratio between the dipyridamole-induced maximal blood flow and resting blood flow. Peripheral artery endothelial function was assessed by measuring the brachial artery flow-mediated dilatation using ultrasound at rest and during reactive hyperaemia. The myocardial perfusion reserve was significantly lower in Fabry patients than in controls (3.3 ± 1.2 vs 4.4 ± 1.6, p = 0.02), while the brachial artery flow-mediated dilatation was similar (5.9% ± 3.9%vs 4.5% ± 3.6%, p = 0.27). Thus, inFabry disease, myocardial perfusion reserve is reduced while the peripheral artery endothelial function is preserved.

Increased basal myocardial perfusion in patients with chronic kidney disease without symptomatic coronary artery disease

BACKGROUND Even minor renal dysfunction is a powerful cardiovascular risk factor. The abnormalities in coronary and peripheral artery function in different stages of chronic kidney disease (CKD) remain poorly understood. Our aim was to test by a positron emission tomography (PET)-based method whether microvascular dysfunction, an early marker of coronary dysfunction, exists already in early stages of CKD. METHODS Myocardial blood flow was measured at baseline and during dipyridamole-induced hyperaemia by PET. Peripheral artery endothelial function was examined by measuring flow-mediated dilatation (FMD) of the brachial artery at rest and during reactive hyperaemia. Twenty-two patients with moderate to severe kidney failure and 10 healthy controls were investigated. Diabetic patients were excluded. Baseline characteristics were similar between the groups with the exception of antihypertensive medication in all CKD patients. RESULTS The basal myocardial perfusion was statistically significantly higher in CKD patients than observed values in similarly aged controls. There was a statistically significant negative correlation between the baseline myocardial perfusion and the estimated glomerular filtration rate. Coronary flow reserve was comparable to healthy controls in all patients. FMD was significantly reduced in all patients with CKD regardless of the stage of kidney failure. CONCLUSIONS Coronary flow reserve was normal although baseline myocardial blood flow was increased in all CKD patients as compared to healthy controls. Peripheral endothelial dysfunction was detected in all patients. Our findings suggest that coronary perfusion and peripheral vascular function are disturbed by different mechanisms in patients with CKD.

Insulin induced increase in coronary flow reserve is abolished by dexamethasone in young men with uncomplicated type 1 diabetes

Objective: To examine the role of the sympathetic nervous system in regulating insulin’s action on coronary perfusion in uncomplicated type 1 diabetes by blocking centrally mediated sympathetic activity with dexamethasone. Methods: Positron emission tomography and oxygen 15 labelled water were used to quantify myocardial blood flow basally and during adenosine infusion with or without simultaneous euglycaemic physiological hyperinsulinaemia in nine non-smoking men with type 1 diabetes and 12 healthy non-diabetic men. Each patient was studied both with and without previous dexamethasone treatment for two days (2 mg/day). Results: Insulin increased coronary flow reserve in diabetic (from 4.3 (0.7) to 5.1 (0.6), p < 0.05) and non-diabetic (from 4.3 (0.3) to 5.4 (0.4), p < 0.05) patients. In contrast to non-diabetic patients dexamethasone pretreatment abolished the insulin induced increase in coronary flow reserve in diabetic patients (p < 0.05) leading to lower coronary flow reserve in diabetic than in non-diabetic patients (3.9 (0.6) v 7.1 (0.9), p < 0.05). Conclusions: These results show that insulin’s ability to modulate coronary perfusion is sustained in young patients with type 1 diabetes without microvascular complications or autonomic neuropathy. Dexamethasone treatment abolished the insulin induced increase in coronary flow reserve in diabetic patients but not in healthy study participants, suggesting that sympathetic activation plays an important part in regulating insulin’s effects on myocardial perfusion in patients with type 1 diabetes.

Effects of CRT on myocardial innervation, perfusion and metabolism.

Heart failure leads to specific changes in cardiac perfusion, metabolism, and innervation. Typically, in the early phase of heart failure, left ventricular (LV) efficiency of forward work is compromised and right ventricular oxidative metabolism increased while resting myocardial perfusion is normal. With advancing disease, LV perfusion and especially the perfusion reserve and oxidative metabolism also become compromised. In addition to the abnormalities linked with the heart failure itself, commonly co-existing left bundle branch block leads to striking, mainly regional imbalance in these parameters. Recent studies have documented that cardiac resynchronization therapy (CRT) has prominent effects on myocardial perfusion, metabolism, and innervation. Cardiac resynchronization therapy normalizes many of these parameters and these changes can be considered to be the signs of successful resynchronization. In contrast, a significant number of patients do not respond to CRT. Some of the metabolic parameters, such as existing glucose metabolism as a marker of viability as well as those related to right ventricle function, may also be linked to the response to CRT.

Lifetime glycaemic exposure predicts reduced coronary vasoreactivity in Type 1 diabetic subjects

Aims  Subjects with Type 1 diabetes have impaired coronary vasoreactivity but the independent role of glycaemic control on myocardial perfusion is less clear. We examined the effect of lifetime glycaemic exposure on coronary vasoreactivity in 43 otherwise healthy Type 1 diabetic subjects.

Both BMI and Waist Circumference Are Associated with Coronary Vasoreactivity in Overweight and Obese Men

Objective: Guidelines differ about the value of assessment of adiposity measures for cardiovascular disease risk prediction. Reduced coronary vasoreactivity appears to be one of the earliest abnormalities in the development of coronary artery disease. We studied the associations of BMI, waist circumference, waist-to-hip ratio (WHR) and percentage of fat with coronary vasoreactivity. Methods: Myocardial blood flow was quantitated in 14 overweight or obese non-smoking men (age 32 ± 7 years, BMI 32 ± 3 kg/m2, waist circumference 106 ± 9 cm, WHR 0.96 ± 0.04, %fat 27.2 ± 3.7) using positron emission tomography and oxygen-15-labelled water. The measurements were performed basally and during adenosine infusion (140 µg/kg/min) to measure coronary vasoreactivity. Results: Adenosine infusion induced significant increase in myocardial blood flow (from 0.8 ± 0.2 to 3.5 ± 0.9 ml/g/min). After adjustment for LDL-cholesterol, HbA1c, systolic blood pressure and age, hyperaemic myocardial blood flow was inversely associated with BMI (r = –0.87, p = 0.001), waist circumference (r = –0.84, p = 0.003), WHR (r = –0.79, p = 0.007) and %fat (r = –0.65, p = 0.04). Conclusions: Both BMI and waist circumference are associated with coronary vasoreactivity in overweight and obese men.