Liisa-Maria Voipio-Pulkki

Apoptosis in Human Acute Myocardial Infarction

BACKGROUNDnAfter reopening of the infarct-related coronary artery, cardiomyocytes continue to die during reperfusion. The mechanisms of cell death have been subject to debate. We studied whether an apoptotic type of cell death occurs in human acute myocardial infarction (AMI).nnnMETHODS AND RESULTSnWe studied myocardial samples of eight patients who died of AMI and had patent infarct-related arteries at autopsy. Six of the patients had received initially successful thrombolysis. Extensive formation of DNA strand breaks, the typical biochemical feature of apoptosis, was detected with the use of the in situ DNA end-labeling method. Apoptotic cardiomyocytes were observed particularly in the border zones of histologically infarcted myocardium, whereas very few apoptotic cells were present in the remote noninfarcted myocardium. Internucleosomal fragmentation was confirmed by agarose gel electrophoresis of DNA isolated from the representative myocardial areas.nnnCONCLUSIONSnThis study provides evidence that in addition to overt necrosis, a subset of myocytes undergo apoptosis during ischemia-reperfusion injury. Apoptosis may provide a new target for cardioprotection during evolving AMI in humans.

Glucose-free fatty acid cycle operates in human heart and skeletal muscle in vivo.

Positron emission tomography permits noninvasive measurement of regional glucose uptake in vivo in humans. We employed this technique to determine the effect of FFA on glucose uptake in leg, arm, and heart muscles. Six normal men were studied twice under euglycemic hyperinsulinemic (serum insulin approximately 500 pmol/liter) conditions, once during elevation of serum FFA by infusions of heparin and Intralipid (serum FFA 2.0 +/- 0.4 mmol/liter), and once during infusion of saline (serum FFA 0.1 +/- 0.01 mmol/liter). Regional glucose uptake rates were measured using positron emission tomography-derived 18F-fluoro-2-deoxy-D-glucose kinetics and the three-compartment model described by Sokoloff (Sokoloff, L., M. Reivich, C. Kennedy, M. C. Des Rosiers, C. S. Patlak, K. D. Pettigrew, O. Sakurada, and M. Shinohara. 1977. J. Neurochem. 28: 897-916). Elevation of plasma FFA decreased whole body glucose uptake by 31 +/- 2% (1,960 +/- 130 vs. 2,860 +/- 250 mumol/min, P less than 0.01, FFA vs. saline study). This decrease was due to inhibition of glucose uptake in the heart by 30 +/- 8% (150 +/- 33 vs. 200 +/- 28 mumol/min, P less than 0.02), and in skeletal muscles; both when measured in femoral (1,594 +/- 261 vs. 2,272 +/- 328 mumol/min, 25 +/- 13%) and arm muscles (1,617 +/- 411 to 2,305 +/- 517 mumol/min, P less than 0.02, 31 +/- 6%). Whole body glucose uptake correlated with glucose uptake in femoral (r = 0.75, P less than 0.005), and arm muscles (r = 0.69, P less than 0.05) but not with glucose uptake in the heart (r = 0.04, NS). These data demonstrate that the glucose-FFA cycle operates in vivo in both heart and skeletal muscles in humans.

In Vivo Detection of Vascular Adhesion Protein-1 in Experimental Inflammation

Vascular adhesion protein-1 (VAP-1) is an inflammation-inducible endothelial glycoprotein which mediates leukocyte-endothelial cell interactions. To study the pathogenetic significance of VAP-1 in inflammatory disorders, an in vivo immunodetection method was used to detect the regulation of luminally expressed VAP-1 in experimental skin and joint inflammation in the pig and dog. Moreover, VAP-1 was studied as a potential target to localize inflammation by radioimmunoscintigraphy. Up-regulation of VAP-1 in experimental dermatitis and arthritis could be visualized by specifically targeted immunoscintigraphy. Moreover, the translocation of VAP-1 to the functional position on the endothelial surface was only seen in inflamed tissues. These results suggest that VAP-1 is both an optimal candidate for anti-adhesive therapy and a potential target molecule for imaging inflammation.

Anxiety and hostility are associated with reduced baroreflex sensitivity and increased beat-to-beat blood pressure variability

Objective The purpose of this study was to determine whether psychological factors are associated with heart rate variability (HRV), blood pressure variability (BPV), and baroreflex sensitivity (BRS) among healthy middle-aged men and women. Methods A population-based sample of 71 men and 79 women (35–64 years of age) was studied. Five-minute supine recordings of ECG and beat-to-beat photoplethysmographic finger systolic arterial pressure and diastolic arterial pressure were obtained during paced breathing. Power spectra were computed using a fast Fourier transform for low-frequency (0.04–0.15 Hz) and high-frequency (0.15–0.40 Hz) powers. BRS was calculated by cross-spectral analysis of R-R interval and systolic arterial pressure variabilities. Psychological factors were evaluated by three self-report questionnaires: the Brief Symptom Inventory, the shortened version of the Spielberger State-Trait Anger Expression Inventory, and the Toronto Alexithymia Scale. Results Psychological factors were not related to HRV. Anxiety was associated with decreased BRS (p = 0.001) and higher low-frequency (p = 0.002) power of systolic arterial pressure variability. These associations were independent of age, gender, other psychological factors, heart rate, and systolic and diastolic blood pressures. Hostility was an independent correlate of increased low-frequency power of diastolic arterial pressure (p = 0.001) and increased high-frequency power of systolic arterial pressure (p = 0.033) variability. Conclusions Anxiety and hostility are related to reduced BRS and increased low-frequency power of BPV. Reduced BRS reflects decreased parasympathetic outflow to the heart and may increase BPV through an increased sympathetic predominance.

Vascular adhesion protein-1, intercellular adhesion molecule-1 and P-Selectin mediate leukocyte binding to ischemic heart in humans

OBJECTIVESnThe expression of endothelial adhesion molecules and their functional significance in leukocyte adhesion to human myocardial blood vessels in acute myocardial infarction (AMI) were studied.nnnBACKGROUNDnLeukocyte extravasation, mediated by specific adhesion molecules, exacerbates tissue injury after restoration of blood supply to an ischemic tissue. Experimental myocardial reperfusion injury can be alleviated with antibodies that block the function of adhesion molecules involved in leukocyte emigration, but the relevant molecules remain poorly characterized in human AMI.nnnMETHODSnSemiquantitative immunohistochemistry and in vitro adhesion assays were used to study the expression and granulocyte binding abilities of different endothelial adhesion molecules in human AMI. Changes in the molecular nature of vascular adhesion protein-1 (VAP-1) were evaluated using immunoblotting.nnnRESULTSnCertain endothelial adhesion molecules (intercellular adhesion molecule [ICAM-2], CD31 and CD73) were expressed in myocardial blood vessels homogeneously in normal and ischemic hearts, whereas others (E-selectin and peripheral lymph node addressin) were completely absent from all specimens. The synthesis of ICAM-1 was locally, and that of P-selectin regionally, upregulated in the infarcted hearts when compared with nonischemic controls. Vascular adhesion protein-1 showed ventricular preponderance in expression and alterations in posttranslational modifications during ischemia-reperfusion. Importantly, P-selectin, ICAM-1 and VAP-1 mediated granulocyte binding to blood vessels in the ischemic human heart.nnnCONCLUSIONSnHuman P-selectin, ICAM-1 and VAP-1 appear to be the most promising targets when antiadhesive interventions preventing leukocyte-mediated tissue destruction after myocardial ischemia are planned.

Different alterations in the insulin-stimulated glucose uptake in the athlete's heart and skeletal muscle.

Physical training increases skeletal muscle insulin sensitivity. Since training also causes functional and structural changes in the myocardium, we compared glucose uptake rates in the heart and skeletal muscles of trained and untrained individuals. Seven male endurance athletes (VO2max 72 +/- 2 ml/kg/min) and seven sedentary subjects matched for characteristics other than VO2max (43 +/- 2 ml/kg/min) were studied. Whole body glucose uptake was determined with a 2-h euglycemic hyperinsulinemic clamp, and regional glucose uptake in femoral and arm muscles, and myocardium using 18F-fluoro-2-deoxy-D-glucose and positron emission tomography. Glucose uptake in the athletes was increased by 68% in whole body (P < 0.0001), by 99% in the femoral muscles (P < 0.01), and by 62% in arm muscles (P = 0.06), but it was decreased by 33% in the heart muscle (P < 0.05) as compared with the sedentary subjects. The total glucose uptake rate in the heart was similar in the athletes and control subjects. Left ventricular mass in the athletes was 79% greater (P < 0.001) and the meridional wall stress smaller (P < 0.001) as estimated by echocardiography. VO2max correlated directly with left ventricular mass (r = 0.87, P < 0.001) and inversely with left ventricular wall stress (r = -0.86, P < 0.001). Myocardial glucose uptake correlated directly with the rate-pressure product (r = 0.75, P < 0.02) and inversely with left ventricular mass (r = -0.60, P < 0.05) or with the whole body glucose disposal (r = -0.68, P < 0.01). Thus, in athletes, (a) insulin-stimulated glucose uptake is enhanced in the whole body and skeletal muscles, (b) whereas myocardial glucose uptake per muscle mass is reduced possibly due to decreased wall stress and energy requirements or the use of alternative fuels, or both.

Cardiac positron emission tomography imaging with [11c]hydroxyephedrine, a specific tracer for sympathetic nerve endings, and its functional correlates in congestive heart failure

The integrative mechanisms of autonomic dysfunction in congestive heart failure (CHF) remain poorly understood. We sought to study cardiac retention of [11C]hydroxyephedrine (HED), a specific tracer for sympathetic presynaptic innervation, and its functional correlates in CHF. Thirty patients with mild to moderate heart failure underwent resting cardiac HED positron emission tomography imaging, spectrum analysis testing of systolic pressure and heart rate variability in the resting supine and 70 degrees head-up tilt positions, and testing of baroreflex sensitivity. Compared with control subjects, global myocardial HED retention index was reduced by 30% (p <0.01) in patients with CHF. The HED retention index did not correlate significantly with heart rate variability. However, it correlated with baroreflex sensitivity at rest (r = 0.43, p = 0.05) and with systolic pressure low-frequency (0.03 to 0.15 Hz) variability at head-up tilt (r = 0.76, p <0.01), as well as with low-frequency systolic pressure variability response from baseline to tilt (r = 0.75, p <0.01). We conclude that cardiac HED retention is reduced in patients with CHF. This correlates with blunted vascular sympathetic effector responses during posture-induced reflex activation and baroreflex control of heart rate, suggesting an interdependence between cardiac presynaptic innervation abnormalities and neural mechanisms important to blood pressure maintenance in CHF.

The effect of four different antihypertensive medications on cardiovascular regulation in hypertensive sleep apneic patients--assessment by spectral analysis of heart rate and blood pressure variability.

AbstractObjective: To study the effect of antihypertensive medications on autonomic nervous system in patients with hypertension and sleep apnea syndrome using frequency domain measures of heart rate and blood pressure variabilities. nn Methods: The β-receptor blocking agent atenolol (50u2009mg), the calcium antagonist isradipine SRO (2.5u2009mg), the diuretic hydrochlorothiazide (25u2009mg) and the ACE inhibitor spirapril (6u2009mg) once daily were given in a double-blind crossover schedule for 8 weeks. Cardiovascular autonomic control was assessed using frequency domain measures of heart rate variability during the spontaneous and controlled breathing tests. During orthostatic maneuver and cold pressor test the blood pressure variability analysis also was performed.nn Results: In general, the responses of heart rate and blood pressure variabilities were abnormal in the patients with arterial hypertension and sleep apnea syndrome compared to reference data. Of the four drugs, only atenolol effected heart rate and blood pressure variabilities as it shifted the autonomic regulation to the vagal direction. Other antihypertensive drugs did not change any parameter of heart rate or blood pressure variabilities.nn Conclusion: The short-term treatment with atenolol in patients with arterial hypertension and sleep apnea syndrome is associated with normalization of autonomic nervous control judged by heart rate and blood pressure variability. Thus, β-receptor blockade may have adjunctive beneficial effects beyond blood pressure reduction in these patients. However, the long-term effects of blood pressure reduction on autonomic nervous control remain to be studied.

Myocardial Glucose Uptake in Patients with NIDDM and Stable Coronary Artery Disease

Whole body insulin resistance characterizes patients with NIDDM, but it is not known whether insulin also has impaired ability to stimulate myocardial glucose uptake (MGU) in these patients. This study was designed to evaluate MGU as measured by 2-[l8F]flu-oro-2-deoxy-D-glucose ([18F]FDG) and positron emission tomography (PET) in patients with NIDDM and stable coronary artery disease (CAD) under standardized metabolic conditions. Eight patients with NIDDM, 11 nondiabetic patients with CAD, and 9 healthy control subjects were enrolled in the study. MGU was quanti-tated in the normal myocardial regions with [18F]FDG and PET and the whole body glucose disposal by glucose-insulin clamp technique (serum insulin, ∼430 pmol/l). Plasma glucose and serum insulin concentrations were comparable in all groups during PET studies. The whole body glucose uptake was 45% lower in NIDDM patients (22 ± 9 pmol · min−1 · kg−1 body wt [mean ± SD]), compared with healthy control subjects (40 ± 17 pmol · min−1 · kg−1 body wt, P < 0.05). In CAD patients, whole body glucose uptake was 30 ± 9 pmol · min−1 · kg−1 body wt (NS between the other groups). MGU was similar in the normal segments in all three groups (69 ± 28 pmol · min−1 · 100 g−1 in NIDDM patients, 72 ± 17 pmol · min−1 · 100 g−1 in CAD patients, and 76 ± 10 pmol. min−1 · 100 g−1 in healthy control subjects, NS). No correlation was found between whole body glucose uptake and MGU. As studied by [18F]FDG PET under stable normoglycemic hyperinsulinemic conditions, MGU is not reduced in patients with NIDDM and CAD in spite of peripheral insulin resistance. These findings suggest that there is no significant defect in MGU in patients with NIDDM.

Generation of Reference Values for Cardiac Enzymes from Hospital Admission Laboratory Data

An approach is described for using patient databases of a hospital information system as a source of reference values for cardiac enzymes. Of a total of 2029 emergency admission patients with serial cardiac enzyme data, 538 patients were considered healthy (having no damage in myocardium) because their discharge diagnoses suggested neither myocardial damage nor any other condition that could lead to elevated enzyme activities, and because their serially collected cardiac enzyme activities remained stable. Enzyme activities of creatine kinase (EC 2.7.3.2), creatine kinase isoenzyme MB, lactate dehydrogenase (EC 1.1.1.28), and lactate dehydrogenase isoenzyme 1 of these patients at admission to hospital were considered as suitable health related reference values. The upper (97.5%) reference limits of activities, measured at 37 degrees C according to Scandinavian recommendations, were as follows (age dependent limits given at 25 and at 75 years of age, U/l): creatine kinase men 268, 192; creatine kinase women 200 (no age effect); creatine kinase-MB 16, 24; lactate dehydrogenase 497, 603; lactate dehydrogenase isoenzyme 1 103, 140. For comparison, reference values were also produced conventionally from a group of 246 healthy subjects. Observed effects of age on enzyme activities were quite similar to those in the selected patient group. Calculated reference limits for isoenzymes creatine kinase-MB and lactate dehydrogenase isoenzyme 1 were also similar but reference limits for less cardiospecific total enzyme activities, creatine kinase and lactate dehydrogenase, were more variable between these two groups.(ABSTRACT TRUNCATED AT 250 WORDS)