Morten Bruvold

Superior Cardiovascular Effect of Aerobic Interval Training Versus Moderate Continuous Training in Heart Failure Patients A Randomized Study

Background— Exercise training reduces the symptoms of chronic heart failure. Which exercise intensity yields maximal beneficial adaptations is controversial. Furthermore, the incidence of chronic heart failure increases with advanced age; it has been reported that 88% and 49% of patients with a first diagnosis of chronic heart failure are >65 and >80 years old, respectively. Despite this, most previous studies have excluded patients with an age >70 years. Our objective was to compare training programs with moderate versus high exercise intensity with regard to variables associated with cardiovascular function and prognosis in patients with postinfarction heart failure. Methods and Results— Twenty-seven patients with stable postinfarction heart failure who were undergoing optimal medical treatment, including &bgr;-blockers and angiotensin-converting enzyme inhibitors (aged 75.5±11.1 years; left ventricular [LV] ejection fraction 29%; &OV0312;o2peak 13 mL · kg−1 · min−1) were randomized to either moderate continuous training (70% of highest measured heart rate, ie, peak heart rate) or aerobic interval training (95% of peak heart rate) 3 times per week for 12 weeks or to a control group that received standard advice regarding physical activity. &OV0312;o2peak increased more with aerobic interval training than moderate continuous training (46% versus 14%, P<0.001) and was associated with reverse LV remodeling. LV end-diastolic and end-systolic volumes declined with aerobic interval training only, by 18% and 25%, respectively; LV ejection fraction increased 35%, and pro-brain natriuretic peptide decreased 40%. Improvement in brachial artery flow-mediated dilation (endothelial function) was greater with aerobic interval training, and mitochondrial function in lateral vastus muscle increased with aerobic interval training only. The MacNew global score for quality of life in cardiovascular disease increased in both exercise groups. No changes occurred in the control group. Conclusions— Exercise intensity was an important factor for reversing LV remodeling and improving aerobic capacity, endothelial function, and quality of life in patients with postinfarction heart failure. These findings may have important implications for exercise training in rehabilitation programs and future studies.

Intracellular manganese ions provide strong T1 relaxation in rat myocardium.

The efficacy of manganese ions (Mn2+) as intracellular (ic) contrast agents was assessed in rat myocardium. T1 and T2 and Mn content were measured in ventricular tissue excised from isolated perfused hearts in which a 5‐min wash‐in with 0, 30, 100, 300, or 1000 μM of Mn dipyridoxyl diphosphate (MnDPDP) was followed by a 15‐min wash‐out to remove extracellular (ec) Mn2+. An inversion recovery (IR) analysis at 20 MHz revealed two T1 components: an ic and short T1‐1 (650–251 ms), and an ec and longer T1‐2 (2712–1042 ms). Intensities were about 68% and 32%, respectively. Tissue Mn content correlated particularly well with ic R1‐1. A two‐site water‐exchange analysis of T1 data documented slow water exchange with ic and ec lifetimes of 11.3 s and 7.5 s, respectively, and no differences between apparent and intrinsic relaxation parameters. Ic relaxivity induced by Mn2+ ions in ic water was as high as 56 (s mM)−1, about 8 times and 36 times higher than with Mn2+ aqua ions and MnDPDP, respectively, in vitro. This value is as high as any reported to date for any synthetic protein‐bound metal chelate. The increased rotational correlation time (τR) between proton and electron (Mn2+) spins, and maintained inner‐sphere water access, might make ic Mn2+ ions and Mn2+‐ion‐releasing contrast media surprisingly effective for T1‐weighted imaging. Magn Reson Med 52:506–514, 2004.

Analyzing equilibrium water exchange between myocardial tissue compartments using dynamical two-dimensional correlation experiments combined with manganese-enhanced relaxography

Water compartments were identified and equilibrium water exchange was studied in excised rat myocardium enriched with intracellular manganese (Mn2+). Standard relaxographic measurements were supplemented with diffusion‐T2 and T1‐T2 correlation measurements. In nonenriched myocardium, one T1 component (800 ms) and three T2 components (32, 120, and 350 ms) were identified. The correlation measurements revealed fast‐ and slow‐diffusing water fractions with mean diffusion coefficients of 1.2 × 10−5 and 3.0 × 10−5 cm2 s−1. The two shortest T2 components, which had different diffusivities, both originated from water in intracellular compartments. A component with longer relaxation time (T1 ≈ 2200 ms; T2 ≈ 1200 ms), originating from extra‐tissue water, was also observed. The presence of this component may lead to erroneous estimations of water exchange rates from multiexponential relaxographic analyses of excised tissues. The tissue T1 value is strongly reduced with increasing enrichment of Mn2+, and eventually a second tissue T1 component emerges, indicating a shift in the equilibrium water exchange between intra‐ and extracellular compartments from the fast‐exchange limit to the slow‐exchange regime. Using a two‐site water exchange analysis, the lifetime of intracellular water, Tic, was found to be 475 ms, with a fraction, pic, of 0.71. Magn Reson Med 58:674–686, 2007.

Manganese-calcium interactions with contrast media for cardiac magnetic resonance imaging: a study of manganese chloride supplemented with calcium gluconate in isolated Guinea pig hearts.

Objectives:Manganese ions (Mn2+) enter cardiomyocytes via calcium (Ca2+) channels and enhance relaxation intracellularly. To prevent negative inotropy, new Mn2+-releasing contrast agents have been supplemented with high Ca2+. The study aim was to investigate how this affects cardiac function and magnetic resonance efficacy. Materials and Methods:MnCl2 based contrast agents, manganese and manganese–calcium (Ca2+:Mn2+ 10:1), were infused during 4 repeated washin–washout sequences in perfused guinea pig hearts. [Mn2+] were 10, 50, 100 and 500 μM. Results:During washin, manganese depressed left ventricular developed pressure (LVDP) by 4, 9, 17, and 53% whereas manganese–calcium increased LVDP by 13, 18, 25, and 56%. After experiments, tissue Mn contents (nmol/g dry wt) were control <40, manganese 3720, and manganese–calcium 1620. T1 was reduced by 85–92% in Mn2+-enriched hearts. Conclusions:High Ca2+ supplements to Mn2+-releasing contrast agents may be counterproductive by inducing a strong positive inotropic response and by reducing the magnetic resonance efficacy.

Hyperosmotic perfusion of the beating rat heart and the role of the Na + /K + /2CI − co-transporter and the Na + /H + exchanger

Abstract The aim of the present study was to investigate the role of the Na+/K+/2CI− co-transporter and the Na+/H+ exchanger on contractile function and electrolyte regulation during hyperosmotic perfusion of the heart.Langendorff perfused rat hearts were subjected to hyperosmolal perfusion in 10-min intervals. Perfusates were made hyperosmotic by adding mannitol to the buffer (370, 450 and 600 mOsmol/kg H2O). Cardiac contractile function was monitored with a balloon in the left ventricle (LV) coupled to a pressure transducer. Cardiac effluent was sampled repeatedly throughout and after hyperosmotic perfusion and analyzed for content of Na+, K+ and CI−.All three hyperosmotic perfusates initially reduced LV developed pressure (LVDP), but for 370 and 450 mOsmol/kg H2, LVDP recovered to baseline within 4 min of perfusion. With 600 mOsmol/kg H2, LVDP recovered slowly and was 50% below baseline after 10 min of hyperosmotic perfusion. Inhibition of the Na+/H+ exchanger with 5-(N-ethyl-N-isopropyl) amiloride (EIPA) and 3-methyl-sulfonyl-4-piperidinobenzoyl-guanidine methanesulfonate (HOE 694) abolished the recovery of LVDP to the 600 mOsmol/kg H2 perfusate, whereas inhibition of the Na+/K+/2CI− co-transporter had no impact on LVDP. Potassium was taken up by the heart during hyperosmotic perfusion and this uptake was significantly reduced with inhibition of the Na+/H+ exchanger. Intracellular pH was assessed with 31P magnetic resonance spectroscopy and hyperosmolality induced a significant alkalosis that was dependent upon the Na+/H+ exchanger.The rat heart responds to moderate elevations in osmolality with a transient reduction in contractile function, whereas an elevation of 300 mOsmol/kg H2 persistently reduces contractile function. The Na+/H+ exchanger, but not the Na+/K+/2CI− co-transporter, is of importance in contractile recovery and electrolyte regulation during hyperosmotic perfusion in the rat heart.

Dynamic water changes in excised rat myocardium assessed by continuous distribution of T1 and T2

Ischemic changes in excised rat myocardium were followed by series of T1 or T2 measurements from 1 to 60 min after isolated perfusion cessation, and the influence of manganese enhancement was investigated. An inverse Laplace transformation (ILT) of T1 or T2 data was used to resolve the number, time constants, and fractions of tissue water components in a continuous distribution. For T1 distributions, one single tissue component ∼900 ms was significantly shortened and dispersed by manganese enhancement (25 and 200 μM MnCl2). For T2 distributions, three tissue components (∼30, ∼100, and ∼350 ms) were obtained initially. The two shortest components merged after ∼10 min to one component (∼40 ms). Both T1 and T2 tissue components became shorter with time. In particular, the T2 distribution dynamics might be compatible with complex sequential changes in tissue water fractions during ischemia. Magn Reson Med 58:442–447, 2007.

Protective Effects of Repetitive Injections of Radiographic Contrast Media on the Subsequent Tolerance to Ischemia in the Isolated Rat Heart

AbstractPurpose: Despite detailed knowledge of the effects of X-ray contrast media on cardiac function, no studies have examined the effect of contrast media injections on the subsequent tolerance to ischemia in the heart. Methods: Isolated perfused rat hearts were exposed to repetitive injections of iohexol, iodixanol, or ioxaglate before 30 min of global ischemia and 120 min of reperfusion. These groups were compared with control (no pretreatment) and ischemic preconditioning known to reduce infarct size. Physiologic variables and infarct size were measured Results: Pretreatment with iodixanol reduced infarct size significantly compared with control and thus afforded protection against ischemia. Injections with iohexol and ioxaglate reduced infarct size, although not significantly, compared with control. Conclusion: Pretreatment of the isolated rat heart with commonly used contrast media enhances the cardiac tolerance to subsequent ischemia. The mechanism behind this protective effect could not be determined, but could involve stretching of the heart and/or generation of nitric oxide.

Effect of low-dose dobutamine on myocardial uptake of manganese - a possible viability marker in cardiac MRI

Introduction The MRI contrast media manganese-dipyridoxyl-diphosphate (MnDPDP) has been shown to be a marker of viability in patients with myocardial infarction, as manganese-ions follow the calcium-pathways and accumulate in viable myocardial cells. However, the contrastto-noise ratio is presently too low for clinical use. In a previous study in rats given manganese-cloride (MnCl2), dobutamine increased the myocardial uptake of Mn significantly.