COVID-19-associated cardiovascular morbidity in older adults: a position paper from the Italian Society of Cardiovascular Researches.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects host cells following binding with the cell surface ACE2 receptors, thereby leading to coronavirus disease 2019 (COVID-19). SARS-CoV-2 causes viral pneumonia with additional extrapulmonary manifestations and major complications, including acute myocardial injury, arrhythmia, and shock mainly in elderly patients. Furthermore, patients with existing cardiovascular comorbidities, such as hypertension and coronary heart disease, have a worse clinical outcome following contraction of the viral illness. A striking feature of COVID-19 pandemics is the high incidence of fatalities in advanced aged patients: this might be due to the prevalence of frailty and cardiovascular disease increase with age due to endothelial dysfunction and loss of endogenous cardioprotective mechanisms. Although experimental evidence on this topic is still at its infancy, the aim of this position paper is to hypothesize and discuss more suggestive cellular and molecular mechanisms whereby SARS-CoV-2 may lead to detrimental consequences to the cardiovascular system. We will focus on aging, cytokine storm, NLRP3/inflammasome, hypoxemia, and air pollution, which is an emerging cardiovascular risk factor associated with rapid urbanization and globalization. We will finally discuss the impact of clinically available CV drugs on the clinical course of COVID-19 patients. Understanding the role played by SARS-CoV2 on the CV system is indeed mandatory to get further insights into COVID-19 pathogenesis and to design a therapeutic strategy of cardio-protection for frail patients.

Glutathionyl-hemoglobin levels in carotid endarterectomy: a pilot study on 12 cases clinically uneventful.

Aim: Carotid endarterectomy is a widely accepted procedure for stroke prevention, and carotid clamping is a necessary surgical step. Glutathionylated haemoglobin (HbSSG) has been recently employed as a biomarker of oxidative stress, its level being increased under several conditions, including hypoxia. This study aims to evaluating whether HbSSG level in peripheral and/or jugular blood is affected during carotid surgery under normal routine operative conditions. Methods: This study enrolled 13 consecutive patients undergoing elective carotid endarterectomy under general anesthesia. At different times during surgery, blood was taken simultaneously from both a peripheral vein and the jugular vein ipsilateral to the clamped carotid. HbSSG was measured in RBC hemolysates by MALDI-ToF mass spectrometry in each sample. Results: Three patients showed a complex pattern of rise and fall of HbSSG levels in different time periods before, during and after surgery. They also showed statistically significant differences between peripheral and jugular blood, with mean HbSSG levels in jugular blood higher by approx. 30% than those of peripheral blood at the end of the period of carotid clamping. In all three patients HbSSG levels fell to pre-clamping values within 2 min from removal of carotid artery clamp. Conclusion: Although effective routine drug management allowed brain safety during carotid clamping time, a number of patients showed a fast modification over time of the HbSSG levels in jugular blood, suggesting that "resident" cerebral biochemical protection mechanisms could play some role to compensate clinically silent brain oxidative stress.

Inhibition of ceramide de novo synthesis as a postischemic strategy to reduce myocardial reperfusion injury.

The injury caused by myocardial reperfusion after ischemia can be contained by interventions aimed at reducing the inflammation and the oxidative stress that underlie exacerbation of tissue damage. Sphingolipids are a class of structural and signaling lipid molecules; among them, the inflammation mediator ceramide accumulates in the myocardium upon ischemia/reperfusion. Here, we show that, after transient coronary occlusion in mice, an increased de novo ceramide synthesis takes place at reperfusion in the ischemic area surrounding necrosis (area at risk). This correlates with the enhanced expression of the first and rate-limiting enzyme of the de novo pathway, serine palmitoyltransferase (SPT). The intraventricular administration at reperfusion of myriocin, an inhibitor of SPT, significantly protected the area at risk from damage, reducing the infarcted area by 40.9 % relative to controls not treated with the drug. In the area at risk, myriocin downregulated ceramide, reduced the content in other mediators of inflammation and reactive oxygen species, and activated the Nrf2-HO1 cytoprotective response. We conclude that an enhanced ceramide synthesis takes part in ischemia/reperfusion injury and that myriocin treatment can be proposed as a strategy for myocardial pharmacological postconditioning.

CO-MP4, a polyethylene glycol-conjugated haemoglobin derivative and carbon monoxide carrier that reduces myocardial infarct size in rats.

BACKGROUND AND PURPOSE: MP4 (Hemospan) is a Hb-based oxygen therapeutic agent, based on polyethylene-glycol (PEG) conjugation to Hb, undergoing clinical trials as an oxygen carrier. This study describes the functional interaction between MP4 and carbon monoxide (CO), as a CO delivery agent, and the effects of CO-MP4 on myocardial infarct size following ischaemia and reperfusion in rats. EXPERIMENTAL APPROACH: Kinetic measurements of CO-MP4 binding were used to evaluate the effects of PEG modification on Hb subunit structure/function and to calculate CO-MP4 equilibrium constants. CO transport by CO-MP4 was shown by ligand (O2/CO) partitioning between MP4 and red blood cell (RBC)-Hb. Pharmacological effects of CO-MP4 were studied on myocardial infarction in rats. KEY RESULTS: CO binding kinetics show primary structural/functional effects on beta chains in MP4, with alpha chains maintaining the ability to undergo tertiary conformational transition. CO confers long-term, room-temperature stability and is able to rapidly re-equilibrate between MP4 and RBCs. In a rat model of myocardial infarct, in contrast to oxy-MP4, CO-MP4 reduced infarct size when administered prior to the induction of ischaemia. CONCLUSIONS AND IMPLICATIONS: MP4 PEGylation chemistry modifies the individual function of Hb subunits, but results in an overall CO equilibrium constant similar to that for unmodified Hb. CO-MP4 is able to deliver CO to the circulation and reduces ischaemia/reperfusion injury in rats, providing the first evidence for this drug as a CO therapeutic agent.

Metabolic modulation induced by chronic hypoxia in rats using a comparative proteomic analysis of skeletal muscle tissue.

Hypoxia-induced changes of rat skeletal muscle were investigated by two-dimensional difference in-gel electrophoresis (2D-DIGE) and mass spectrometry. The results indicated that proteins involved in the TCA cycle, ATP production, and electron transport are down-regulated, whereas glycolytic enzymes and deaminases involved in ATP and AMP production were up-regulated. Up-regulation of the hypoxia markers hypoxia inducible factor 1 (HIF-1alpha) and pyruvate dehydrogenase kinase 1 (PDK1) was also observed, suggesting that in vivo adaptation to hypoxia requires an active metabolic switch. The kinase protein, mammalian target of rapamycin (mTOR), which has been implicated in the regulation of protein synthesis in hypoxia, appears unchanged, suggesting that its activity, in this system, is not controlled by oxygen partial pressure.

Trimetazidine reduces basal cytosolic Ca2+ concentration during hypoxia in single Xenopus skeletal myocytes.

We tested the hypotheses that: (1) Ca(2+) handling and force production would be irreversibly altered in skeletal muscle during steady-state contractions when subjected to severe, prolonged hypoxia and subsequent reoxygenation; and (2) application of the cardio-protective drug trimetazidine would attenuate these alterations. Single, living skeletal muscle fibres from Xenopus laevis were injected with the Ca(2+) indicator fura 2, and incubated for 1 h prior to stimulation in 100 micro M TMZ-Ringer solution (TMZ; n = 6) or standard Ringer solution (CON; n = 6). Force and relative free cytosolic Ca(2+) concentration ([Ca(2+)](c)) were measured during continuous tetanic contractions produced every 5 s as fibres were sequentially perfused in the following manner: 3 min high extracellular P(O(2)) (159 mmHg), 15 min hypoxic perfusion (3-5 mmHg) then 3 min high P(O(2)). Hypoxia caused a decrease in force and peak [Ca(2+)](c) in both the TMZ and CON fibres, with no significant (P < 0.05) difference between groups. However, basal [Ca(2+)](c) was significantly lower during hypoxia in the TMZ group vs. the CON group. While reoxygenation generated only modest recovery of relative force and peak [Ca(2+)](c) in both groups, basal [Ca(2+)](c) remained significantly less in the TMZ group. These results demonstrated that in contracting, single skeletal muscle fibres, TMZ prevented increases in basal [Ca(2+)](c) generated during a severe hypoxic insult and subsequent reoxygenation, yet failed to protect the cell from the deleterious effects of prolonged hypoxia followed by reoxygenation.

Triglycerides impair postischemic recovery in isolated hearts: roles of endothelin-1 and trimetazidine.

There is growing evidence that hypertriglyceridemia exacerbates ischemic injury. We tested the hypothesis that triglycerides impair myocardial recovery from low-flow ischemia in an ex vivo model and that such an effect is related to endothelin-1. Hyperglycemic (glucose concentration = 12 mmol/l) and hyperinsulinemic (insulin concentration = 1.2 micromol/l) isolated rat hearts were perfused with Krebs-Henseleit buffer (PO(2) = 670 mmHg, pH 7.4, 37 degrees C) added with increasing triglycerides (0, 1,000, 2,000, and 4,000 mg/dl, n = 6-9 rats/group). Hearts were exposed to 60 min of low-flow ischemia (10% of basal coronary flow), followed by 30 min of reperfusion. We found that increasing triglycerides impaired both the diastolic (P < 0.005) and systolic (P < 0.02) recovery. The release of endothelin-1 during reperfusion increased linearly with triglyceride concentration (P = 0.0009). Elevated triglycerides also increased the release of nitrite and nitrate (NO(x)), the end products of nitric oxide, up to 6 micromol/min. Trimetazidine (1 micromol) further increased NO(x) release, blunted endothelin-1 release, and protected myocardial function during recovery. We conclude that high triglyceride levels impair myocardial recovery after low-flow ischemia in association with endothelin-1 release. The endothelium-mediated effect of triglycerides on both contractile recovery and endothelin-1 release is prevented by 1 microM trimetazidine.

Hypoxia-dependent protein expression: erythropoietin.

Normal cell homeostasis relies on the ordered flow of nutrients and substrates through metabolic pathways. Any perturbation of this flow eventually leads to dysfunction, impairment of defense mechanisms, loss of viability and death. High altitude and pathological hypoxia represent a serious and frequent cause for the loss of cell viability. Although organisms customarily respond by triggering adaptive or maladaptive mechanisms, all forms of life eventually succumb to hypoxia if it is severe enough, irrespectively of the primary cause. This paper reviews one of the mechanisms by which organisms respond to hypoxia: erythropoiesis. Although such response is not always beneficial, the discovery of the biochemical mechanisms underlying erythropoiesis has triggered an active field of research that is actually applying lessons learned in the mountains to a more clinical environment.

Tolerance of isolated rat hearts to low-flow ischemia and hypoxia of increasing duration: protective role of down-regulation and ATP during ischemia.

We tested the hypothesis that down-regulated hearts, as observed during low-flow ischemia, adapt better to low O2 supply than non-down-regulated, or hypoxic, hearts. To address the link between down-regulation and endogenous ischemic protection, we compared myocardial tolerance to ischemia and hypoxia of increasing duration. To that end, we exposed buffer-perfused rat hearts to either low-flow ischemia or hypoxia (same O2 shortage) for 20, 40 or 60 min (n = 8/group), followed by reperfusion or reoxygenation (20 min, full O2 supply). At the end of the O2 shortage, the rate-pressure product was less in ischemic than hypoxic hearts (p < 0.0001). The recovery of the rate-pressure product after reperfusion or reoxygenation was not different for t = 20 min, but was better in ischemic than hypoxic hearts for t = 40 and 60 min (p < 0.02 and p < 0.0002, respectively). The end-diastolic pressure remained unchanged during low-flow ischemia (0.024 +/- 0.013 mmHg x min(-1)), but increased significantly during hypoxia (0.334 +/- 0.079 mmHg x min(-1)). We conclude that, while the duration of hypoxia progressively impaired the rate-pressure product and the end-diastolic pressure, hearts were insensitive of the duration of low-flow ischemia, thereby providing evidence that myocardial down-regulation protects hearts from injury. Excessive ATP catabolism during ischemia in non-down-regulated hearts impaired myocardial recovery regardless of vascular, blood-related and neuro-hormonal factors. These observations support the view that protection is mediated by the maintenance of the ATP pool.

Swim training improves myocardial resistance to ischemia in rats.

As the relationship between training and ischemic heart disease is not yet unraveled, we test the hypothesis that, in a model free from environmental, behavioural, and neuro-hormonal factors, endurance training improves myocardial resistance to ischemia. As carbohydrate metabolism is relevant for myocardial resistance to ischemia, we also test whether hyperglycemia blunts the protective effect of training. Eight-week old rats were randomly assigned to four groups (n = 6-8): sedentary or trained (3-week swim program, up to 2 h/day), and normal or high-carbohydrate diet (50 g/l sucrose in drinking water). Excised hearts were perfused isovolumically (flow = 15 ml/min) with Krebs-Henseleit (2 mM free Ca++, 11 mM glucose, pH 7.38 +/- 0.02, PO2 = 670 +/- 6 mmHg, PCO2 = 43 +/- 1 mmHg, mean +/- SE), exposed to 60 min low-flow (1.5 ml/min) ischemia, and then reperfused for 30 min (15 ml/min). In normally fed rats training increased the stroke volume index (97.5 +/- 13.0 vs. 72.6 +/- 6.2 microl, P = 0.05), depressed diastolic contracture (+2.3 +/- 2.0 vs. +24.2 +/- 6.7 mmHg, P = 0.02), improved the recovery of developed pressure x heart rate (33.8 +/- 2.3 vs. 24.1 +/- 3.3 mmHg/min/1000, P = 0.05), and decreased arrhythmias (P = 0.05). In high-carbohydrate-fed rats training induced myocardial hypertrophy (1.95 +/- 0.08 vs. 1.67 +/- 0.03 g, P = 0.02) and decreased arrhythmias but did not affect stroke volume, developed pressure x heart rate, and diastolic contracture. Thus endurance training improves myocardial resistance to ischemia but a high-carbohydrate diet partially blunts this protection. The occurrence of an inducible alteration able to modulate myocardial tolerance to ischemia may give clues to extend our knowledge of ischemic preconditioning.

Detection of haemoglobins with abnormal oxygen affinity by single blood gas analysis and 2,3-diphosphoglycerate measurement.

The aim is to determine if a single measurement of blood 2,3-diphosphoglycerate combined with gas analysis (pH, PCO2, PO2 and saturation) can identify the cause of an altered blood-oxygen affinity: the presence of an abnormal haemoglobin or a red cell disorder. The population (n=94) was divided into healthy controls (A, n=14), carriers of red cell disorders (B, n=72) and carriers of high oxygen affinity haemoglobins (C, n=8). Those variables were measured both in samples equilibrated at selected PCO2 and PO2 and in venous blood. In the univariable approach applied to equilibrated samples, we correctly identified C subjects in 93.6% or 96.8% of the cases depending on the selected variable, the standard P50 (PO2 at which 50% of haemoglobin is oxygenated) or a composite variable calculated from the above measurements. After introducing the haemoglobin concentration as a further discriminating variable, the A and B subjects were correctly identified in 91.9% or 94.2% of the cases, respectively. These figures become 93.0% or 86.1%, and 93.7% or 94.9% of the cases when using direct readings from venous blood, thereby avoiding the blood equilibration step. This test is feasible also in blood samples stored at 4 degrees C for 48 h, or at room temperature for 8 h.

Biochemical consequences of electrical pacing in ischemic-reperfused isolated rat hearts.

It is still unclear if performance recovery in postischemic hearts is related to their tissue level of high-energy phosphates before reflow. To test the existence of this link, we monitored performance, metabolism and histological damage in isolated, crystalloid-perfused rat hearts during 20 min of low-flow ischemia (90% coronary flow reduction) and reflow. To prevent interference from different ischemia times and perfusing media compositions, the ischemic ATP level was varied by changing energy demand (electrical pacing at 330 min(-1)). Under full coronary flow conditions, work output, as well as ATP and phosphocreatine contents were the same in control, spontaneously contracting (n = 23) and paced (n = 21) hearts. During low-flow ischemia, the higher work output (p < 0.0001) in paced hearts decreased their tissue content of ATP, phosphocreatine and total adenylates and purines (p < 0.05), as opposed to maintained values in control hearts. During reflow, the recovery of mechanical performance and O2 uptake was 94 +/- 5% and 110 +/- 9% (p = NS vs. baseline) in controls, vs. 71 +/- 5% and 74 +/- 6% in paced hearts (p < 0.004 vs. baseline). The levels of ATP and total adenylates and purines remained constant in control, but were markedly depressed (p < 0.05 vs. baseline) in paced hearts. Phosphocreatine+creatine was the same in both groups. These data, together with the observed lack of creatine kinase leakage and of structural damage, indicate that myocardial recovery during reflow reflects the tissue level of ATP, phosphocreatine and total adenylates and purines during ischemia, regardless of physical cell damage.

Atenolol depresses post-ischaemic recovery in the isolated rat heart.

Metabolic events during ischaemia are probably important in determining post-ischaemic myocardial recovery. The aim of this study was to assess the effects of the beta-blocker atenolol and the high energy demand in an ischaemia-reperfusion model free of neurohormonal and vascular factors. We exposed Langendorff-perfused isolated rat hearts to low-flow ischaemia (30 min) and reflow (20 min). Three groups of hearts were used: control hearts (n =11), hearts that were perfused with 2.5 micrograms l-1atenolol (n =9), and hearts electrically paced during ischaemia to distinguish the effect of heart rate from that of the drug (n =9). The hearts were freeze-clamped at the end of reflow to determine high-energy phosphates and their metabolites. During ischaemia, the pressure-rate product was 2.3+/-0.2, 5.2+/-1.1, and 3.3+/-0.3 mmHg 10(3)min in the control, atenolol and paced hearts, respectively. In addition, the ATP turnover rate, calculated from venous (lactate), oxygen uptake and flow, was higher in atenolol (11.2+/-1.7 micromol min-1) and paced (8.1+/-0.8 micromol min-1) hearts than in control (6.2+/-0.8 micromol min-1). At the end of reflow, the pressurexrate product recovered 75.1+/-6.4% of baseline in control vs 54.1+/-9.1 and 48.8+/-4.4% in atenolol and paced hearts (P<0.05). In addition, the tissue content of ATP was higher in the control hearts (15.8+/-1. 0 micromol g(dw)(-1)) than in atenolol (10.5+/-2.6 micromol g(dw)(-1)) and paced (10.9+/-1.3 micromol g(dw)(-1)) hearts. Thus, by suppressing the protective effects of down-regulation, both atenolol and pacing apparently depress myocardial recovery in this model.

Differential depression of myocardial function and metabolism by lactate and H+.

The effects of both high blood H+ concentration ([H+]) and high blood lactate concentration ([lactate]) under ischemia-reperfusion conditions are receiving attention, but little is known about their effects in nonischemic hearts. Isolated rat hearts were Langendorff perfused at constant flow with media at two pH values (7.4 and 7.0) and two [lactate] (0 and 20 mM) in various sequences (n = 6/group). Coronary flow and arterial O2 content were kept constant at levels that allowed hearts to function without O2 supply limitation. We measured contractility, O2 uptake, diastolic pressure, and at the end of the protocol, tissue [lactate] and pH. Perfusion with high [lactate] raised tissue [lactate] from 5.5 +/- 0.1 to 17.5 +/- 2.6 micromol/heart (P < 0.0001), whereas decreasing the pH of the medium decreased tissue pH from 6.94 +/- 0.02 to 6.81 +/- 0.06 (P = 0.002). Heart rate was not affected by high [lactate] but was reversibly depressed by high [H+] (P = 0.004). Developed pressure declined by 20% in response to high [lactate], high [H+], and high [lactate] + high [H+] (P = 0.002). After the high-[lactate] challenge was withdrawn, pressure continued to decline. In contrast, withdrawing the high [H+] challenge allowed partial recovery. The behavior of diastolic pressure mirrored that of developed pressure. Although unaffected by high [lactate], the O2 uptake was reversibly depressed by high [H+]. This suggests higher O2 cost per contraction in the presence of high [lactate]. We conclude that for similar acute contractility depression, high [lactate] induces irreversible damage, likely at some point in the pathway of O2 utilization. In contrast, the effect of high [H+] appears reversible. These differential behaviors may have implications for heart function during heavy exercise and ischemia-reperfusion events.

Faster adjustment of O2 delivery does not affect V(O2) on-kinetics in isolated in situ canine muscle.

The mechanism(s) limiting muscle O2 uptake (VO2) kinetics was investigated in isolated canine gastrocnemius muscles (n = 7) during transitions from rest to 3 min of electrically stimulated isometric tetanic contractions (200-ms trains, 50 Hz; 1 contraction/2 s; 60-70% of peak V(O2)). Two conditions were mainly compared: 1) spontaneous adjustment of blood flow (Q) [control, spontaneous Q (C Spont)]; and 2) pump-perfused Q, adjusted approximately 15 s before contractions at a constant level corresponding to the steady-state value during contractions in C Spont [faster adjustment of O2 delivery (Fast O2 Delivery)]. During Fast O2 Delivery, 1-2 ml/min of 10(-2) M adenosine were infused intra-arterially to prevent inordinate pressure increases with the elevated Q. The purpose of the study was to determine whether a faster adjustment of O2 delivery would affect V(O2) kinetics. Q was measured continuously; arterial (Ca(O2)) and popliteal venous (Cv(O2)) O2 contents were determined at rest and at 5- to 7-s intervals during contractions; O2 delivery was calculated as Q x Ca(O2), and V(O2) was calculated as Q x arteriovenous O2 content difference. Times to reach 63% of the difference between baseline and steady-state VO2 during contractions were 23.8 +/- 2.0 (SE) s in C Spont and 21.8 +/- 0.9 s in Fast O2 Delivery (not significant). In the present experimental model, elimination of any delay in O2 delivery during the rest-to-contraction transition did not affect muscle V(O2) kinetics, which suggests that this kinetics was mainly set by an intrinsic inertia of oxidative metabolism.

Bioenergetics of contracting skeletal muscle after partial reduction of blood flow.

The purpose of this study was to examine the bioenergetics and regulation of O2 uptake (VO2) and force production in contracting muscle when blood flow was moderately reduced during a steady-state contractile period. Canine gastrocnemius muscle (n = 5) was isolated, and 3-min stimulation periods of isometric, tetanic contractions were elicited sequentially at rates of 0.25, 0.33, and 0.5 contractions/s (Hz) immediately followed by a reduction of blood flow [ischemic (I) condition] to 46 +/- 3% of the value obtained at 0.5 Hz with normal blood flow. The VO2 of the contracting muscle was significantly (P < 0.05) reduced during the I condition [6.5 +/- 0.8 (SE) ml . 100 g-1 . min-1] compared with the same stimulation frequency with normal flow (11.2 +/- 1.5 ml . 100 g-1 . min-1), as was the tension-time index (79 +/- 12 vs. 123 +/- 22 N . g-1 . min-1, respectively). The ratio of VO2 to tension-time index remained constant throughout all contraction periods. Muscle phosphocreatine concentration, ATP concentration, and lactate efflux were not significantly different during the I condition compared with the 0. 5-Hz condition with normal blood flow. However, at comparable rates of VO2 and tension-time index, muscle phosphocreatine concentration and ATP concentration were significantly less during the I condition compared with normal-flow conditions. These results demonstrate that, in this highly oxidative muscle, the normal balance of O2 supply to force output was maintained during moderate ischemia by downregulation of force production. In addition, 1) the minimal disruption in intracellular homeostasis after the initiation of ischemia was likely a result of steady-state metabolic conditions having already been activated, and 2) the difference in intracellular conditions at comparable rates of VO2 and tension-time index between the normal flow and I condition may have been due to altered intracellular O2 tension.

High-energy phosphates metabolism and recovery in reperfused ischaemic hearts.

BACKGROUND: The aim of this study was to assess how coronary flow, oxygen supply and energy demand affect myocardial ATP, phosphocreatine and their metabolites during oxygen shortage and recovery. METHODS: Isolated rat hearts were exposed for 20 min to either low-flow ischaemia or hypoxaemia at the same oxygen supply, followed by return to baseline conditions (20 min). Seventy-three hearts were divided into four groups: ischaemic or hypoxaemic, spontaneously beating or paced to increase energy demand. RESULTS: During O2 shortage, myocardial performance was less in ischaemic, spontaneously beating hearts (SpIs), than in the other groups (14 +/- 1% of baseline vs. 25-48%). Consequently, the tissue levels of ATP, total adenylates and phosphocreatine were maintained in SpIs, in contrast to marked decreases in the other groups. Upon reflow, the recovery of performance and of myocardial ATP was 94 +/- 5% in SpIs (P = NS vs. baseline) compared with 64-85% (P < 0.05 vs. baseline) in the other groups. The degree of recovery was positively related to the ischaemic contents of ATP (P = 0.03) and adenylates (P = 0.001), but not to that of phosphocreatine (P = NS). CONCLUSION: The maintenance of the ATP pool under low oxygen supply conditions is essential for good recovery. The most important factors that determine the ATP pool size are the energy demand, which increases the formation of diffusible ATP catabolites, and the coronary flow, which removes these catabolites, rather than the oxygen supply per se.

Effects of trimetazidine on metabolic and functional recovery of postischemic rat hearts.

The objective of this study was to test the hypothesis that the beneficial effect of trimetazidine during reflow of ischemic hearts is mediated by energy sparing and ATP pool preservation during ischemia. Isolated rat hearts (controls and rats treated with 10(-6) M trimetazidine, n = 17 per group) underwent the following protocol: baseline perfusion at normal coronary flow (20 minutes), low-flow ischemia at 10% flow (60 minutes), and reflow (20 minutes). We measured contractile function, O2 uptake, lactate release, venous pH and PCO2, and the tissue content of high-energy phosphates and their metabolites. During baseline, trimetazidine induced higher venous pH and lower PCO2 without influencing performance and metabolism. During low-flow ischemia, trimetazidine reduced myocardial performance (P = 0.04) and ATP turnover (P = 0.02). During reflow, trimetazidine improved performance (91 +/- 6% versus. 55 +/- 6% of baseline), prevented the development of diastolic contracture and coronary resistance, and reduced myocardial depletion of adenine nucleotides and purines. ATP turnover during low-flow ischemia was inversely related to recovery of the rate-pressure product (P = 0.002), end-diastolic pressure (P = 0.007), and perfusion pressure (P = 0.05). We conclude that trimetazidine-induced protection of ischemic-reperfused hearts is also mediated by energy sparing during ischemia, which presumably preserves the ATP pool during reflow.

Acid-base balance and O2 transport at high altitude.

Ear lobe blood pHa, PaCo2, PaO2, and O2 saturation (SaO2) were measured in healthy Caucasians and Sherpas at 3400 m (Namche Bazaar, Nepal, n = 4/5), 5050 m (Pyramid Laboratory, Lobuche, Nepal, n = 20/5) and 6450 m (Camp II of Mt Everest, n = 11/7). In the investigated altitude range, pHa increased progressively with altitude from 7.463 +/- 0.005 (mean +/- SE) to 7.496 +/- 0.006 in Caucasians whereas it remained essentially constant (7.45-7.46) in Sherpas. At all altitudes, PaCO2 was higher in Sherpas than in Caucasians (P < 0.02). By contrast, PaO2 and SaO2 were the same in Caucasians and Sherpas at all investigated altitudes. Moreover, in Caucasians sojourning for 3 weeks at 5050 m, PaCO2 kept decreasing whereas pHa, PaO2 and SaO2 remained constant. These data suggest that; (1) respiratory alkalosis was a common finding both in Caucasians and Sherpas; (2) at 6450 m. Sherpas were less alkalotic due to higher PaCO2 than Caucasians, possibly a consequence of a blunted ventilatory response; (3) at 6450 m, SaO2 and PaO2 were the same in Caucasians and Sherpas despite different PaCO2 values. The latter finding could be the consequence of one or more of the following adjustments in Sherpas: (1) an increased efficiency of alveolar O2 transfer, i.e. smaller alveolar-arterial O2 gradient; (2) a decreased (arterial-mixed venous) O2 difference possibly due to increased cardiac output; (3) a reduced increase of the [2,3-DPG]/[Hb] ratio; but not (4) an elevated gas exchange ratio (R). It is concluded that both physiological and biochemical variables contribute to optimize the O2 transport at altitude. Apparently a more efficient adaptation to hypoxia allows Sherpas to limit alkalosis through a lower ventilatory drive and to maintain SaO2 at the same PaO2 by decreasing the [2,3-DPG]/[Hb] ratio.