Costas Pantos

Hyperthyroidism is associated with preserved preconditioning capacity but intensified and accelerated ischaemic contracture in rat heart.

Background: The present study was undertaken to define the effects of thyroxine administration on ischaemic preconditioning (PC) and the ischaemic contracture. Methods: Hyperthyroidism was induced by administration of L-thyroxine in rats (THYR) while normal animals served as controls (NORMa). Isolated rat hearts were perfused in a Langendorff preparation. NORMa control (n = 16) and THYR control (n = 9) hearts underwent 20 min of ischaemia and 45 min reperfusion while NORMa PC (n = 16) and THYR PC (n = 14) were subjected to PC before ischaemia. Additional normal hearts were subjected to 30 min of ischaemia with and without PC, NORMb control, n = 8 and NORMb PC, n = 6. Postischaemic recoveries of left ventricular (LV) developed pressure were expressed as % of the initial value (LVDP%). Severity of contracture was measured by the time (Tmax) and magnitude (Cmax) of peak contracture. Results: LVDP% was significantly higher after PC, both in NORMa and THYR rats. In NORMa control hearts, ischaemic contracture had not yet reached a plateau at 20 min of ischaemia. Contracture appeared earlier in THYR control and PC than in NORMa control and PC groups. Tmax was 22.1 (0.9) vs 16.8 (1.4) min for NORMb control and PC, p < 0.05 and 12.5 (1.0) vs 9.3 (1.1) min for THYR control and PC hearts, p < 0.05. Tmax was earlier in both THYR groups compared to NORMb groups, p < 0.05. Cmax was significantly higher in both THYR groups compared to both NORMb groups. Conclusion: Ischaemic contracture is both accelerated and accentuated in thyroxine treated hearts while preconditioning capacity is preserved. Preconditioning and thyroxine administration shorten Tmax in an additive way, whereas Cmax in hyperthyroid hearts did not further increase by preconditioning.

Enhanced tolerance of the rat myocardium to ischemia and reperfusion injury early after acute myocardial infarction

AbstractIt is now recognized that changes occurring during cardiac remodeling may influence the tolerance of the myocardium to ischemic stress. Therefore, the present study investigated the response of the post-infarcted heart to ischemia in an experimental model of ischemia and reperfusion injury and the possible underlying mechanisms. Acute myocardial infarction (AMI) was induced in Wistar male rats by ligating the left coronary artery (AMI, n = 13), while sham-operated rats were used as controls (SHAM, n = 11). At 2 weeks, cardiac dysfunction was observed in AMI, as indicated by the reduction of the left ventricular EF%. Isolated hearts were then subjected to 30 min of zero-flow global ischemia followed by 45 min of reperfusion. Ischemic contracture was significantly depressed in AMI hearts. Postischemic left ventricular end diastolic pressure (LVEDP45) in mmHg and LDH release in IU/g were markedly decreased; LVEDP45 was 52.1 (7.5) for AMI vs 96.6 (7.5),P < 0.05 and LDH release was 7.5 (1.0) in AMI vs 11.4 (0.56) in SHAM, P < 0.05. This response was associated with 2-fold increase in HSP70 expression in AMI hearts (noninfarcted segment), P < 0.05 vs SHAM and 1.7 fold increase in the expression of the phospho-HSP27, P < 0.05, while the expression of PKCε was shown to be 1.4-fold less in AMI, P < 0.05. In conclusion, the post-infarcted heart seems to be resistant to ischemiareperfusion injury and heat shock protein 70 and 27 may be involved in this response.

Myocardial protection in man—from research concept to clinical practice

Myocardial protection aims at preventing myocardial tissue loss: (a) In the acute stage, i.e., during primary angioplasty in acute myocardial infarction. In this setup, the attenuation of reperfusion injury is the main target. As a “mechanical” means, post-conditioning has already been tried in man with encouraging results. Pharmacologic interventions that could be of promise are statins, insulin, peptide hormones, including erythropoietin, fibroblast growth factor, and many others. (b) The patient with chronic coronary artery disease offers another paradigm, with the target of avoidance of further myocyte loss through apoptosis and inflammation. Various pharmacologic agents may prove useful in this context, together with exercise and “mechanical” improvement of cardiac function with attenuation of myocardial stretch, which by itself is a noxious influence. A continuous effort toward acute and chronically preserving myocardial integrity is a concept concerning both the researcher and the clinician.

Heart dysfunction induced by choline-deficiency in adult rats: The protective role of l-carnitine

Choline is a B vitamin co-factor and its deficiency seems to impair heart function. Carnitine, a chemical analog of choline, has been used as adjunct in the management of cardiac diseases. The study investigates the effects of choline deficiency on myocardial performance in adult rats and the possible modifications after carnitine administration. Wistar Albino rats (n=24), about 3 months old, were randomized into four groups fed with: (a) standard diet (control-CA), (b) choline deficient diet (CDD), (c) standard diet and carnitine in drinking water 0.15% w/v (CARN) and (d) choline deficient diet and carnitine (CDD+CARN). After four weeks of treatment, we assessed cardiac function under isometric conditions using the Langendorff preparations [Left Ventricular Developed Pressure (LVDP-mmHg), positive and negative first derivative of LVDP were evaluated], measured serum homocysteine and brain natriuretic peptide (BNP) levels and performed histopathology analyses. In the CDD group a compromised myocardium contractility compared to control (P=0.01), as assessed by LVDP, was noted along with a significantly impaired diastolic left ventricular function, as assessed by (-) dp/dt (P=0.02) that were prevented by carnitine. Systolic force, assessed by (+) dp/dt, showed no statistical difference between groups. A significant increase in serum BNP concentration was found in the CDD group (P<0.004) which was attenuated by carnitine (P<0.05), whereas homocysteine presented contradictory results (higher in the CDD+CARN group). Heart histopathology revealed a lymphocytic infiltration of myocardium and valves in the CDD group that was reduced by carnitine. In conclusion, choline deficiency in adult rats impairs heart performance; carnitine acts against these changes.

Experimental hyperthyroidism increases expression of parathyroid hormone‐related peptide and type‐1 parathyroid hormone receptor in rat ventricular myocardium of the Langendorff ischaemia–reperfusion model

Parathyroid hormone‐related peptide (PTHrP) is released under ischaemic conditions and it improves contractile function of stunned myocardium. The actions of PTHrP are mediated primarily by the type 1 parathyroid hormone receptor (PTH.1R), while PTHrP and PTH.1R expression levels are increased in ventricular hypertrophy associated with experimental hyperthyroidism. Since chronic administration of thyroxine (T4) improves postischaemic recovery in isolated heart models subjected to ischaemia–reperfusion stress, we tested the hypothesis that experimentally induced hyperthyroidism is associated with elevated expression of PTHrP and PTH.1R in rat myocardium. Hyperthyroid and control male Wistar rats were subjected to ischaemia–reperfusion stress using the Langendorff technique, and the PTHrP and PTH.1R expression was assessed by relative quantitative reverse transcriptase‐polymerase chain reaction, Western blot analysis and immunohistochemistry. In the Langendorff model, the recovery of left ventricular developed pressure at the end of the stablization period and 45 min into the reperfusion period was used to assess the cardioprotective actions of T4 administration. Our data show that hyperthyroid animals had increased tolerance to the ischaemia–reperfusion stress and that this was associated with an increase of PTHrP and PTH.1R expression levels compared with those of control animals. In the control animals, the expression of PTHrP was increased 45 min into the reperfusion phase, while the PTH.1R expression pattern was significantly and gradually decreased throughout the ischaemia and reperfusion phases. In the hyperthyroid animals, the PTHrP and PTH.1R expression pattern was significantly higher throughout the ischaemia and reperfusion phases compared with that of control hearts. Our data suggest that increasing levels of PTHrP and PTH.1R expression can mediate, at least in part, the T4 administration‐induced cardioprotection in rat ventricular myocardium.

Myocardial remodeling, an overview

Myocardial remodeling (REM) is a deleterious processcharacterized by gradual cardiac enlargement, cardiacdysfunction and typical molecular changes. It is a universalphenomenon, being caused by many pathological condi-tions [1, 2].Of these, myocardial infarction is the more common. Ithas been estimated that even with the timely use of primaryangioplasty, and with the subsequent use of all the cur-rently recommended drug therapies, which will be dis-cussed later, the emergence of REM is around 30%,eventually leading to heart failure and death [3, 4]. It hasbeen stressed that if 20% of the ‘‘myocardium at risk’’ issalvaged, the course toward heart failure can be avoided[5].Moreover, uncontrolled hypertension is still a majorcause of heart failure, evolving to REM. It must not beforgotten that valvular heart disease, even with the progressof cardiac surgery, can still lead to cardiac dilatation,effectively REM.Only very recently it was stated that in mitral regurgi-tation, operation before the left ventricular end-systolicdiameter exceeds 40 mm, survival is higher [6]. REM isalso an end result of cardiomyopathy, either post-myocar-ditis or genetically produced, and cancer chemotherapy [7].The term was first introduced by Janice Pfeffer’s group in1985 [8].A comprehensive review was given 4 years ago by Opieet al. [9]. One part of the 1990 definition which theyre-iterate is very important, i.e. it represents an importanttherapeutic target. REM must be viewed as a process that isinitially ‘‘adaptive’’; aiming at offsetting an unfavorablesituation. Thus, in aortic stenosis and hypertension, theensuing left ventricular concentric hypertrophy results inreduced myocardial wall stress; conversely, in the course,in mitral and aortic regurgitation, left ventricular eccentrichypertrophy concerns stroke volume conservation. Thus,hypertrophy finally leads to ventricular dilatation andbecomes ‘‘maladaptive’’ and detrimental [10].However, it is not only the myocardium that undergoespathological changes. It is currently widely recognized thattwo more elements contribute to REM and cardiacmalfunction:– The development of myocardial fibrosis, resultingfrom increased abnormal collagen production. Fibrosisresults in systolic but also diastolic dysfunction throughincreased cardiac stiffness [11].– The inadequate increase in capillary density of thehypertrophying and remodeling myocardium thatresults in inadequate oxygenation [12]. Indeed, evenafter an acute myocardial infarction, capillary density isdecreased as REM ensues [13]As already mentioned, a main characteristic of theremodeling myocardium is the return to the ‘‘fetal’’ phe-notype, which is characterized by decreased contractilitybut also lower energy consumption [14]. Also, the ratioHMC a/b is decreased, ANP and BNP and a-actin over-expressed, and the SERCA/phospholamban activitydecreased.

SARCOPLASMIC RETICULUM CALCIUM UPTAKE CHANGES AND CELL SURVIVAL AFTER EXPERIMENTAL ACUTE MYOCARDIAL INFARCTION

Apoptosis is the main determination of cell death after early acute cardiac ischemia/reperfusion (AMI/R). We evaluated the effects of AMI/R on SR Ca-cycling and survival/apoptotic proteins. Male rats were subjected to left coronary artery ligation, while sham-operated animals served as controls.