Is Intrinsic Cardioprotection a Laboratory Phenomenon or a Clinically Relevant Tool to Salvage the Failing Heart?

Cardiovascular diseases, especially ischemic heart disease, as a leading cause of heart failure (HF) and mortality, will not reduce over the coming decades despite the progress in pharmacotherapy, interventional cardiology, and surgery. Although patients surviving acute myocardial infarction live longer, alteration of heart function will later lead to HF. Its rising incidence represents a danger, especially among the elderly, with data showing more unfavorable results among females than among males. Experiments revealed an infarct-sparing effect of ischemic "preconditioning" (IPC) as the most robust form of innate cardioprotection based on the heart's adaptation to moderate stress, increasing its resistance to severe insults. However, translation to clinical practice is limited by technical requirements and limited time. Novel forms of adaptive interventions, such as "remote" IPC, have already been applied in patients, albeit with different effectiveness. Cardiac ischemic tolerance can also be increased by other noninvasive approaches, such as adaptation to hypoxia- or exercise-induced preconditioning. Although their molecular mechanisms are not yet fully understood, some noninvasive modalities appear to be promising novel strategies for fighting HF through targeting its numerous mechanisms. In this review, we will discuss the molecular mechanisms of heart injury and repair, as well as interventions that have potential to be used in the treatment of patients.

The Molecular Mechanisms of Iron Metabolism and Its Role in Cardiac Dysfunction and Cardioprotection.

Iron is an essential mineral participating in different functions of the organism under physiological conditions. Numerous biological processes, such as oxygen and lipid metabolism, protein production, cellular respiration, and DNA synthesis, require the presence of iron, and mitochondria play an important role in the processes of iron metabolism. In addition to its physiological role, iron may be also involved in the adaptive processes of myocardial "conditioning". On the other hand, disorders of iron metabolism are involved in the pathological mechanisms of the most common human diseases and include a wide range of them, such as type 2 diabetes, obesity, and non-alcoholic fatty liver disease, and accelerate the development of atherosclerosis. Furthermore, iron also exerts potentially deleterious effects that may be manifested under conditions of ischemia/reperfusion (I/R) injury, myocardial infarction, heart failure, coronary artery angioplasty, or heart transplantation, due to its involvement in reactive oxygen species (ROS) production. Moreover, iron has been recently described to participate in the mechanisms of iron-dependent cell death defined as "ferroptosis". Ferroptosis is a form of regulated cell death that is distinct from apoptosis, necroptosis, and other types of cell death. Ferroptosis has been shown to be associated with I/R injury and several other cardiac diseases as a significant form of cell death in cardiomyocytes. In this review, we will discuss the role of iron in cardiovascular diseases, especially in myocardial I/R injury, and protective mechanisms stimulated by different forms of "conditioning" with a special emphasis on the novel targets for cardioprotection.

Importance of tissue preparation methods in FTIR micro-spectroscopical analysis of biological tissues: 'traps for new users'.

Fourier Transform Infrared (FTIR) micro-spectroscopy is an emerging technique for the biochemical analysis of tissues and cellular materials. It provides objective information on the holistic biochemistry of a cell or tissue sample and has been applied in many areas of medical research. However, it has become apparent that how the tissue is handled prior to FTIR micro-spectroscopic imaging requires special consideration, particularly with regards to methods for preservation of the samples. We have performed FTIR micro-spectroscopy on rodent heart and liver tissue sections (two spectroscopically very different biological tissues) that were prepared by desiccation drying, ethanol substitution and formalin fixation and have compared the resulting spectra with that of fully hydrated freshly excised tissues. We have systematically examined the spectra for any biochemical changes to the native state of the tissue caused by the three methods of preparation and have detected changes in infrared (IR) absorption band intensities and peak positions. In particular, the position and profile of the amide I, key in assigning protein secondary structure, changes depending on preparation method and the lipid absorptions lose intensity drastically when these tissues are hydrated with ethanol. Indeed, we demonstrate that preserving samples through desiccation drying, ethanol substitution or formalin fixation significantly alters the biochemical information detected using spectroscopic methods when compared to spectra of fresh hydrated tissue. It is therefore imperative to consider tissue preparative effects when preparing, measuring, and analyzing samples using FTIR spectroscopy.

When early life growth restriction in rats is followed by attenuated postnatal growth: effects on cardiac function in adulthood.

PURPOSE: Epidemiological and experimental studies demonstrate that intrauterine growth restriction (IUGR) followed by accelerated postnatal growth leads to increased risk of developing cardiac disease in adulthood. The aim of this study was to examine the effect of early life growth restriction on cardiac structure and function in young adult rats. METHODS: IUGR was induced in Wistar Kyoto dams through administration of a low protein diet (LPD; 8.7% casein) during pregnancy and lactation; controls received a normal protein diet (NPD; 20% casein). Cardiac function and structure were assessed in female NPD (n = 7) and LPD (n = 7) offspring at 18 weeks of age by echocardiography and pressure-volume techniques, and systolic blood pressure by tail-cuff sphygmomanometry. RESULTS: LPD offspring remained significantly smaller throughout life compared to controls. There were no differences in the levels of systolic blood pressure, left ventricular cardiac dimensions, heart rate, ejection fraction and fractional shortening of the cardiac muscle between the investigated groups. Aortic peak systolic velocity was significantly reduced in the LPD group (P = 0.02). CONCLUSION: Our findings support the idea that the programming of adult cardiovascular disease can be prevented or delayed in IUGR offspring when postnatal growth trajectory resembles that of in utero.

Developmental programming of cardiovascular disease following intrauterine growth restriction: findings utilising a rat model of maternal protein restriction.

Over recent years, studies have demonstrated links between risk of cardiovascular disease in adulthood and adverse events that occurred very early in life during fetal development. The concept that there are embryonic and fetal adaptive responses to a sub-optimal intrauterine environment often brought about by poor maternal diet that result in permanent adverse consequences to life-long health is consistent with the definition of "programming". The purpose of this review is to provide an overview of the current knowledge of the effects of intrauterine growth restriction (IUGR) on long-term cardiac structure and function, with particular emphasis on the effects of maternal protein restriction. Much of our recent knowledge has been derived from animal models. We review the current literature of one of the most commonly used models of IUGR (maternal protein restriction in rats), in relation to birth weight and postnatal growth, blood pressure and cardiac structure and function. In doing so, we highlight the complexity of developmental programming, with regards to timing, degree of severity of the insult, genotype and the subsequent postnatal phenotype.

Evidence of altered biochemical composition in the hearts of adult intrauterine growth-restricted rats.

PURPOSE: Epidemiological studies clearly link intrauterine growth restriction with increased risk of cardiac disease in adulthood. The mechanisms leading to this increased risk are poorly understood; remodeling of the myocardium is implicated. The aim was to determine the effect of early life growth restriction on the biochemical composition of the left ventricular myocardium in adult rats. METHODS: Wistar Kyoto dams were fed either a low protein diet (LPD; 8.7 % casein) or normal protein diet (NPD; 20 % casein) during pregnancy and lactation; from weaning, the offspring were fed normal rat chow. At 18 weeks of age, the biochemical composition of the hearts of NPD control (n = 9) and LPD intrauterine growth-restricted (n = 7) offspring was analyzed using Fourier Transform Infrared (FTIR) micro-spectroscopy. RESULTS: Body weights at postnatal day 4 were significantly lower and remained lower throughout the experimental period in the LPD offspring compared to controls. FTIR analysis of the infrared absorption spectra across the whole "fingerprint" region (1,800-950 cm(-1)) demonstrated wider variation in absorbance intensity in the LPD group compared to controls. In particular, there were marked differences detected in the protein (1,540 cm(-1)), lipid (1,455 and 1,388 cm(-1)), proteoglycan (1,228 cm(-1)) and carbohydrate (1,038 cm(-1)) bands, indicating increased lipid, proteoglycan and carbohydrate content in the growth-restricted myocardium. CONCLUSION: In conclusion, changes in the biochemical composition of the myocardium provide a likely mechanism for the increased vulnerability to cardiovascular disease in offspring that were growth restricted in early life.

Low Birth Weight due to Intrauterine Growth Restriction and/or Preterm Birth: Effects on Nephron Number and Long-Term Renal Health.

Epidemiological studies have clearly demonstrated a strong association between low birth weight and long-term renal disease. A potential mediator of this long-term risk is a reduction in nephron endowment in the low birth weight infant at the beginning of life. Importantly, nephrons are only formed early in life; during normal gestation, nephrogenesis is complete by about 32-36 weeks, with no new nephrons formed after this time during the lifetime of the individual. Hence, given that a loss of a critical number of nephrons is the hallmark of renal disease, an increased severity and acceleration of renal disease is likely when the number of nephrons is already reduced prior to disease onset. Low birth weight can result from intrauterine growth restriction (IUGR) or preterm birth; a high proportion of babies born prematurely also exhibit IUGR. In this paper, we describe how IUGR and preterm birth adversely impact on nephrogenesis and how a subsequent reduced nephron endowment at the beginning of life may lead to long-term risk of renal disease, but not necessarily hypertension.

Elevated vascular resistance and afterload reduce the cardiac output response to dobutamine in early growth-restricted rats in adulthood.

Epidemiological studies have linked intra-uterine growth restriction (IUGR) with an increased risk of CVD later in life. The aim of the present study was to examine the effect of maternal protein restriction on cardiac function in adulthood during dobutamine (DOB) stimulation. IUGR was induced in Wistar Kyoto dams through administration of a low-protein diet (LPD; 8.7 % casein) during pregnancy and lactation; the control group received a normal-protein diet (NPD; 20 % casein). At 14 weeks of age, cardiac function was assessed in male and female NPD (eight females and eight males) and LPD offspring (ten females and ten males) by pressure volumetry using an anaesthetised closed-chest approach. We determined mean arterial pressure (MAP), heart rate and left ventricular pressure-volume indices under baseline conditions and DOB stimulation (2 and 4 µg/kg per min). During ß-adrenergic activation in LPD offspring, increases in cardiac output (CO, P < 0.018) and stroke volume (SV, P < 0.005) were attenuated in comparison with NPD offspring, while increases in ejection fraction and the maximal rate of ventricular pressure development were not affected. LPD females maintained a smaller end-diastolic volume (P < 0.017). MAP did not differ between the groups and did not change significantly during DOB infusion. Arterial elastance and total peripheral resistance decreased in all rats but remained significantly elevated in LPD offspring (P < 0.015 and < 0.01). Early growth restriction did not affect ventricular contractility but led to an increased afterload and impaired the ability to increase SV and CO during ß-adrenergic stimulation.

Nephrogenesis and the renal renin-angiotensin system in fetal sheep: effects of intrauterine growth restriction during late gestation.

Previous studies have shown that intrauterine growth restriction (IUGR) can impair nephrogenesis, but uncertainties remain about the importance of the gestational timing of the insult and the effects on the renal renin-angiotensin system (RAS). We therefore hypothesized that induction of IUGR during late gestation alters the RAS, and this is associated with a decrease in nephron endowment. Our aims were to determine the effects of IUGR induced during the later stages of nephrogenesis on 1) nephron number; 2) mRNA expression of angiotensin AT(1) and AT(2) receptors, angiotensinogen, and renin genes in the kidney; and 3) the size of maculae densae. IUGR was induced in fetal sheep (n = 7) by umbilical-placental embolization from 110 to 130 days of the approximately 147-day gestation; saline-infused fetuses served as controls (n = 7). Samples of cortex from the left kidney were frozen, and the right kidney was perfusion fixed. Total kidney volume, nephron number, renal corpuscle volume, total maculae densae volume, and the volume of macula densa per glomerulus were stereologically estimated. mRNA expression of AT(1) and AT(2) receptors, angiotensinogen, and renin in the renal cortex was determined. In IUGR fetuses at 130 days, body and kidney weights were significantly reduced and nephron number was reduced by 24%. There was no difference in renin, angiotensinogen, or AT(1) and AT(2) receptor mRNA expression levels in the IUGR kidneys compared with controls. We conclude that fetal growth restriction late in nephrogenesis can lead to a marked reduction in nephron endowment but does not affect renal corpuscle or macula densa size, or renal RAS gene expression.