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Several aspects of heart development are reviewed such as development of excitability and electrical and mechanical activity of the heart. Special emphasis is made upon metabolic changes during heart development and its possible consequences on electrical and mechanical activity.
Sensory-evoked changes in heart rate (HR) are often used to assess sensory function in infants, but HR measures have not been applied in studies of perinatal sensory function. Normative HR data are needed to judge whether baseline characteristics and response properties of the late fetal and newborn heart are appropriate as a dependent measure in sensory studies. We compared parameters of HR development and phasic cardiac responses to stimulation across the perinatal period in Norway rats. EKG was measured in cesarean-delivered prenatal rats (embryonic day 20-day of birth; conception = E0) and compared to both cesarean and vaginally delivered neonates (day of birth-postnatal day 2; birth = P0). Resting heart rate increased monotonically across the perinatal period, except between E21 and DOB (Experiment 1). During an hour-long test, HR was strong and stable. Variations in HR across successive measurement intervals (10 sec) were uniformly low (less than 2%) in all age groups. In Experiment 2, fetuses and neonates responded with dramatic HR decelerations (20-80 bpm) to an intraoral infusion of lemon extract. HR responses did not appear to be reflexively mediated by changes in respiration. These findings suggest that parameters of resting HR and cardiac responses to stimulation are well suited to studies of perinatal sensory function.
Cardiac malformations due to aberrant development of the atrioventricular (AV) valves are among the most common forms of congenital heart disease. At localized swellings of extracellular matrix known as the endocardial cushions, the endothelial lining of the heart undergoes an epithelial to mesenchymal transition (EMT) to form the mesenchymal progenitors of the AV valves. Further growth and differentiation of these mesenchymal precursors results in the formation of portions of the atrial and ventricular septae, and the generation of thin, pliable valves. Gata4, which encodes a zinc finger transcription factor, is expressed in the endothelium and mesenchyme of the AV valves. Using a Tie2-Cre transgene, we selectively inactivated Gata4 within endothelial-derived cells. Mutant endothelium failed to undergo EMT, resulting in hypocellular cushions. Mutant cushions had decreased levels of Erbb3, an EGF-family receptor essential for EMT in the atrioventricular cushions. In Gata4 mutant embryos, Erbb3 downregulation was associated with impaired activation of Erk, which is also required for EMT. Expression of a Gata4 mutant protein defective in interaction with Friend of Gata (FOG) cofactors rescued the EMT defect, but resulted in a decreased proliferation of mesenchyme and hypoplastic cushions that failed to septate the ventricular inlet. We demonstrate two novel functions of Gata4 in development of the AV valves. First, Gata4 functions as an upstream regulator of an Erbb3-Erk pathway necessary for EMT, and second, Gata4 acts to promote cushion mesenchyme growth and remodeling.
Hypertension is a well-known risk factor that predisposes to the development of left ventricular hypertrophy, coronary flow abnormalities, and systolic and diastolic dysfunction. This complex of abnormalities is known as hypertensive heart disease and eventually leads to heart failure. Structural lesions underlying this process include excess deposition of collagens and cellular infiltration, with an increase in the size of cardiac myocytes (remodeling). The occurrence of arteriolar lesions may lead to impediments of flow. Clinically, hypertensive heart disease manifests itself by anginal complaints and sometimes by silent ischemia, arrhythmias, and sudden death. Alterations in systolic and/or diastolic function may be associated with symptoms of heart failure. Although successful treatment of hypertension can probably retard the process of cardiac impairment, there is as yet no evidence that heart failure can be prevented.
The effect of calcium activation on energy production was investigated in isolated perfused hearts from rats treated with triiodothyronine (T3) during 15 days (0.2 mg/kg/day) and in hearts of rats allowed to recover after T3-treatment during 15 days. Changes in phosphorylated compound concentrations were followed in the isolated hearts perfused with a glucose-pyruvate medium by 31P-NMR spectroscopy, when the external calcium concentration was increased from 0.5-1, 1.5 and 2 mM. As expected, T3-treatment resulted in the hypertrophy of the heart (50% increase in HW/BW) that was nearly reversible 15 days after discontinuation of the treatment. When compared to controls, creatine, phosphocreatine (PCr) and glycogen contents were lower (58, 24 and 17% decrease respectively) in the hypertrophied hearts and higher (10, 14 and 18% respectively) after regression of hypertrophy. Intracellular pH, ATP, inorganic phosphate concentrations and the phosphorylation potential were not altered under T3-treatment and after regression of hypertrophy, while calculated free ADP concentration was lower in hypertrophied hearts (control: 40 +/- 2 microM, T3-treatment: 21 +/- 1 microM, regression: 37 +/- 1 microM). Increasing the calcium concentration induced a similar increase in left ventricular developed pressure in the three groups of hearts, with inorganic phosphate concentration increasing with cardiac work. The PCr concentration slightly decreased while the ATP concentration did not change. In spite of different initial PCr concentrations, the evolutions of PCr and Pi concentrations for each stepwise increase in external calcium were similar in the three groups. It is concluded that, in spite of the well-known decrease in efficiency induced by the drug, the mechanisms of PCr (ATP) production remain able to respond to an acute moderate increase in energy demand provoked by a physiological stimulus. This adaptation also persists after the treatment when the energy metabolism balance is apparently improved.
The cardiac mutant axolotl is an interesting model for studying heart development. The mutant gene results in a failure of heart cells to form organized myofibrils and as a consequence the heart fails to beat. Experiments have shown that mutant hearts can be "rescued" (i.e., turned into normally contracting organs) by the addition of RNA purified from conditioned media produced by normal embryonic anterior endoderm-mesoderm cultures. These corrected hearts form myofibrils of normal morphology. New advances in recombinant DNA technology applied to this system should provide significant insights into the regulatory mechanisms of myofibrillogenesis as well as the inductive processes related to the control of gene expression during embryonic heart development. In a broader biological sense, the use of gene c in axolotls is potentially capable of helping to solve major unanswered questions in modern biology related to the genetic regulation of differentiation in vertebrates.
Mef2c belongs to the myocyte enhancer factor 2 (MEF2) family of MADS-box containing transcription factors, which have been shown to be important for various processes involved in cell differentiation, cell survival, and apoptosis. Previous gene-targeting studies have demonstrated a role for mef2c in early heart development since mice lacking mef2c die at embryonic day 9.5 due to cardiac and vascular defects. Since the early embryonic lethality of mef2c prevents an examination of its role in the later stages of heart development, conditional mef2c(loxP/loxP) mice were generated to allow for temporal- and tissue-specific analyses. We report here that general Cre recombinase-mediated removal of the second coding exon of mef2c phenocopied the original mef2c null. Additionally, myocardial-specific removal of mef2c resulted in viable offspring, demonstrating that while mef2c is required for the early development of the heart, it is not necessary for the formation of the heart after looping morphogenesis.
The heart undergoes marked ultrastructural alterations during fetal and postnatal development. Early in fetal development, cardiac myocytes contain abundant pools of glycogen, scattered mitochondria and sparse, peripheral myofibrils. Transverse tubules are absent, and sarcoplasmic reticulum and intercalated discs are poorly developed. During late fetal and early postnatal development, myofibrils extend into the myocyte interior and attain a mature appearance, and the glycogen pools are reduced in size. In addition, transverse tubules develop and the morphological appearance of the sarcoplasmic reticulum and intercalated disc becomes increasingly complex. Experimental studies in sheep, corroborated by clinical studies in humans, also point to marked functional changes during development. In the fetus, the right ventricle is the dominant pumping chamber because right ventricular output exceeds left ventricular output, while pulmonary arterial and aortic pressures are similar. This functional difference is reflected in myocardial blood flow patterns, with blood flow to the right ventricle exceeding that to the left ventricle. The ventricular outputs equalize after birth, but a functional left ventricular dominance rapidly emerges following a postnatal increase in systemic vascular resistance and a decrease in pulmonary vascular resistance. This postnatal switchover in functional dominance is accompanied by a corresponding alteration in the relative level of ventricular myocardial blood flows. Consistent with right ventricular dominance in utero, myocytes in the right ventricle of the fetal sheep are larger and contain more myofibrillar material than those in the left ventricle. Left ventricular myocytes become larger than right ventricular myocytes after birth, but this adaptation to altered postnatal haemodynamics requires some weeks to become fully established.
The authors studied the incidence of smoking among 20-69 years old males and its relation to ischemic heart disease. Ischemic heart disease morbidity and intermittent claudication was highest in males who have been smoking for more than 30 years. Statistical data indicate that the age of beginning of smoking is of more importance in the development of ischemic heart disease as compared with the duration of smoking. Prophylactic measures are discussed with consideration of the obtained data.
The inotropic response of rat hearts in vivo was tested by infusion of 2 mmol/kg/h calcium chloride after 14 days of daily 3,3',5-triiodo-L-thyronine (T3) treatment and 14 days following discontinuation of T3 treatment. The hyperthyroid state was characterized by marked cardiac hypertrophy (57% increase in the heart weight/body weight ratio) which was more pronounced in the right ventricle (63% increase). Heart rate and cardiac output index were elevated by 56 and 63%, respectively, and total peripheral resistance was reduced by 40%. Left ventricular systolic pressure (LVSP) was elevated by 15%, the maximal rate of rise in left ventricular pressure (LV dp/dtmax) by 106%, and LV pressure-volume performance by 192%. Right ventricular systolic pressure (RVSP) was elevated by 71%, RV dp/dtmax by 126%, and RV pressure-volume performance by 371%. Intravenous infusion of calcium induced an elevation in heart rate and LV dp/dtmax, the increase of the latter was less pronounced than in the control heart. After 14 days subsequent to discontinuation of T3 treatment, there was a regression of cardiac hypertrophy. However, the LV was still hypertrophied by 12% and the RV by 24%. Heart rate and contractility were normal. The pressure-volume performance of both LV and RV was still enhanced by 24 and 18%, respectively. The inotropic response of the LV to calcium infusion was similar to that of the normal heart. Thus, 14 days after discontinuation of T3 treatment, the regression of cardiac hypertrophy was not complete, although heart rate and contractility as well as the inotropic response to calcium, were normal. The remaining cardiac hypertrophy correlated with the still existing elevation in the pressure-volume performance.
To test the ability of the heart to express characteristic geometric features of concentric and eccentric hypertrophy concurrently, constriction of the ascending aorta was performed in 4-week-old rats. Simultaneously, these rats were treated with an arteriolar dilator minoxidil. An examination 6 weeks after induction of the hemodynamic overload revealed no signs of congestion in systemic or pulmonary circulation in rats with aortic constriction or minoxidil-treated sham-operated rats. The magnitude of hemodynamic overload caused by aortic constriction or minoxidil treatment could be considered as equivalent, because the same enlargement of left ventricular pressure-volume area was necessary to compensate for either pressure or volume overload. Myocardial contractility decreased in rats with aortic constriction, and the compensation was achieved wholly by the marked concentric hypertrophy. Volume overload in minoxidil-treated rats was compensated partially by the eccentric hypertrophy and partially by the increased myocardial contractility. In contrast, increased lung weight and pleural effusion were found in all minoxidil-treated rats with aortic constriction. Unfavorable changes in left ventricular mass and geometry, relatively high chamber stiffness, and depressed ventricular and myocardial function were responsible for the massive pulmonary congestion.
Prosthetic heart valves are routinely used for replacing diseased natural heart valves. Even today, after five decades of prosthetic heart valve development, in the authors opinion the main problem associated with these valves is the risk of thromboembolic complications caused by unnatural hemodynamics. Further growing application of prosthetic heart valves is their use in the pulsatile ventricular assist devices (VADs). VADs may provide life-saving solutions to patients with severe cardiovascular diseases and are superior to drug therapy for patients with severe heart failure. However, the clinical applications of VADs still suffer from thromboembolic complications due to thrombus formations in the vicinity of the valves. Wherever the flow is stagnant or flow separation occurs, a thrombus is likely to form. The design of the heart valves with flow avoiding the formation of stagnant zones is one of the main goals in the development of new valves. This article reviews some innovative design approaches of the valves specially designed for use in VADs. Three design concepts are presented; one is based on the tilting disk valve, the second on the natural valve geometry and the third on the ball valve principle. However, these three different concepts have one common basic idea; the use of the freedom of the valve-housing design. This additional design freedom, which is available in VADs, is a key factor in the development of new valves with optimal hemodynamic performance.
Tumor necrosis factor-alpha converting enzyme (TACE) is a membrane-anchored, Zn-dependent metalloprotease, which belongs to the ADAM (a disintegrin and metalloprotease) family. TACE functions as a membrane sheddase to release the ectodomain portions of many transmembrane proteins, including the precursors of TNFalpha, TGFalpha, several other cytokines, as well as the receptors for TNFalpha, and neuregulin (ErbB4). Mice with TACE(DeltaZn/DeltaZn) null mutation die at birth with phenotypic changes, including failure of eyelid fusion, hair and skin defects, and abnormalities of lung development. Abnormal fetal heart development was not previously described. Herein, we report that TACE(DeltaZn/DeltaZn) null mutant mice by late gestation exhibit markedly enlarged fetal hearts with increased myocardial trabeculation and reduced cell compaction, mimicking the pathological changes of noncompaction of ventricular myocardium. In addition, larger cardiomyocyte cell size and increased cell proliferation were observed in ventricles of TACE(DeltaZn/DeltaZn) knockout mouse hearts. At the molecular level, reduced expression of epidermal growth factor receptor, attenuated protein cleavage of ErbB4, and changes in MAPK activation were also detected in TACE(DeltaZn/DeltaZn) knockout heart tissues. The data suggest that TACE-mediated cell surface protein ectodomain shedding plays an essential and a novel regulatory role during cardiac development and modeling.
The autonomic innervation of the canine heart develops with considerable regional asymmetry during the early neonatal period. To examine the development of the peptidergic component of the innervation, 28 mongrel puppies 1-6 weeks of age from five litters were studied at weekly intervals. Four of the mothers were also studied as adult and breed controls. Tissue neuropeptide Y (NPY) and vasoactive intestinal peptide (VIP) concentrations were determined by radioimmunoassay in myocardial specimens obtained from several specific sites of the cardiac chambers and from the proximal coronary arteries. Data were analysed according to age, cardiac chamber/vessel, gender and individual litter. In general, NPY concentrations in pg/mg protein were six- to eight-fold higher than those of VIP. Also concentrations for both peptides were about two-fold higher in the coronary arteries than the myocardium and differed among chambers, being higher and similar in the atria and lower in the ventricles, particularly for NPY. No gender differences were identified. Concentrations varied among litters, but the developmental pattern was similar with the highest peptide concentrations identified in the first and fourth week. Whereas the differences among chambers may also reflect differing rates of developmental increase of myocardial mass, the pattern corresponds only in part to previously identified functional changes in sympathetic innervation since, in contrast to previous findings, high NPY concentrations in the first 2 weeks suggest anatomically advanced innervation.
We examined alterations in left ventricular (LV) G protein receptor kinase (GRK) and adenylyl cyclase (AC) isoform expression during the development of pacing-induced congestive heart failure (CHF). AC isoform and GRK expression were assessed 4 (mild CHF) and 28 (severe CHF) days after initiation of pacing. LV beta-adrenergic receptor (beta-AR) number and G protein content were unchanged by mild CHF. LV AC isoform mRNA content was unaltered by mild CHF, but there were increases in total GRK activity (P < 0.01), total GRK5 protein content (P < 0.04), and GRK5 mRNA (P = 0.003); total GRK2 protein content and GRK2 mRNA were unchanged. Mild CHF was associated with decreased beta-AR coupling (P < 0.01) and reduced beta-AR stimulation of AC (P < 0.05). Severe CHF was associated with LV beta-AR downregulation (P = 0.0001) and uncoupling (P < 0.001) and marked generalized reduction of AC activity (mean P = 0.01). LV ACVI isoform mRNA content was reduced (P = 0.002), but ACII and ACV isoform mRNA contents were unaffected. Persistent elevations in LV total GRK activity (P < 0.01), total GRK5 protein content (P < 0.001), and GRK5 mRNA (P = 0.01) were found; in contrast, total GRK2 protein content was unchanged and GRK2 mRNA was reduced (P = 0.02). These studies indicate that increased GRK activity is an early charge in heart failure that predates alterations in AC isoform expression. Impaired hormonal stimulation of AC, associated with beta-AR uncoupling, may result from increased GRK5 expression. AC downregulation is isoform specific and accompanies severe but not mild CHF.
BACKGROUND: Although treatment of myocardial overload effectively reduces death from progression of heart failure, it is not known whether the retardation of progressive coronary artery disease obtained with lipid lowering treatment will prevent the onset and consequences of heart failure in patients without previous symptoms of heart failure. METHODS AND RESULTS: In the Scandinavian Simvastatin Survival Study, 4444 patients with coronary heart disease without evidence of heart failure were randomized to placebo (n = 2223) or simvastatin 20-40 mg (n = 2221) and followed for more than 5 years. Among the patients who received placebo, 228 (10.3%) were diagnosed with heart failure during follow-up evaluation compared with 184 (8.3%) of patients who received simvastatin (P < .015). Mortality was 31.9% in the placebo group and 25.5% in the simvastatin group among patients who developed heart failure. These compare with 9.2 and 6.6%, respectively, among non-heart failure patients. There were 45 hospitalizations because of acute heart failure in the placebo group and 23 in the simvastatin group (NS). Patients who developed heart failure were more likely to have suffered a recurrent myocardial infarction and have a history of diabetes, peripheral artery disease, and hypertension than patients who did not develop congestive heart failure. CONCLUSION: Long-term prevention with simvastatin reduces the occurrence of heart failure in a cohort of patients with coronary heart disease without previous evidence of congestive heart failure.
Development of pharyngeal muscle in nematodes and cardiac muscle in vertebrates and insects involves the related homeobox genes ceh-22, nkx2.5, and tinman, respectively. To determine whether the nematode and vertebrate genes perform similar functions, we examined activity of the zebrafish nkx2.5 gene in transgenic Caenorhabditis elegans. Here, we report that ectopic expression of nkx2.5 in C. elegans body wall muscle can directly activate expression of both the endogenous myo-2 gene, a ceh-22 target normally expressed only in pharyngeal muscle, and a synthetic reporter construct controlled by a multimerized CEH-22 binding site. nkx2.5 also efficiently rescues a ceh-22 mutant when expressed in pharyngeal muscle. Together, these results indicate that nkx2.5 and ceh-22 provide a single conserved molecular function. Further, they suggest that an evolutionarily conserved mechanism underlies heart development in vertebrates and insects and pharyngeal development in nematodes.
Embryonic hemoglobin circulated by the developing heart in the early vertebrate embryo is widely assumed (without substantiation) to perform the same vital role of O2 carriage that it does in fetuses and adults. In order to challenge this assumption, we measured highly O2-dependent physiological variables like O2 consumption, cardiac performance, and initial swim bladder filling in the presence and absence of functional hemoglobin in the embryos and early larvae of the zebra fish, Danio ( = Brachydanio) rerio. Functional ablation of hemoglobin by carbon monoxide or phenylhydrazine did not reduce whole-animal O2 consumption, which was approximately 85 to 90 mumol.g-1.h-1. Similarly, no differences in heart variables like ventricular pressure development or heart rate, which increased from 135 to 175 bpm between stages 36h and 96h (indicating developmental stages 36 and 96 hours after fertilization, respectively), were observed in these experiments. Initial opening of the swim bladder was not influenced in the presence of CO-occupied hemoglobin but was significantly impaired when the embryonic hemoglobin was chemically modified by incubation with phenylhydrazine. That aerobic processes continue without hemoglobin O2 transport indicates the adequacy in the embryo of simple O2 diffusion alone even in developmental stages with extensive convective blood circulation generated by the heart.