Growth hormone and heart performance. A novel mechanism of cardiac wall stress regulation in humans

OBJECTIVES: This study was designed to assess systolic wall stress and ventricular function in patients with deranged growth hormone secretion, in an attempt to elucidate the mechanisms of growth hormone interaction with heart performance. DESIGN: A case-control study. SUBJECTS: Thirty patients with active acromegaly, free of diabetes mellitus and coronary artery disease, and 25 subjects with congenital growth hormone deficiency were studied. Twelve growth hormone-deficient subjects were reevaluated after 12 months of recombinant human growth hormone therapy. Two groups of 30 normal subjects each were used as controls for the acromegalic and growth hormone-deficient patients, respectively. RESULTS: In the acromegalics, end-systolic wall stress was reduced (-20%; P < 0.01) due to ventricular wall thickening (+ 26%; P < 0.001), whereas cardiac output was significantly increased (+ 20%; P < 0.01). The velocity of fibre shortening was unchanged. In growth hormone-deficient subjects, end-systolic wall stress was markedly increased (+ 38%; P < 0.001) due to a significant reduction of ventricular wall thickness (- 28%; P < 0.001), whereas cardiac output was significantly decreased (-44%; P < 0.001). Replacement therapy with recombinant human growth hormone produced a partial correction of wall thickness and stress. Consequently, systolic performance and cardiac output improved significantly. CONCLUSION: This study demonstrates that growth hormone plays a role in the control of cardiac wall stress and performance through a mechanism mediated by the effect of growth hormone on myocardial tissue growth. The data may have therapeutic implications in cardiac diseases that lead to heart failure.     

Perioperative management of pulmonary hypertension after heart transplantation in childhood

BACKGROUND: Pulmonary hypertension is responsible for a substantial part of perioperative and postoperative mortality and morbidity after cardiac transplantation. Treatment of right ventricular failure after increased pulmonary vascular resistance is difficult especially in infants and children. Therefore we started a preventive therapy of pulmonary hypertension after cardiac transplantation to avoid right ventricular failure and compared the results with a group of patients with conventional therapy. METHODS: Group 1 (n = 13), with transplantation from 1988 to 1991, was treated with vasodilators when symptoms of right ventricular failure developed. Group 2 (n = 19) had preventive treatment with prostaglandin E1 (PGE1), the phosphodiesterase-III inhibitor enoximone, and alkalinazation starting during weaning from cardiopulmonary bypass. RESULTS: Six patients in group 1 died; four of them as the result of right ventricular failure in the immediate postoperative course despite aggressive treatment. In group 2 there were three deaths as the results of rejection (2) and infection (1). None of these patients developed right ventricular failure (p = 0.02). Cold ischemic time, extracorporeal circulation time, and waiting time before transplantation were significantly longer in group 2. Side effects of this preventive therapy were not observed. CONCLUSIONS: We conclude that prophylactic therapy of pulmonary hypertension with vasodilators in infants and children after heart transplantation is safe and effective in preventing right ventricular failure in the postoperative course.     

A placebo-controlled study of growth hormone in patients with congestive heart failure

AIM: Experimental data in heart failure models and an open trial of seven patients with idiopathic dilated cardiomyopathy have suggested beneficial effects of growth hormone on cardiac function. The aim of the present study was to evaluate growth hormone effects on cardiac function in a placebo-controlled study. METHODS: Twenty two patients with congestive heart failure of different aetiologies in NYHA II and III and an echocardiographic ejection fraction <0.45 were studied in a 3 month double-blind placebo-controlled study with growth hormone added to optimal heart failure therapy. Patients received either placebo (n=11) or recombinant human growth hormone (n=11) in an initial dose of 0.1 IU x kg(-1) week(-1) for 1 week, and thereafter 0.25 IU x kg(-1) week(-1) for the rest of the treatment period. Cardiac function was assessed by equilibrium radionuclide angiography and Doppler echocardiography. Functional capacity was evaluated by computerized bicycle exercise electrocardiography. RESULTS: Recombinant human growth hormone had no significant effect on systolic or diastolic cardiac function, exercise capacity or neuroendocrine activation. In addition, there was no overall improvement in functional class or dyspnoea grade. Insulin-like growth factor-I significantly increased demonstrating that the growth hormone had an endocrine effect. CONCLUSION: This is the first double-blind and placebo-controlled study of the administration, over 3 months, of recombinant human growth hormone in patients with congestive heart failure of different aetiologies. The treatment was safe and without serious side effects. However, no beneficial effects on cardiac function or structure could be detected.     

An investigation into the interaction between drug efficacy and drug price of praziquantel in determining the cost-effectiveness of school-targeted treatment for Schistosoma mansoni using a population dynamic model

The data from animal and human in-vivo studies suggest that cardiac function is dependent in part on the normal function of the GH/IGF-1 axis (growth hormone/insulin-like growth factor-1). The syndrome of heart failure appears to be associated with a perturbation of the GH/IGF-1 axis. So far encouraging results from phase II clinical trials evaluating the effects of long-term growth hormone treatment in patients with moderate to severe chronic congestive heart failure due to dilated cardiomyopathy have been published. In these studies growth hormone (i.e., DNA-derived recombinant human growth hormone) was not used alone but in addition to standard optimal therapy for chronic heart failure. The following rationale is the basis of this new approach for the treatment of chronic congestive heart failure due to dilated cardiomyopathy. According to Laplace's Law, cardiac wall stress(i.e., the force acting per unit of cross-sectional area of the ventricular wall) is directly related to intraventricular pressure and ventricular radius and inversely related to ventricular wall thickness. Cardiac (ventricular) wall stress if increased in dilated cardiomyopathy (mainly because of the dilatation of the ventricles and to a minor extent because of the relative reduction in ventricular thickness). Growth hormone seems to be capable of increasing ventricular wall thickness in dilated cardiomyopathy, thus, reducing cardiac wall stress which in turn leads to an improvement in systolic cardiac performance. Recombinant human growth hormone as a pharmacologic treatment is not only an expensive but also risky therapeutic modality (e.g., potential risk of inducing colonic carcinoma, de-novo leukemias, relapses of leukemias and central nervous system tumors). Given these prerequisites and a receptivity for cost effectiveness and risk-benefit analyses, it seems as if subcutaneous recombinant human growth hormone-as an additional therapeutic substance in conjunction with one of the widely accepted drugs for end-stage chronic congestive heart failure due to dilated cardiomyopathy-e.g., angiotensin converting-enzyme inhibitors, diuretics, nitrates, digoxin, and beta-adrenergic receptor blockers (Carvedilol) could either become a bridge to transplantation (i.e., supporting patients awaiting transplantation) or an alternative to the very expensive cardiac transplantation. There are three reasons for this hypothesis. First, the fact that end-state dilated cardiomyopathy along with ischemic heart disease are the main indications for heart transplantation in adults; second, the worldwide small supply of human donor organs for heart transplantation; and, third, the urgent need to find alternative cost-effective and risk-beneficial therapeutic modalities.     

Is Down syndrome a risk factor for poor outcome after repair of congenital heart defects?

Down syndrome is commonly associated with significant congenital heart disease with the potential for early development of pulmonary hypertension. As such, children with Down syndrome may be at increased risk for both perioperative and long-term mortality. The purpose of this study, using data collected from a population-based outcomes study, is to analyze the potential role that Down syndrome plays in the outcome of surgically "corrected" congenital heart disease. Data were collected from a registry of all Oregon residents who, in the period 1958 to the present, had a reparative operation for one of 14 congenital cardiac malformations when younger than 18 years (N = 3965 patients). Down syndrome was present in 289 (7%) of the total registry patients. In evaluating the cardiac mortality associated with Down syndrome for each of the repaired cardiac malformations, only complete atrioventricular septal defect was associated with significantly higher perioperative (13% vs 5%) as well as higher overall late cardiac mortality through 20 years after the operation (20% vs 5%; p = 0.04). The survival outcomes for each of the other cardiac malformations were similar for children with and without Down syndrome.     

Hypertrophic cardiomyopathy during adrenocorticotrophic hormone administration in infants: a case report

We report a 2-month-old child with infantile myoclonic seizures, who developed congestive heart failure secondary to hypertrophic cardiomyopathy while receiving adrenocorticotropic hormone (ACTH) therapy. Treatment with propranolol and withdrawal of ACTH led to the resolution of cardiac hypertrophy as determined by two-dimensional echocardiography. Possible links between ACTH therapy and the development of hypertrophic cardiomyopathy are examined. Our report confirms that a careful monitoring is required to detect cardiac abnormalities during ACTH administration.     

Heart surgery in the elderly

The number of octogenarian patients undergoing an open heart procedure in our unit is the fastest increasing group of patients. Between June 1985 and July 1994 112 octogenarians (mean age 81.7 years, 60 males, 52 females) underwent cardiac operations. The postoperative course was uneventful in 90 patients (80.4%). The perioperative mortality rate was 8.9% (10 patients). Mortality was lowest in the group receiving aortic valve replacement, with one death out of 30 patients (3.3%). The cause of death was left- or biventricular heart failure in more than half of the fatalities. Postoperative complications included: AV-block III (n = 1), postoperative bleeding (n = 2), unstable sternum (n = 3), acute cholecystitis (n = 1), low cardiac output syndrome (n = 1), stroke (n = 1), pneumothorax (n = 2) and urinary tract infections (n = 1). We consider open heart procedures in octogenarians, despite a mortality rate of 8.9%, as justified. According to the severity and course of clinical symptoms and the type of surgery required, selection of patients for operation should be decided on at an early stage of the disease. Not only life expectancy increases, but there is also a significant increase in life quality for these patients.     

Assessment of cardiovascular perioperative risk in non-cardiac surgery

Patients with cardiovascular disease undergoing non cardiac surgery are exposed to three cardiac risks: myocardial infarction, heart failure and death. To estimate cardiac risk, clinical predictors of perioperative cardiovascular risk are classified as major, intermediate and minor and non cardiac surgery is stratified in high risk (greater than 5%), intermediate (from 1 to 5%), minor (lower than 1%) procedures. Efficient perioperative assessment of cardiac patients is obtained by teamwork and usually, indications for further cardiac investigations are the same as those in the nonoperative setting. An simplified algorithm, easier to use than original algorithm given in the guidelines of the American college of cardiology and the American heart association, may be helpful for the indication of further investigations. Five questions must be answered before using algorithm: is it an emergency surgical procedure?, was a coronary revascularization required in the past five years? has the patient had a coronary evaluation in the past two years?, are there identified clinical predictors of cardiac risk?, is it major or minor surgery? Three tests evaluate the preoperative cardiac risk: exercise testing, dipyridamole thallium scintigraphy, dobutamine stress echocardiography. Their accuracy is similar, their negative predictive value is high, their positive predictive value is low. These guidelines may be helpful to indicate further cardiac investigations which will have an impact on patient's treatment, monitoring during or after surgery and outcome.     

Corticosteroid therapy in cardiac sarcoidosis

Corticosteroid treatment of cardiac sarcoidosis is not conclusive, although sarcoid granulomas in the heart may be more responsive to steroid therapy than in other organs. Healing of sarcoidosis lesions in the heart results in fibrosis and sinning of the myocardium, which may lead to aneurysm formation causing congestive heart failure or sudden death. Congestive heart failure is the leading cause of death in patients with cardiac sarcoidosis in Japan. It is reasonable to initiate steroid therapy as soon as the diagnosis of cardiac sarcoidosis is established in order to prevent fibrosis. Early initiation of steroid therapy with conventional treatment for specific cardiac manifestations (antiarrhythmic therapy, pacemaker implantation and heart failure medication) should bring improvement in the left ventricular systolic and diastolic function with prevention from malignant arrhythmias. Systemic disorder represents a contraindication to organ transplantation, but heart transplantation is now a feasible treatment for patients with end-stage cardiac sarcoidosis with congestive heart failure.     

The role of echocardiography in preoperative diagnosis of cardiac risk in patients before non-cardiac surgical interventions

Echocardiography is a noninvasive method for cardiac evaluation. A review of the current literature shows that the routine use of echocardiography for assessing perioperative cardiac risk in patients undergoing noncardiac surgery can not be supported. Only patients with suspected relevant heart valve diseases, acute heart failure, cardiomyopathy or condition after heart or heart-lung transplantation may benefit from preoperative echocardiography. In patients with suspected or proven coronary artery disease stress echocardiography offers the most relevant additional information for the anaesthesiologist. However, because of the high financial and personal implications it should be reserved to those patients who are not able to perform a normal stress test. Besides in patients in whom transthoracic echocardiography doesn't offer sufficient information or is not possible transesophageal echocardiography plays only a minor role in preoperative cardiac evaluation.     

Bromocriptine treatment over 12 years in acromegaly: effect on glucose tolerance and insulin secretion

It is not known whether the beneficial effect of bromocriptine on glucose homeostasis in acromegaly is limited by a certain duration of therapy. To elucidate this problem, oral glucose tolerance tests were performed in 12 acromegaly patients before bromocriptine medication, under therapy (15.0 +/- 6.8 mg/day for 12 +/- 3 years), and during a 2-week drug withdrawal after long-term treatment. Initially altered glucose tolerance was normalized in 4 of 5 patients under bromocriptine therapy. During drug withdrawal the mean fasting glucose level and the mean glucose concentration at 120 min after oral glucose load increased from 5.05 +/- 0.61 to 5.77 +/- 0.78 mmol/l and from 5.61 +/- 2.05 to 7.55 +/- 3.05 mmol/l, respectively. A deterioration in glucose homeostasis was observed in 9 patients, and impaired glucose tolerance was ameliorated (but not to normal range) in 2 when bromocriptine was withdrawn. The proportion of alterations in glucose tolerance during drug withdrawal corresponded to that before the beginning of long-term bromocriptine treatment. Impaired glucose tolerance, observed in 2 patients under bromocriptine treatment, seemed to be compensated because a distinct elevation of glycosylated hemoglobin A1c was not observed. Bromocriptine led to a significant decrease in basal as well as glucose-stimulated insulin levels, and growth hormone secretion during oral glucose load was reduced in all 12 patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

Growth hormone levels in acromegaly after external radiotherapy

A 56-year-old acromegalic patient was treated with conventional radiotherapy. One year after treatment, the patient's growth hormone level was normal and remained so for a full year. Subsequently, the growth hormone level returned to the pretreatment, acromegalic range. The attainment of a normal growth hormone level after treatment of acromegaly is no assurance that the level will remain normal. Repeated growth hormone level determinations are necessary before cure can be considered permanent.     

Establishment of functional human pituitary tumor cell cultures

Five primary human pituitary tumor cell cultures were initiated from adenoma fragments obtained from patients with prolactin-secreting adenomas and acromegaly. Functional cell cultures were maintained and propagated in monolayer or suspension culture for up to 9 months. Optimal cell viability and growth were achieved using Ham's F10 medium enriched with 20% fetal bovine serum, although cells from a patient with acromegaly also grew in serum-free, defined, hormone-containing medium. Bromocriptine (100 ng/ml) did not alter the growth curve of replicating cells derived from a patient with acromegaly. These cells initially secreted 5.5 micrograms human growth hormone/10(6) cells, and hormone production diminished after 6 wk. Prolactin secretion by cells derived from prolactinomas (0.5 to 1.3 micrograms/10(6) cells/24 h) was stimulated by thyrotropin-releasing hormone (10 ng/ml) in two of the cultures. Both dopamine (10 ng/ml) and nickel chloride (1 mM) suppressed PRL secretion. These studies demonstrate that responsive human pituitary tumor cell cultures can be initiated and maintained.     

Esterase D polymorphism: phenotype- and gene frequencies in Northern Germany (Schleswig-Holstein) (author''s transl)]

We have observed an apparent hypoglobulinemia in 17 of 35 patients (48.6%) with acromegaly. This unexpected finding was persistent and reproducible up to six years for five acromegalic patients, and more than one year for nine other patients. Serum globulin was analyzed by three different methods, and the deficiency was most noticeable in the alpha globulin fraction (alpha1 greater than alpha2). When hypoglobulinemia occurred in control hospital in-patients (11%) it was associated with chronic or severe illnesses, and limited nutritional intake, but similar medical problems were absent in the acromegalic patients. There was no correlation of the hypoglobulinemia in the 35 acromegalic patients to their growth hormone (GH) concentration (r = 0.07), ages, sex, treatment status, or to the seriousness or duration of the acromegaly. The pathophysiology of the apparent hypoglobulinemia in acromegaly is unknown, but may be related to transport and/or disposal of excess growth hormone, or a defect in protein synthesis.     

Conserved residues amino-terminal of cytoplasmic tyrosines contribute to the SHP-1-mediated inhibitory function of killer cell Ig-like receptors

The heart has been recognized as a major target of thyroid hormone action. Our study investigates both the regulation of cardiac-specific genes and contractile behavior of the heart in the presence of a mutant thyroid hormone receptor beta1 (T3Rbeta1-delta337T) derived from the S kindred. The mutant receptor was originally identified in a patient with generalized resistance to thyroid hormone. Cardiac expression of the mutant receptor was achieved by a transgenic approach in mice. As the genes for myosin heavy chains (MHC alpha and MHC beta) and the cardiac sarcoplasmic reticulum Ca2+ adenosine triphosphatase (SERCA2) are known to be regulated by T3, their cardiac expression was analyzed. The messenger RNA levels for MHC alpha and SERCA2 were markedly down-regulated, MHC beta messenger RNA was up-regulated. Although T3 levels were normal in these animals, this pattern of cardiac gene expression mimics a hypothyroid phenotype. Cardiac muscle contraction was significantly prolonged in papillary muscles from transgenic mice. The electrocardiogram of transgenic mice showed a substantial prolongation of the QRS interval. Changes in cardiac gene expression, cardiac muscle contractility, and electrocardiogram are compatible with a hypothyroid cardiac phenotype despite normal T3 levels, indicating a dominant negative effect of the T3Rbeta mutant.     

Polymorphonuclear neutrophil granulocyte chemotactic hyperresponsiveness in a case of canine acromegaly

Growth hormone (GH) has recently been shown to affect polymorphonuclear neutrophil granulocyte (PMN) function and to be secreted by mononuclear cells, indicating that the hormone may be active in an immunophysiologic network, acting as an endo- or paracrine priming agent. The purpose of the present study was to evaluate the chemotactic responsiveness of canine peripheral PMN in a dog with acromegaly, caused by spontaneous, progesterone-induced hypersecretion of GH and, secondary to this, a seven-fold increase in insulin-like growth factor I (IGF-I). The chemotactic responsiveness towards zymosan-activated serum (ZAS) and leukotriene B4 (LTB4) was evaluated at a time when the dog suffered from acromegaly and again 57 days after corrective surgery (ovariohysterectomy). The experiments showed that PMN from the patient exhibited enhanced chemotactic migration that appeared to be associated with the hypersomatotropic condition as judged from the reversibility of the phenomenon. The glucose intolerance and elevated serum alkaline phosphatase that were observed in the acromegalic dog were also shown to be reversible following surgery.     

Acromegalic cardiomyopathy: an echocardiographic study

Thirty eight acromegalic patients (A) and a control group (C) of subjects without heart disease, were studied with echocardiography. Acromegalies were divided in two groups, A1 and A2, who had increase or normal serum growth hormone (GH) levels respectively after treatment (pituitary adenectomy and/or bromocriptine), at the time of the study. In acromegalic patients (A) mean left ventricular (LV) dimensions were normal while LV wall and septal thickness, LV mass and left atrial (LA) dimension were increased compared to control subjects. LVH was present in 79% of acromegalic patients. Asymmetric septal hypertrophy (ASH) was found in 10,5% of our patients. In group A1, IVS, LVPW, LVMM/m2 were significantly increased as compared to group A2. Fractional shortening (FS), ejection fraction (EF), mean velocity of circumferential fibre shortening (Vcf), frequency-normalized Vcf (Vcfn), posterior left ventricular wall velocity (PWV), and normalized PWV (PWVn) were normal in both groups. In patients with active acromegaly (Al) IVS and LVMM/m2 correlated well with the total duration of the disease (r=0.550 p less than 0.01 for IVS; r=0.624 p less than 0.01 for LVMM/m2) and with the duration of acromegaly before treatment (r=0.568, p less than 0.01 for IVS; r=0.500 p less than 0.01 for LVMM/m2). Furthermore a positive correlation was found between IVS and GH levels (r=0,550 p less than 0.01). Concomitant coronary artery disease and or hypertension did not seem to play any role in causing the above mentioned echocardiographic changes. Echocardiography is useful in assessing the cardiac involvement in patients with acromegaly.     

CD30: expression and function in health and disease

Pituitary adenomas are the most common pituitary disorder affecting pregnancy, and prolactinomas are the most common of the hormone-secreting pituitary adenomas. Hyperprolactinemia must be corrected to allow ovulation and fertility. Bromocriptine has been shown to be safe for use during early gestation. There is less than a 2% risk of microprolactinoma enlargement during pregnancy but a greater than 15% risk of symptomatic enlargement of a macroprolactinoma. Treatment options for patients with macroadenomas include stopping bromocriptine when pregnancy is diagnosed and reinstituting with tumor enlargement, continuous bromocriptine throughout pregnancy, and prepregnancy tumor debulking by surgery. The diagnosis of acromegaly may be difficult to make during pregnancy and relies, in part, on the persistence of the normal pulsatile secretion of growth hormone and loss of this secretory characteristic with a tumor. The growth hormone oversecretion may exacerbate tendencies to gestational diabetes, fluid retention, and hypertension. Treatment for acromegaly and other tumors generally may be deferred until after delivery. There are rare reports of enlargement of clinically nonfunctioning and growth hormone secreting tumors during pregnancy, and surveillance is needed. Tumors may need to be differentiated from lymphocytic hypophysitis. Patients with chronic hypopituitarism usually will need treatment with gonadotropins or pulsatile GnRH to become pregnant and may need increased steroid coverage during labor and delivery. Hypopituitarism developing during pregnancy is usually caused by lymphocytic hypophysitis and usually also will require steroid replacement therapy. Hypopituitarism arising postpartum may be caused by either lymphocytic hypophysitis or Sheehan's syndrome, and the latter may present as an acute or chronic syndrome. Borderline diabetes insipidus may manifest during pregnancy because of increased vasopressin degradation caused by markedly increased levels of placental vasopressinase. Treatment with desmopressin usually is satisfactory. Patients presenting with either anterior or posterior pituitary insufficiency in the peripartum period should always be evaluated for function of the other portion of the pituitary.     

Myocardial damage after minimally invasive coronary artery bypass grafting on the beating heart

BACKGROUND: In conventional coronary artery bypass grafting, the rate of perioperative myocardial infarction is reported in the 2% to 6% range; however, significantly higher rates are observed if sensitive myocardial marker proteins are used to detect perioperative myocardial damage. For minimally invasive direct coronary artery bypass grafting, few data are available concerning myocardial marker protein release. METHODS: Fifteen consecutive patients (11 male, 4 female; mean age, 59.6 +/- 8.5 years) received minimally invasive direct coronary artery bypass grafting procedures via minithoracotomy on the beating heart. Electrocardiography and transesophageal and transthoracic echocardiography as well as determination of creatine kinase-MB mass concentration and cardiac troponin I level were used for ischemic monitoring. RESULTS: One patient had a perioperative myocardial infarction according to standard criteria and died despite mechanical circulatory support. Determination of cardiac troponin I level showed small but definitive ischemic damage in 4 of 9 patients (44%) who presented transient ischemic signs intraoperatively or postoperatively. In 2 of these 4 patients pathologic findings could be detected on angiographic restudies. CONCLUSIONS: Subclinical myocardial injury is a common event in minimally invasive coronary artery bypass grafting on the beating heart. Cardiac troponin I could serve as an adequate diagnostic tool for diagnosis of perioperative myocardial infarction in minimally invasive direct coronary artery bypass grafting.     

Cyanosis and multiple pulmonary nodules

Though thyroid hormone abnormalities have been identified in many cardiac conditions, the role of thyroid hormones in congestive heart failure has not been well defined. In a population of patients with advanced heart failure, a reduction in triiodothyronine (T3) with an increase in reverse T3 was identified in many patients, with an abnormally low ratio of T3/reverse T3 being the strongest predictor of mortality. Normalization of thyroid indices appeared to be necessary for prolonged survival to occur. To address the concern of T3 administration possibility exacerbating a hypermetabolic state, basal metabolic rate was measured in a group of advanced heart failure patients and was found to be generally within the normal range. A preliminary safety study of short-term intravenous T3 administration (bolus +/- 6 h infusion, total dose 0.15-2.7 micrograms/kg) was then performed in 23 patients under hemodynamic and electrocardiographic monitoring. There were neither adverse events nor substantial hemodynamic changes, but some patients had an increase in cardiac output, consistent with a peripheral vasodilatory effect. With this foundation, further investigation into the possible role of T3 and its analogs in congestive heart failure therapy may be pursued.