Morbidities in patients with hypoplastic left heart syndrome.

We sought to document morbidities and growth for patients with hypoplastic left heart syndrome (HLHS) to inform the initial surgical decision and understand healthcare needs. Data were obtained on 137 patients with HLHS, born between 1989 and 1994, who survived staged surgery ( n = 62) or transplantation ( n = 75) and had follow-up information available from four pediatric cardiac surgical centers. In patients with HLHS older than 1 year of age at follow-up, 93% experienced at least one major postsurgical morbidity. Morbidities depended on the surgery received. Hypertension, renal compromise, and abnormal infections were more common in transplanted patients than staged surgery patients. Staged surgery patients used more anticongestive medications and experienced more morbidities requiring interventional catheterization than did transplanted patients. Rejection was common for transplanted patients. On average these children spent 23 days per year in the hospital. Patients with HLHS were small for their age; 43% of staged surgery patients weighed below the third percentile at last information, compared to 19% of transplanted patients ( p = 0.003). The median height percentile was the 10th in both groups. Normal activity level was reported in more transplanted patients (90%) than staged surgery patients (49%; p < 0.001). Trade-offs between mortality and morbidity outcomes can help inform the initial surgical decision.

A comparison of treatment strategies for hypoplastic left heart syndrome using decision analysis.

OBJECTIVES: We sought to identify the optimal treatment strategy for hypoplastic left heart syndrome (HLHS). BACKGROUND: Surgical treatment of HLHS involves either transplantation (Tx) or staged palliation of the native heart. Identifying the best treatment for HLHS requires integrating individual patient risk factors and center-specific data. METHODS: Decision analysis is a modeling technique used to compare six strategies: staged surgery; Tx; stage 1 surgery as an interim to Tx; and listing for transplant for one, two, or three months before performing staged surgery if a donor is unavailable. Probabilities were derived from current literature and a dataset of 231 patients with HLHS born between 1989 and 1994. The goal was to maximize first-year survival. RESULTS: If a donor is available within one month, Tx is the optimal choice, given baseline probabilities; if no donor is found by the end of one month, stage 1 surgery should be performed. When survival and organ donation probabilities were varied, staged surgery was the optimal choice for centers with organ donation rates < 10% in three months and with stage 1 mortality <20%. Waiting one month on the transplant list optimized survival when the three-month organ donation rate was > or =30%. Performing stage 1 surgery before listing, or performing stage 1 surgery after an unsuccessful two- or three-month wait for transplant, were almost never optimal choices. CONCLUSIONS: The best strategy for centers that treat patients with HLHS should be guided by local organ availability, stage 1 surgical mortality and patient risk factors.

Maturation-dependent differences in regulation of sarcoplasmic reticulum Ca(2+) ATPase in sheep myocardium in response to pressure overload: a possible mechanism for maturation-dependent systolic and diastolic dysfunction.

We have previously demonstrated that pressure-overload hypertrophy in adult sheep is associated with myocardial dysfunction whereas that in young lambs is associated with normal contractility. To probe for possible mechanisms of these age-dependent differences, we assessed mRNA expression of genes encoding critical components of myocardial Ca(2+) handling in the same animal model. We studied left ventricular myocardium of young and adult sheep with short-term (48 h) and long-term (6 wk) pressure overload induced by ascending aortic constriction. Six weeks of pressure overload induced the significant left ventricular hypertrophy (36 and 39% increase in left ventricular/body weight ratio in lambs and sheep, respectively). The Ca(2+) ATPase and Na(+)/Ca(2+) exchanger mRNA decreased with pressure overload only in the adult (p < 0.05). Ca(2+) channel mRNA was slightly increased by pressure overload regardless of age (p < 0.05). Calsequestrin, sarcoplasmic reticulum Ca(2+) release channel, or myosin heavy-chain mRNA levels did not significantly differ. In adult sheep after 6 wk of pressure overload, decreases in load-adjusted midwall shortening (systolic dysfunction) and prolongation of relaxation time constant (diastolic dysfunction) correlated with decreases in Ca(2+)-ATPase mRNA. The sarcoplasmic reticulum Ca(2+)-ATPase protein level and Ca(2+) uptake activity of isolated sarcoplasmic reticulum vesicles were depressed only in the adult with pressure-overload hypertrophy but not in the young. We demonstrated age-dependent differences in mRNA expression of Ca(2+)-handling protein genes in response to pressure overload, which preceded the occurrence of hypertrophy and myocardial dysfunction. Thus, altered expression of Ca(2+)-handling protein genes may be one of the primary responses to pressure overload rather than a phenomenon secondary to myocardial hypertrophy.

Survival analysis and risk factors for mortality in transplantation and staged surgery for hypoplastic left heart syndrome.

OBJECTIVES: We compared survival in treatment strategies and determined risk factors for one-year mortality for hypoplastic left heart syndrome (HLHS) using intention-to-treat analysis. BACKGROUND: Staged revision of the native heart and transplantation as treatments for HLHS have been compared in treatment-received analyses, which can bias results. METHODS: Data on 231 infants with HLHS, born between 1989 and 1994 and intended for surgery, were collected from four pediatric cardiac surgical centers. Status at last contact for survival analysis and mortality at one year for risk factor analysis were the outcome measures. RESULTS: Survival curves showed improved survival for patients intended for transplantation over patients intended for staged surgery. One-year survival was 61% for transplantation and 42% for staged surgery (p < 0.01); five-year survival was 55% and 38%, respectively (p < 0.01). Survival curves adjusted for preoperative differences were also significantly different (p < 0.001). Waiting-list mortality accounted for 63% of first-year deaths in the transplantation group. Mortality with stage 1 surgery accounted for 86% of that strategy's first-year mortality. Birth weight <3 kg (odds ratio [OR] 2.4), highest creatinine > or =2 mg/dL (OR 4.7), restrictive atrial septal defect (OR 2.7) and, in staged surgery, atresia of one (OR 4.2) or both (OR 11.0) left-sided valves produced a higher risk for one-year mortality. CONCLUSIONS: Transplantation produced significantly higher survival at all ages up to seven years. Patients with atresia of one or both valves do poorly in staged surgery and have significantly higher survival with transplantation. This information may be useful in directing patients to the better strategy for them.

Effects of chronic heparin administration on coronary vascular adaptation to hypertension and ventricular hypertrophy in sheep.

BACKGROUND: Hypertension decreases myocardial perfusion capacity in adults for several reasons, including insufficient coronary angiogenesis with left ventricular (LV) hypertrophy, arteriolar hypertrophy, and altered vasomotion. Heparin influences growth factors that promote angiogenesis and vasodilation and inhibit arteriolar wall thickening. METHODS AND RESULTS: Adult sheep were given heparin 200 U/kg body wt SC twice daily throughout 6 weeks of LV and coronary hypertension from a progressively constricted ascending aortic band (n=14). They were compared with untreated sheep with (n=13) and without (n=13) aortic stenosis. After 6 weeks, maximum myocardial perfusion was measured during adenosine infusion in the conscious state by the microsphere method. Sheep with aortic stenosis had less maximum coronary flow per gram, less conductance reserve, and thicker arteriolar walls in the LV and nonhypertrophied right ventricle. Capillary density decreased in the LV endomyocardium and remained unchanged in the right ventricle. Heparin-treated sheep had significant partial normalization of coronary conductance reserve and maximum perfusion in both ventricles and capillary density in the LV endomyocardium. Arteriolar wall thickness was unchanged. Compared with untreated sheep with aortic stenosis, in heparin-treated sheep LV FGF-2 protein increased 2-fold, whereas FGF-2 mRNA remained unchanged. VEGF mRNA and protein increased 3-fold and 1.4-fold, respectively, whereas TGF-beta(1) mRNA declined 3-fold. CONCLUSIONS: Heparin administration during LV hypertension increases heparin-binding angiogenic factors FGF-2 and VEGF in the LV and ameliorates decreases in LV perfusion capacity and capillary density.

Cardiac inflammatory pseudotumor: rapid appearance in an infant with congenital heart disease.

The rapid growth of an inflammatory pseudotumor in the right atrium of an infant with pulmonary valve stenosis and atrial septal defect is documented. Systemic manifestations, including fever, weight loss, leukocytosis, and hypergammaglobulinemia, suggested infection; the diagnosis was made after surgical resection. Sixteen months after surgery the infant is asymptomatic, and the hypergammaglobulinemia and leukocytosis have resolved. Trauma may have been the inciting factor for this inflammatory pseudotumor.

Effect of young age on coronary adaptations to left ventricular pressure overload hypertrophy in sheep.

OBJECTIVES: This study attempted to determine the effect of young age on changes in coronary conductance and capillary density with left ventricular pressure overload hypertrophy. Mechanisms responsible for age differences in perfusion capacity were examined. BACKGROUND: Hypertension in adults causes alterations in the coronary vasculature, resulting in diminished coronary perfusion capacity and myocardial ischemia. These processes are worsened in adults by advanced age. Young age may provide advantages in coronary adaptation to hypertension. METHODS: Coronary conductance was examined in conscious chronically instrumented 10-week old lambs and adult sheep with progressive ascending aortic stenosis of 6-week's duration and age-matched control sheep by means of the microsphere technique and vasodilators. Capillary density was measured post-mortem. RESULTS: Adult sheep with aortic stenosis had a decrease in left ventricular subendomyocardial capillary density by 17% and maximal coronary conductance with adenosine by 67%. In the nonhypertrophied right ventricle, maximal coronary conductance was depressed by 47%, whereas capillary density was normal, implying an effect of coronary hypertension on resistance vessels. In contrast, lambs with aortic stenosis maintained normal left ventricular capillary density, maximal coronary conductance and coronary reserve and had relatively little impairment of conductance in the right ventricular coronary bed (-15%, p = NS). Similar responses were found with other vasodilators, isoproterenol and chromonar. CONCLUSIONS: Young age confers advantages to coronary adaptation to left ventricular pressure overload, including angiogenesis proportionate to hypertrophy, resulting in normal capillary density and coronary conductance. There is also less hypertension-induced impairment of coronary conductance distinct from the effects of hypertrophy.

Changes in the microvascular network during cardiac growth, development, and aging.

Quantitative changes in the terminal vascular bed of the mammalian heart were assessed during postnatal development and aging. The most striking feature is a considerable formation of new capillaries in the early postnatal period, accompanied by a moderate formation of new arterioles. On the other hand, coronary arterioles seem to disappear at a higher rate than capillaries in the senescent heart. We proposed a three-dimensional structural model of tissue capillary supply, defined as capillary domain area times capillary segment length. This so called capillary supply unit increases as a function of age and body growth. It is very similar in size and shape (length to width ratio) to cardiac myocytes.

Transition from compensated hypertrophy to intrinsic myocardial dysfunction during development of left ventricular pressure-overload hypertrophy in conscious sheep. Systolic dysfunction precedes diastolic dysfunction.

BACKGROUND: Patients with aortic stenosis have a period of compensated left ventricular hypertrophy but may eventually develop congestive heart failure. Previous experimental studies showed either normal myocardial contractility in mild short-term pressure overload or myocardial dysfunction with severe pressure overload. Transition from compensated left ventricular hypertrophy to myocardial dysfunction has not been experimentally demonstrated in an adult large animal. Controversial issues in pressure-overload hypertrophy include whether the left ventricular dysfunction is due to insufficient hypertrophy (afterload mismatch) or to intrinsic myocardial dysfunction and whether diastolic dysfunction precedes systolic dysfunction. METHODS AND RESULTS: We induced left ventricular hypertrophy (41% increase in left ventricular to body weight ratio) by gradually tightening a hydraulic constrictor around the ascending aorta in 9 chronically instrumented conscious sheep. Afterload (end-systolic stress) elevation remained constant (approximately 33% greater than baseline) by adjustment of the aortic constrictor over 6 weeks, gradually increasing left ventricular pressure (from 117 +/- 6 to 163 +/- 5 mm Hg) as hypertrophy developed. Four sets (baseline, 2 weeks, 4 weeks, and 6 weeks) of serial hemodynamic studies were performed in each animal with beta-blockade, first with and then without aortic constriction to mechanically match loading conditions. Stepwise methoxamine infusion was performed to obtain load-independent assessment of myocardial contractility. Midwall shortening (P < .05) and shortening rate (P < .05) at mechanically matched loading conditions showed that myocardial dysfunction developed between the fourth and the sixth week. Shortening-preload-afterload (P < .05) and shortening rate-preload-afterload (P < .05) relations, load-independent contractility indices based on the systolic myocardial stiffness concept, also revealed depressed myocardial contractility at the sixth week. Time constant of left ventricular isovolumic relaxation and diastolic myocardial stiffness constant did not change over the 6 weeks. CONCLUSIONS: Transition from normal myocardial contractility to myocardial dysfunction was demonstrated. This transition occurred even when the elevation of afterload remained constant as hypertrophy incompletely adapted to increasing left ventricular pressure. Systolic dysfunction preceded diastolic dysfunction in this model.

Response of the hypertrophied left ventricle to tachycardia: importance of maturation.

Pressure overload left ventricular (LV) hypertrophy (LVH) induces ventricular dysfunction during stress, which is commonly attributed to diminished myocardial capillary density and ischemia. Immature hearts with LVH have a normal coronary flow reserve and capillary density. The purpose of this study was to determine 1) whether young lambs with LVH had an abnormal response to chronotropic stress, 2) whether nonischemic mechanisms contributed to the abnormal response, and 3) whether the age at which LVH was induced affected the response. We assessed LV endomyocardial function, perfusion, and Ca(2+)-adenosinetriphosphatase (ATPase) mRNA levels in chronically instrumented lambs with and without LVH and adult sheep with and without LVH. Rapid pacing induced diastolic dysfunction, increased time constant of isovolumic relaxation using an iterative fit (tM), and elevated LV diastolic pressures in young lambs and adult sheep with LVH. During pacing, tM was greater in the adult sheep with LVH than in the young lambs with LVH. Ca(2+)-ATPase mRNA levels were 79% less in adult sheep with LVH than in those without. Ca(2+)-ATPase mRNA levels in lambs with and without LVH and adult sheep without LVH were similar. Diastolic dysfunction occurred in the absence of subendomyocardial hypoperfusion, suggesting a nonischemic mechanism. In adult sheep with LVH diastolic dysfunction was associated with a marked reduction in Ca(2+)-ATPase mRNA levels.

Different responses of extent and velocity of contraction to dobutamine in conscious sheep.

The shortening- and shortening rate-preload-afterload relations, based on the concept of the myocardial end-systolic stress-strain relation (ESSSR), are a newly developed load- and size-independent assessment of myocardial contractility. The purpose of this study was to apply this assessment to compare extent and velocity of myocardial contraction during graded infusions of dobutamine. Seven chronically instrumented unsedated sheep were studied at rest and during graded infusions of dobutamine (2.5-20 micrograms.kg-1.min-1). The ESSSR were linear over a wide range of load alterations, whereas the end-systolic pressure-diameter relations (ESPDR) were generally nonlinear. Midwall shortening rate (SRm) at common preload and afterload representing contraction extent increased with each dose of dobutamine through 20 micrograms.kg-1.min-1. In contrast, midwall shortening (Sm) increased through dobutamine 5 micrograms.kg-1.min-1 but not at higher dobutamine infusion rates. Conventional endocardial shortening and the slope of the ESPDR, fitted to a linear model, exhibited responses similar to Sm. The velocity of circumferential endocardial fiber shortening (Vcf,c), Vcf,c-afterload relation, and maximum first derivative of left ventricular pressure exhibited responses similar to SRm. Thus both the extent and velocity of contraction increased at low doses of dobutamine, whereas only the velocity increased at high doses. Potential mechanisms for the saturated response of the extent of contraction include 1) shorter systolic time for contraction due to earlier onset of relaxation and 2) the utilization of myocardial contractile energy for left ventricular wall deformation at small cavity volumes at high doses of dobutamine.

Morphometry of human coronary capillaries during normal growth and the effect of age in left ventricular pressure-overload hypertrophy.

BACKGROUND: In adults, acquired pressure-overload left ventricular hypertrophy can result in myocardial ischemia, which may be due in part to insufficient capillary growth during development of hypertrophy. The coronary microvascular response to congenital pressure-overload hypertrophy in children has not been previously characterized. METHODS AND RESULTS: Average capillary density and heterogeneity of capillary spacing were measured in 63 postmortem human hearts with left ventricular hypertrophy and control hearts without heart disease. Pathology specimens were chosen that had left ventricular hypertrophy caused by 1) congenital isolated aortic valve stenosis in infants less than 1 year old at death, children 9-14 years old, and adults 15-30 years old; 2) congenital isolated coarctation of the aorta in adults 15-39 years old; and 3) acquired aortic stenosis in adults 51-86 years old. Major findings of the study were: 1) Human left ventricular capillary density and heterogeneity of capillary spacing are similar to other mammalian species. 2) Capillary density is higher in infants (3,315 +/- 85 capillaries per square millimeter), decreases with increasing heart weight during normal growth in early childhood (children, 2,388 +/- 75 capillaries per square millimeter, p less than 0.05), and thereafter remains relatively constant. 3) Capillary density with left ventricular hypertrophy is dependent on the age of onset. Congenital aortic stenosis and coarctation are characterized by an increase in capillary supply proportional to myocyte volume, maintaining capillary density similar to control hearts. Adults with acquired aortic stenosis have decreased capillary density (1,671 +/- 66 capillaries per square millimeter, p less than 0.01 versus control). CONCLUSIONS: Pressure-overload left ventricular hypertrophy in children demonstrates proportional capillary angiogenesis, whereas in adults, hypertrophy appears to be associated with failure of compensatory angiogenesis.

Myocardial function in immature and mature sheep with pressure-overload hypertrophy.

The effect of pressure-overload left ventricular hypertrophy (LVH) on myocardial function is controversial. A major factor in the controversy may be the age at which the pressure overload was induced. The goal of this study was to determine whether the age at which the LVH was induced affected systolic myocardial function. We studied lambs (n = 8) and sheep (n = 7) with LVH induced by constricting the ascending aorta and their sham-operated controls (n = 7 and n = 7). This new, unsedated, ovine model of LVH was large enough to accommodate chronic surgical implantation of instrumentation and the induction of pressure-overload hypertrophy in both young and adult age groups. Solid-state intraventricular pressure transducers and sonomicrometer crystal were used to assess instantaneous left ventricular pressure and dimensions. Myocardial contractility was assessed with midwall shortening at common preload and afterload. Load alterations were induced by graded infusion of methoxamine. There was depressed myocardial function in adult sheep with LVH compared with adult controls. Lambs with and without LVH had normal left ventricular myocardial function, similar to adult controls. Similar results were obtained in studies after beta-adrenergic receptor blockade. We conclude that maturation decreases the ability of the myocardium to maintain normal contractility in the presence of pressure-overload hypertrophy.

Myocardial angiogenesis and coronary perfusion in left ventricular pressure-overload hypertrophy in the young lamb. Evidence for inhibition with chronic protamine administration.

In contrast to young growing animals, pressure-overload hypertrophy in adults is frequently associated with diminished myocardial capillary density and maximal coronary flow per gram. To determine the role of angiogenesis in maintaining perfusion capacity in the hypertrophying heart, the angiogenesis inhibitor protamine sulfate was administered to young lambs during the development of left ventricular (LV) pressure-overload hypertrophy. Baseline and maximum (adenosine) myocardial perfusion was measured in four groups of chronically instrumented 10-week-old lambs subjected to 1) ascending aortic bands since the age of 4 weeks (LVH group, n = 10), 2) sham operation at the age of 4 weeks (SHAM group, n = 8), 3) aortic bands and twice daily injections of protamine since the age of 4 weeks (LVH + P group, n = 9), 4) sham operation and injection of protamine (SHAM + P group, n = 8). Capillary density was measured postmortem. Peak LV pressure and the LV/body weight ratio were similarly increased in LVH and LVH + P compared with sham-operated lambs (p less than 0.001). In LVH lambs, LV capillary number increased by 32% compared with sham-operated lambs (p less than 0.05), and capillary density, coronary flow reserve, and minimal coronary resistance remained normal. In contrast, LVH + P lambs had no significant increase over SHAM lambs in LV capillaries and total maximum coronary flow. The LVH + P lambs had lower LV subendomyocardial capillary density and higher minimal coronary resistance per gram (p less than 0.05 versus LVH lambs). Right ventricular capillary density and minimal resistance were similar in all groups. These findings support the hypotheses that myocardial angiogenesis with pressure-overload hypertrophy is important in maintaining maximal LV coronary flow in the young and that impairment of angiogenesis results in diminished coronary flow capacity.

Bidirectional cavopulmonary anastomosis as interim palliation for high-risk Fontan candidates. Early results.

Thirty-eight patients considered to be at increased risk for a Fontan repair underwent bidirectional cavopulmonary anastomosis. Twenty-one of the 38 had concurrent pulmonary artery reconstruction. Fontan risk factors included pulmonary artery distortion, elevated pulmonary artery resistance (greater than 2 Woods units) and/or pulmonary artery pressure (mean, greater than 18 mm Hg), atrioventricular valve regurgitation, systemic ventricular dysfunction, complex venous anatomy, and subaortic obstruction. There were no deaths, either early or late. Median arterial oxygen saturation increased from 79% to 84% (p less than 0.01). Median hospital stay was 8 days. No patient had pleural effusions after 7 days. Three patients had significant surgical complications. Five patients had inadequate relief of cyanosis; three of these had venous collaterals and two had severe ventricular dysfunction; the latter two patients subsequently had strokes. One of the patients with persistent cyanosis required a systemic-to-pulmonary artery shunt. We conclude that a bidirectional cavopulmonary shunt, with pulmonary artery reconstruction when indicated, provides adequate relief of cyanosis in most patients with single-ventricle lesions who are considered to be at increased risk for a Fontan repair. Relief of ventricular volume overload and pulmonary artery distortion may improve Fontan candidacy. Also, patients with persistent cyanosis after bidirectional cavopulmonary anastomosis should be catheterized for location and occlusion of venous collaterals. Further follow-up is necessary to determine the place of bidirectional cavopulmonary anastomosis in the management of patients at increased risk for a Fontan repair.

Relationship between CSF and fluid dynamics in the neural canal.

There is a relationship between fluid dynamics in the neural canal and cranial vault. This relationship can be affected by posture, respiration and pathology. In addition, several chiropractic disciplines have advocated that axial skeletal improprieties may also affect fluid dynamics in the canal and vault. This paper reviews literature pertinent to these issues. The information it contains is relevant to those disciplines that attempt to manipulate fluid dynamics in the canal and vault, as well as to those that treat neurological disorders.

Tetralogy of Fallot with obstruction of the ventricular septal defect: spectrum of echocardiographic findings.

Tetralogy of Fallot with a restrictive ventricular septal defect and suprasystemic right ventricular pressure is an uncommon anomaly with a high mortality rate. In previous studies, the identity of the tissue obstructing the ventricular septal defect has usually not been determined preoperatively. This report describes the echocardiographic and anatomic features in 4 patients with a restrictive ventricular septal defect among 269 patients with tetralogy of Fallot undergoing surgical repair. Echocardiography determined the presence and identity of the obstructing tissue in all four patients. In one patient, the defect was small in association with marked septal hypertrophy. In three patients, accessory or excessive tricuspid valve tissue obstructed the defect in a manner similar to spontaneous closure of isolated membranous ventricular septal defects. Autopsy and catheterization findings are also presented of an additional case with a unique mechanism of obstruction by a tricuspid valve with Ebstein's anomaly. In patients with tetralogy of Fallot, recognition of an obstructed ventricular septal defect is important because it appears to have a poor prognosis.

Changing trends of congenital heart disease in adults: a catheterization laboratory perspective.

Advances in cardiac surgery now enable many children with congenital heart disease (CHD) to survive to adulthood. The influence of such advances on the frequency of various lesions among adult patients undergoing cardiac catheterization (CC) has not previously been addressed. This retrospective analysis of 329 adults with CHD undergoing CC at an adult and at a pediatric referral center demonstrates that when compared to 20 years ago, adults with CHD who now undergo CC are more likely to have complex cardiac disease, and more have had prior surgery. In addition, despite more aggressive surgical management, ventricular dysfunction and dysrhythmias are now commonly encountered residua of CHD in adults who require diagnostic CC. Premature coronary artery disease appears uncommon. These changing characteristics of adults with CHD require consideration in the planning of future health care for these patients.