Novel lamin A/C mutations in two families with dilated cardiomyopathy and conduction system disease.

BACKGROUND: The LMNA gene, one of 6 autosomal disease genes implicated in familial dilated cardiomyopathy, encodes lamins A and C, alternatively spliced nuclear envelope proteins. Mutations in lamin A/C cause 4 diseases: Emery-Dreifuss muscular dystrophy, limb girdle muscular dystrophy type 1B, Dunnigan-type familial partial lipodystrophy, and dilated cardiomyopathy. METHODS AND RESULTS: Two 4-generation white families with autosomal dominant familial dilated cardiomyopathy and conduction system disease were found to have novel mutations in the rod segment of lamin A/C. In family A a missense mutation (nucleotide G607A, amino acid E203K) was identified in 14 adult subjects; disease was manifest as progressive conduction disease in the fourth and fifth decades. Death was caused by heart failure. In family B a nonsense mutation (nucleotide C673T, amino acid R225X) was identified in 10 adult subjects; disease was also manifest as progressive conduction disease but with earlier onset (third and fourth decades), ventricular dysrhythmias, left ventricular enlargement, and systolic dysfunction. Death was caused by heart failure and sudden cardiac death. Skeletal muscle disease was not observed in either family. CONCLUSIONS: Novel rod segment mutations in lamin A/C cause variable conduction system disease and dilated cardiomyopathy without skeletal myopathy.

Distribution and declines in cardiac allograft radionuclide left ventricular ejection fractions in relation to late mortality.

BACKGROUND: Cardiac allograft left ventricular ejection fraction (LVEF) is an important measure of left ventricular systolic function. Despite widespread use of LVEF after transplantation, its normal range and prognostic value in cardiac allografts has not been defined. METHODS: We conducted a retrospective cohort study among 292 consecutive adult heart transplant patients. Left ventricular ejection fractions were performed at 1, 3, 12, 24, and 48 months after transplantation using radionuclide ventriculography. Endomyocardial biopsies assessed rejection, right heart catheterization assessed loading conditions, and angiography assessed allograft coronary artery disease. We used Cox proportional hazards model to examine the predictive value of LVEF on late mortality. RESULTS: Of the patients who survived > or =4 years, the mean allograft LVEF decreased 4.7 units at 3 months, from 63.8 to 59.7; an additional 4.1 units at 12 months, from 59.7 to 55.6 (p < 0.001); and remained stable afterward. These changes were not associated with concurrent changes in loading conditions, episodes of rejection, or development of allograft coronary artery disease. Left ventricular ejection fraction lower than the 95% normal limit (<40%) at 12 months was inversely associated with risk for late cardiac mortality (relative risk = 3.5, 95% confidence interval = 1.0-12.2), while controlling for recipient age, sex, donor age, and rejection episodes. CONCLUSIONS: The cardiac-allograft LVEF frequently decreases in the first year after transplantation. The 95th percentile of allograft LVEF value (<40%) at Year 1 predicts late cardiac mortality among transplant recipients.

Prospective evaluation of an outpatient heart failure management program.

BACKGROUND: Although considerable effort has been devoted to the follow-up of hospitalized patients, the effectiveness and process of heart failure outpatient management have not been well demonstrated. METHODS AND RESULTS: All new patients referred to the program from April 1997 to September 1998 were followed and managed by comprehensive strategies including preemptive hospitalization. Quality of life (QOL) and patients' self-care adherence behaviors were measured at baseline, 3 months, and 6 months. Clinical outcomes were compared for the 6 months before and 6 months after referral. A total of 108 patients were recruited. Patients' self-care knowledge score was improved over time (difference score = 0.9, P <.01). The proportion of patients weighing themselves daily increased by 24% (P =.02). The proportion of patients with New York Heart Association (NYHA) class III to IV was 67.6% at baseline and 49.1% at 6 months (P =.01). Compared with 6 months before referral, the program intervention was accompanied by a 52% reduction in the risk of hospitalization for cardiovascular causes (56.1% v 27.2%, P <.001) and a 72% reduction in emergency room visits (53.6% v 14.5%, P <.01). The total hospital admissions for cardiovascular causes decreased by 59% from 94 to 39; the total emergency room visits decreased by 77% from 83 to 19. The patients' QOL was improved over time with a change score of 11.2 (P <.001) at 3 months and 10.7 (P <.001) at 6 months. CONCLUSION: Our study shows the effectiveness of this heart failure outpatient management program.

Genetic Counseling and Screening Issues in Familial Dilated Cardiomyopathy.

Idiopathic dilated cardiomyopathy (IDC), a treatable condition characterized by left ventricular dilatation and systolic dysfunction of unknown cause, has only recently been recognized to have genetic etiologies. Although familial dilated cardiomyopathy (FDC) was thought to be infrequent, it is now believed that 30-50% of cases of IDC may be familial. Echocardiographic and electrocardiographic (ECG) screening of first-degree relatives of individuals with IDC and FDC is indicated because detection and treatment are possible prior to the onset of advanced, symptomatic disease. However, such screening often creates uncertainty and anxiety surrounding the significance of the results. Furthermore, FDC demonstrates incomplete penetrance, variable expression, and significant locus and allelic heterogeneity, making genetic counseling complex. The provision of genetic counseling for IDC and FDC will require collaboration between cardiologists and genetics professionals, and may also improve the recognition of FDC, the availability of support services, and overall outcomes for patients and families.

Comparative responsiveness of Short-Form 12 and Minnesota Living With Heart Failure Questionnaire in patients with heart failure.

BACKGROUND: The Short-Form 12 (SF-12) and Living With Heart Failure Questionnaire (LHFQ) are commonly used to measure quality of life (QOL) in heart failure outcomes research. Their comparative responsiveness, however, has not been documented. METHODS AND RESULTS: A prospective cohort study was conducted among patients attending a university-based heart failure clinic between April 1997 and September 1998. All patients received comprehensive heart failure care management. QOL of patients was assessed by the SF-12 and LHFQ at baseline and 3 months. Of 87 patients completing follow-up, the mean change score was 10.1 for the LHFQ and 5.8 for the SF-12 (both Ps < .001). The change scores of the instruments were correlated (r = 0.61; P < .001). The SF-12 had a greater ability than the LHFQ to statistically detect change in physical health but was less sensitive to changes in mental health. The LHFQ performed better than the SF-12 in the ability to distinguish the differences in perceived global health transition. CONCLUSION: The LHFQ is more responsive than the SF-12 to changes in QOL. The SF-12 should not be used alone to measure the changes in QOL of patients with heart failure.

Familial dilated cardiomyopathy: echocardiographic diagnostic criteria for classification of family members as affected.

BACKGROUND: Echocardiographic criteria for left ventricular enlargement (LVE) used to classify subjects as affected in families with familial dilated cardiomyopathy (FDC) have been inconsistent. A recent report from a large Framingham echocardiographic study provides an opportunity to improve the assignment of LVE and FDC in kindreds, principally with a dilated phenotype. The objective of this study is to evaluate an alternative diagnostic criteria for FDC based only on LVE with no measure of fractional shortening (FS). METHODS AND RESULTS: We compared our proposed criteria for LVE and FDC with previous approaches by applying them to 166 adults derived from three large FDC pedigrees. Our proposed FDC diagnostic criteria are a sex- and height-specific method based only on LVE, without regard for FS, set as a 97.5% upper limit for left ventricular end-diastolic dimension (LVEDD) from the Framingham study. Other methods used to assign LVE were (1) a 95% upper limit for LVEDD by the Framingham study; (2) the method of Henry et al. (1980) based on age and body surface area (BSA); and (3) the National Heart, Lung, and Blood Institute (NHLBI) method with a cut point of LVEDD greater than 2.7 cm/BSA. Three other commonly used diagnostic criteria for FDC were based on various LVE standards combined with an FS of 27% to 30%. For LVE, the Framingham-97.5% was the most stringent (21 of 134 subjects identified; 15.7%), the NHLBI standard the least stringent (57 of 161 subjects identified; 35.4%), and the Henry-112% method intermediate (44 of 161 subjects identified; 27.3%). More women were identified with the Framingham method (57.1%) versus the Henry-112% (40.9%). The Henry-112% and NHLBI methods identified 11.4% and 7.0% of subjects with body mass indices (BMIs) of 35 or greater, respectively. For FDC, our proposed FDC diagnostic criteria identified similar numbers of subjects (21 subjects) as the three other criteria (range, 22 to 27 subjects), but inconsistency was noted (54.2% to 66.7%), with kappa values from 0.49 to 0.55 resulting from different sensitivities to sex, LVE, FS, and BMI. CONCLUSION: Our proposed FDC diagnostic criteria are stringent to assign FDC family members as affected compared with other commonly used criteria. The use of LVEDD alone may be preferable for FDC family screening, although further validation of this approach with phenotypic and genotypic data from other large FDC pedigrees is needed.

Clinical profiles of four large pedigrees with familial dilated cardiomyopathy: preliminary recommendations for clinical practice.

OBJECTIVES: This study aimed to characterize the clinical profile of familial dilated cardiomyopathy (FDC) in the families of four index patients initially diagnosed with idiopathic dilated cardiomyopathy (IDC) and to provide clinical practice recommendations for physicians dealing with these diseases. BACKGROUND: Recent evidence indicates that approximately one-half of patients diagnosed with IDC will have FDC, a genetically transmissible disease, but the clinical profile of families screened for FDC in the U.S. has not been well documented. Additionally, recent ethical guidelines suggest increased responsibilities in caring for patients with newly found genetic cardiovascular disease. METHODS: After identification of four families with FDC, we undertook clinical screening including medical history, physical examination, electrocardiogram and echocardiogram. Diagnostic criteria for FDC-affected status of asymptomatic family members was based on left ventricular enlargement (LVE). Subjects with confounding cardiovascular diagnoses or body mass indices >35 were excluded. RESULTS: We identified 798 living members from the four FDC pedigrees, and screened 216 adults and 129 children (age <16 years). Twenty percent of family members were found to be affected with FDC; 82.8% of those affected were asymptomatic. All four pedigrees demonstrated autosomal dominant patterns of inheritance. The average left ventricular end-diastolic dimension was 61.4 mm for affected and 48.4 mm for unaffected subjects, with an average age of 38.3 years (+/- 14.6 years) for affected and 32.1 years for unaffected subjects. The age of onset for FDC varied considerably between and within families. Presenting symptoms when present were decompensated heart failure or sudden death. CONCLUSIONS: We propose that with a new diagnosis of IDC, a thorough family history for FDC should be obtained, followed by echocardiographic-based screening of first-degree relatives for LVE, assuming their voluntary participation. If a diagnosis of FDC is established, we suggest further screening of first-degree relatives, and all subjects with FDC undergo medical treatment following established guidelines. Counseling of family members should emphasize the heritable nature of the disease, the age-dependent penetrance and the unpredictable clinical course.

Extracellular signal-regulated protein kinase activation is required for the anti-hypertrophic effect of atrial natriuretic factor in neonatal rat ventricular myocytes.

Atrial natriuretic factor (ANF) inhibits proliferation in non-myocardial cells and is thought to be anti-hypertrophic in cardiomyocytes. We investigated the possibility that the anti-hypertrophic actions of ANF involved the mitogen-activated protein kinase signal transduction cascade. Cultured neonatal rat ventricular myocytes treated for 48 h with the alpha(1)-adrenergic agonist phenylephrine (PE) had an 80% increase in cross-sectional area (CSA). ANF alone had no effect but inhibited PE-induced increases in CSA by approximately 50%. The mitogen-activated protein kinase/ERK kinase (MEK) inhibitor PD098059 minimally inhibited PE-induced increases in CSA, but it completely abolished ANF-induced inhibition of PE-induced increases. ANF-induced extracellular signal-regulated protein kinase (ERK) nuclear translocation was also eliminated by PD098059. ANF treatment caused MEK phosphorylation and activation but failed to activate any of the Raf isoforms. ANF induced a rapid increase in ERK phosphorylation and in vitro kinase activity. PE also increased ERK activity, and the combined effect of ANF and PE appeared to be additive. ANF-induced ERK phosphorylation was eliminated by PD098059. ANF induced minimal phosphorylation of JNK or p38, indicating that its effect on ERK was specific. ANF-induced activation of ERK was mimicked by cGMP analogs, suggesting that ANF-induced ERK activation involves the guanylyl cyclase activity of the ANF receptor. These data suggest that there is an important linkage between cGMP signaling and the mitogen-activated protein kinase cascade and that selective ANF activation of ERK is required for the anti-hypertrophic action of ANF. Thus, ANF expression might function as the natural defense of the heart against maladaptive hypertrophy through its ability to activate ERK.

Analysis of trends in hospitalizations for heart failure.

BACKGROUND: Over the past 10 years, efforts have been made to control the cost of care for patients with congestive heart failure (CHF) through reducing hospitalizations and shortening lengths of stay. Few data are available regarding the effectiveness of these intervention strategies on a community basis. METHODS AND RESULTS: We analyzed the Oregon hospital discharge database. Multivariable methods were used to assess trends while controlling for confounding factors, such as age, sex, and comorbidity. The hospital admission rates for CHF were stable over time in all age groups. The age- and sex-standardized admission rate among people aged 65 years or older decreased slightly from 13.9/1,000 in 1991 to 12.9/1,000 in 1995. The annual hospital readmission rate remained constant over time, with an average rate of 15.3%. The average length of hospital stay decreased from 5.01 days in 1991 to 3.95 days in 1995. The in-hospital mortality rate decreased from 6.9% in 1991 to 4.7% in 1995, independent of length of stay. CONCLUSION: We observed stable hospital admission and readmission rates for CHF, accompanied by a decreasing trend in the length of hospital stay and in-hospital mortality. Our findings raise the possibility of improved care management for heart failure over time.

Factors influencing knowledge of and adherence to self-care among patients with heart failure.

BACKGROUND: Patient education has been shown to be a key component in comprehensive heart failure management. Few data, however, are available regarding patients' knowledge of and adherence to self-care recommendations for the disease. OBJECTIVES: To assess the knowledge level of and adherence to self-care among patients with heart failure and to determine associated factors. METHODS: We conducted a needs-assessment survey among new patients visiting a heart failure clinic from April 1997 through June 1998. Multiple linear regression analysis was used to assess the factors predictive of patients' knowledge level and adherence behaviors. RESULTS: Of the 113 patients surveyed, 77% were referred by cardiologists and 60% had New York Heart Association class III or IV status. Two thirds of the patients reported receiving information or advice about self-care from health care providers. When asked how much they knew about congestive heart failure, however, 37% said "a little or nothing," 49% said "some," and only 14% said "a lot." Approximately 40% of the patients did not recognize the importance of weighing themselves daily and 27% weighed themselves twice a month or less often. Although 80% of the patients knew they should limit their salt intake, only one third always avoided salty foods. Additionally, 25% of the patients did not appreciate the risk of alcohol use and 36% believed they should drink a lot of fluids. The multiple linear regression analysis indicated that a higher knowledge score was associated with being married, prior hospitalization, and having received both advice and information about self-care from physicians or nurses. A poor adherence behavior score was associated with being unmarried, lower perceived self-efficacy, a lack of knowledge about self-care, and no prior hospitalization. CONCLUSIONS: We observed a gap between patients receiving and absorbing or retaining information on self-care for congestive heart failure supplied by health care providers. Self-care education needs to be directed to outpatients in addition to inpatients.

Was the decreasing trend in hospital mortality from heart failure attributable to improved hospital care? The Oregon experience, 1991-1995.

OBJECTIVE: To assess the trend in risk-adjusted hospital mortality from heart failure. STUDY DESIGN: Oregon hospital discharge data from 1991 through 1995 were analyzed. PATIENTS AND METHODS: A total of 29,530 hospitalizations because of heart failure in elderly patients (age > or = 65 years) were identified from International Classification of Diseases, 9th Revision, codes 428.0-428.9. The logistic regression and life table analyses were used to assess the risk-adjusted trend in hospital mortality from heart failure. RESULTS: From 1991 through 1995, 1757 (5.9%) patients with heart failure died in the hospital; 920 (52.4%) of them died within 3 days. The percentage of patients discharged to skilled nursing facilities increased from 6.1% in 1991 to 9.8% in 1995 (P value for trend < .001), whereas the percentage of patients discharged directly to home decreased from 69.2% in 1991 to 62.4% in 1995 (P value for trend < .001). The mean length of stay decreased from 5.15 days in 1991 to 3.97 days in 1995. The age- and sex-standardized mortality rate decreased by 33.8% from 7.4 in 1991 to 4.8 in 1995 (P value for trend < .01). Additional adjustment for comorbidity using multiple logistic regression revealed a greater reduction of 41.0% in the mortality rate (odds ratio = 0.59; 95% confidence interval = 0.50, 0.69) and a reduction of 46.0% in the 3-day mortality rate (odds ratio = 0.54; 95% confidence interval = 0.43, 0.67) across the 5-year period. Life table analysis showed consistently lower cumulative mortality rates during the first week after admission in 1995 compared with those in 1991 (P < .001). CONCLUSION: There was a decreasing trend over time in the risk-adjusted hospital mortality rates from heart failure, which was not an artifact of decreasing length of stay. Our findings raised the possibility of improved hospital care for heart failure in Oregon.

Managed care and outcomes of hospitalization among elderly patients with congestive heart failure.

BACKGROUND: Little was known about the impact of the health maintenance organization-managed care on patients hospitalized for congestive heart failure. Understanding this issue is important with regards to the increasing prevalence of congestive heart failure among the elderly population as well as the growing enrollment of Medicare beneficiaries in managed care. OBJECTIVE: To examine the impact of the health maintenance organization-managed care on the outcomes of hospitalization among patients with congestive heart failure. PATIENTS AND METHODS: We analyzed the Oregon hospital discharge data set. Study subjects were all patients with congestive heart failure aged 65 years or older (N=5821) discharged from hospitals in 1995 and classified into 6 insurance groups: managed care, Medicare, Medicaid, commercial or private insurance, self-pay, and other. RESULTS: The percentage of patients admitted to hospitals via emergency departments was significantly higher in the managed care patients (69%) than in other health insurance coverage groups (29.0%-58.5%; P<.001). After adjusting for age, sex, and comorbidity, the managed care patients experienced a similar length of hospital stay (3.6 days) as the commercial or private insurance patients (3.7 days; P = .67), but a shorter length of hospital stay than the Medicare patients (4.0 days; P<.001), self-pay patients (4.5 days; P<.001), and other patients (4.8 days; P<.001). No difference in the in-hospital mortality rate was seen among the insurance groups (P = .37). The readmission rate was slightly higher in managed care patients (9.1%) than in commercial insurance patients (6.8%) and Medicare patients (7.5%). The differences, however, were not statistically significant after adjusting for the confounding factors (P = .59). CONCLUSIONS: Our results suggest no association between managed care and poor short-term outcomes of hospitalization in patients with congestive heart failure. Attention, however, needs to be paid to the increased use of emergency departments by managed care patients.

Clinical outcomes, quality of life, and cost outcomes after cardiac transplantation.

Cardiac transplantation improves survival in patients with advanced heart failure, especially those who are dependent on intravenous inotropic support or mechanical assistance. However, cardiac transplantation remains a treatment modality rather than a curative procedure, and thus, necessitates long-term care and indefinite immunosuppression. Although quality of life is improved for most cardiac transplant recipients, concerted effort is necessary for long-term care and follow-up of the transplanted heart. The economics of cardiac transplantation are receiving increased scrutiny, especially because of the increasing pretransplant hospital expenditures that have resulted from transplantation in more patients in the hospital who require intravenous inotropic support or mechanical devices. This shift ultimately is related to the reduced supply of donors relative to the demand. The ultimate impact of managed care on cardiac transplantation is not clear, but it probably will continue to reduce expenditures in the near term.

Carvedilol produces dose-related improvements in left ventricular function and survival in subjects with chronic heart failure. MOCHA Investigators.

BACKGROUND: We conducted a multicenter, placebo-controlled trial designed to establish the efficacy and safety of carvedilol, a "third-generation" beta -blocking agent with vasodilator properties, in chronic heart failure. METHODS AND RESULTS: Three hundred forty-five subjects with mild to moderate, stable chronic heart failure were randomized to receive treatment with placebo, 6.25 mg BID carvedilol (low-dose group), 12.5 mg BID carvedilol (medium-dose group), or 25 mg BID carvedilol (high-dose group). After a 2- to 4-week up-titration period, subjects remained on study medication for a period of 6 months. The primary efficacy parameter was submaximal exercise measured by two different techniques, the 6-minute corridor walk test and the 9-minute self-powered treadmill test. Carvedilol had no detectable effect on submaximal exercise as measured by either technique. However, carvedilol was associated with dose-related improvements in LV function (by 5, 6, and 8 ejection fraction [EF] units in the low-, medium-, and high-dose carvedilol groups, respectively, compared with 2 EF units with placebo, P < .001 for linear dose response) and survival (respective crude mortality rates of 6.0%, 6.7%, and 1.1% with increasing doses of carvedilol compared with 15.5% in the placebo group, P < .001). When the three carvedilol groups were combined, the all-cause actuarial mortality risk was lowered by 73% in carvedilol-treated subjects (P < .001). Carvedilol also lowered the hospitalization rate (by 58% to 64%, P = .01) and was generally well tolerated. CONCLUSIONS: In subjects with mild to moderate heart failure from systolic dysfunction, carvedilol produced dose-related improvements in LV function and dose-related reductions in mortality and hospitalization rate.

Pharmacologic and hemodynamic effects of combined beta-agonist stimulation and phosphodiesterase inhibition in the failing human heart.

STUDY OBJECTIVES: We measured the individual and combined effects of the beta-agonist dobutamine and the phosphodiesterase inhibitor enoximone both in vitro and in vivo in the failing human heart. DESIGN: This was an unblinded, prospective study. SETTING AND PATIENTS: The in vitro measurements were performed on 20 hearts obtained from subjects with end-stage biventricular failure and from seven normal hearts. The in vivo measurements were performed in eight subjects with class IV heart failure. INTERVENTIONS AND MEASUREMENTS: The in vitro measurements of enoximone, dobutamine, and the combination of these agents were phosphodiesterase activity using a sarcoplasmic reticulum-enriched preparation, cyclic adenosine monophosphate (cAMP) accumulation using particulate fractions, and tension response using isolated right ventricular trabeculae. The dose response to dobutamine, the combination of enoximone and dobutamine, and the combination of nitroprusside and dobutamine were measured in vivo using invasive hemodynamic monitoring. RESULTS: In vitro, enoximone exhibited dose-dependent inhibition of phosphodiesterase activity. The addition of enoximone to dobutamine resulted in an upward and leftward shift of the dobutamine dose-response curve for both cAMP production and contractile response. In vivo, enoximone significantly shifted the dobutamine dose-response curves for cardiac index, left ventricular stroke work index, and heart rate upward and to the left; and shifted the dobutamine dose-response curves for right atrial, pulmonary arterial, and pulmonary wedge pressures downward and to the right. CONCLUSIONS: Enoximone exerts favorable effects on cardiac performance that are additive to those produced by dobutamine. These effects are mediated by increasing cellular cAMP concentrations through independent, additive mechanisms.

The somatostatin receptor SSTR1 is coupled to phosphotyrosine phosphatase activity in CHO-K1 cells.

Somatostatin receptors are abundantly expressed on a variety of human endocrine and epithelial tumors. The ability of these receptors to couple to effector pathways that inhibit the growth of these tumor cells has prompted the use of somatostatin agonists in the treatment of human neoplasms. It has been demonstrated that somatostatin stimulates a phosphotyrosine phosphatase in human tumor cells through a receptor-mediated process. This stimulation may counteract the growth-promoting properties of growth factors and the receptor tyrosine kinases that they activate. The recent cloning and characterization of distinct somatostatin receptor subtypes raise the possibility that different receptor subtypes mediate distinct effector pathways. To determine whether cloned somatostatin receptors could mediate coupling to phosphotyrosine phosphotyrosine phosphatase activity, we examined phosphatase activity after somatotostatin activation of the rat somatostatin receptors SSTR1 and SSTR2 after their stable expression in heterologous Chinese Hamster Ovary (CHO-K1) cells. We found that stimulation of SSTR1 cells was capable of increasing phosphotyrosine phosphatase activity, despite the coupling of both receptors to the inhibition of adenylyl cyclase in these cells. This activation was characterized by an EC50 of 70 nM and was sensitive to pertussis toxin. In addition, we demonstrate that activation of phosphotyrosine phosphatase activity in pituitary cell lines correlates with the endogenous expression of the SSTR1 gene within these cells.

The somatostatin receptors SSTR1 and SSTR2 are coupled to inhibition of adenylyl cyclase in Chinese hamster ovary cells via pertussis toxin-sensitive pathways.

Somatostatin exerts multiple effects throughout the body by binding to specific somatostatin receptors. Two classes of somatostatin receptors, SRIF1 and SRIF2, have been distinguished biochemically and pharmacologically. Two cDNAs have been recently isolated that encode somatostatin receptors 1 and 2 (SSTR1 and SSTR2, respectively). The pharmacological characteristics of receptors expressing these cDNAs resemble those of the SRIF2 and SRIF1 classes of somatostatin receptors, respectively. We stably expressed the rat homologs of both receptors in Chinese hamster ovary (CHO) cells (type K1). These transfected cell lines recognized the endogenous ligands SS14 and SS28 with high affinity, whereas the synthetic analog MK678 identified only SSTR2. In preparations of CHO-SSTR1 or CHO-SSTR2 cells, SS14 and SS28 inhibited forskolin-stimulated adenylyl cyclase activity by approximately 35%, with ED50 values in the nanomolar range. The adenylyl cyclase inhibition was dependent upon the guanine nucleotide GTP and could be ablated with pertussis toxin preincubation. The present data indicate that SSTR1 and SSTR2 are coupled to inhibition of adenylyl cyclase via pertussis toxin- sensitive G-proteins.

Heart transplantation in patients with previous cardiac operations. Excellent clinical results.

A significant proportion of potential transplant recipients have undergone previous cardiac procedures and may be subject to an increased risk because of technical and other factors inherent in a reoperation. Between December 1985 and June 1991, 155 orthotopic heart transplantations were carried out in 146 patients. Eighty-five transplantations (54.8%) were carried out as the initial cardiac operation (group I); 61 operations (45.2%) were performed in patients who had previous nontransplant cardiac operations (group II). Preoperative variables including hemodynamic indexes, renal function, and status on the waiting list were similar between these groups; however, group II patients tended to be older than group I patients (51.9 +/- 10.7 versus 47.7 +/- 11.6 years, respectively; p < 0.05) and were more likely to have ischemic heart disease (80.3% versus 34.1%) than were those in group I. Significantly longer cardiopulmonary bypass time (127.6 +/- 44.7 minutes versus 108.2 +/- 18.8 minutes, p < 0.01) and duration of operation (448.1 +/- 120.9 minutes versus 353.2 +/- 85.1 minutes, p < 0.01) was found in group II. Operative mortality in group I was 4.7% and in group II was 6.6% (p > 0.9). Group I actuarial survival at 1 year and 5 years was 87.1% +/- 3.6% and 72.9% +/- 6.2%, respectively. Group II actuarial survival was 85.3% +/- 4.5% and 76.0% +/- 6.6%, respectively, for the same time periods. In spite of the greater technical challenge implied by previous cardiac operations, no significant survival differences occurred between these groups (p > 0.9). However, patients undergoing a second cardiac transplantation (n = 9) were identified as a high-risk subset with operative mortality of 22.8% and 1-year survival of only 33.3% +/- 15.7% (p < 0.0003). Cardiac transplantation in patients who have undergone previous nontransplant cardiac operations can be carried out without compromising immediate or long-term outcome.