A functional polymorphism of the Galphaq (GNAQ) gene is associated with accelerated mortality in African-American heart failure.

Galphaq, encoded by the human GNAQ gene, is an effector subunit of the Gq heterotrimeric G-protein and the convergence point for signaling of multiple Gq-coupled neurohormonal receptors. To identify naturally occurring mutations that could modify GNAQ transcription, we examined genomic DNA isolated from 355 normal subjects for genetic variants in transcription factor binding motifs. Of seven variants identified, the most common was a GC to TT dinucleotide substitution at -694/-695 (allele frequency of 0.467 in Caucasians and 0.329 in African Americans) within a GC-rich domain containing consensus binding sites for Sp-1, c-rel and EGR-1. In promoter-reporter analyses, the TT substitution increased promoter activity in cultured neonatal rat cardiac myocytes and human HEK fibroblasts by approximately 30% at baseline and after stimulation with phorbol ester. Two other relatively common polymorphisms, -173G/A and -168G/A, did not affect promoter activity. Since altered expression/activity of Galphaq is implicated in heart disease, we re-sequenced the GNAQ promoter in 1052 prospectively followed heart failure patients. The TT variant was not increased in heart failure, but was associated with decreased survival time among African Americans, with an adjusted RR of death/cardiac transplant of 1.95 (95% CI = 1.21-3.13) for heterozygotes and 2.4 (95% CI = 1.36-4.26) for homozygotes. Gel mobility shift assays showed that this GC/TT substitution eliminated Sp-1 binding without affecting c-rel or EGR-1 binding to this promoter fragment. Thus, the GNAQ -694/-695 promoter polymorphism alters transcription factor binding, increases promoter activity and adversely affects outcome in human heart failure.

Activity of the uptake-1 norepinephrine transporter as measured by I-123 MIBG in heart failure patients with a loss-of-function polymorphism of the presynaptic alpha2C-adrenergic receptor.

BACKGROUND: Patients with a deletion of 4 consecutive amino acids in the gene encoding for the alpha(2C)-adrenergic receptor (alpha(2C)Del322-325) have an increased prevalence of clinical heart failure, worse clinical status, and a lower left ventricular ejection fraction compared with patients without this deletion. We postulated that patients with the alpha(2C)Del322-325 polymorphism would have a compensatory increase in norepinephrine uptake-1 transporter activity as measured by iodine 123 metaiodobenzylguanidine (MIBG). METHODS AND RESULTS: Thirty-nine patients with heart failure related to idiopathic dilated cardiomyopathy were studied. Demographic characteristics, left ventricular ejection fraction, maximum oxygen consumption, exercise duration, and plasma norepinephrine levels did not differ between patients with the alpha(2C) receptor polymorphism (n = 9) and those without it (n = 30). Patients with the alpha(2C)Del322-325 polymorphism had significantly greater heart-to-mediastinum ratios of I-123 MIBG at 4 hours after tracer injection (1.60 +/- 0.19 vs 1.41 +/- 0.19, P =.0117) and greater background-corrected heart counts per pixel at 4 hours compared with patients without the polymorphism. CONCLUSIONS: Patients with genetic impairment of the alpha(2C)-adrenergic receptor have augmented activity of the norepinephrine uptake-1 transporter as measured by I-123 MIBG. Further studies are needed to clarify the mechanism by which uptake-1 transporter activity is increased in this setting.

Sympathetic nervous system function as measured by I-123 metaiodobenzylguanidine predicts transplant-free survival in heart failure patients with idiopathic dilated cardiomyopathy.

BACKGROUND: Heightened activity of the sympathetic nervous system in heart failure patients is a major contributor to disease progression and death. I-123 metaiodobenzylguanidine (MIBG) provides an accurate, noninvasive method to assess cardiac sympathetic nerve activity. METHODS: Thirty-seven patients with New York Heart Association class II, III, or IV heart failure underwent baseline measurement of I-123 MIBG heart-to-mediastinum ratios, maximum oxygen consumption, radionuclide left ventricular ejection fraction, and plasma norepinephrine levels. Patients were followed 48.8+/-8.6 months to endpoints of cardiac death or transplantation. The heart-to-mediastinum ratio of I-123 MIBG activity measured 15 minutes after injection was the only independent predictor of transplant-free survival (P<.0001). I-123 MIBG imaging at 15 minutes identified patients with subsequent cardiac transplantation or death with a sensitivity of 92% and specificity of 72%, whereas the corresponding values for maximum oxygen consumption were 75% and 56%. By Kaplan-Meier survival analysis, the time to a cardiac endpoint was significantly shorter in patients with a 15-minute I-123 MIBG heart-to-mediastinum ratio below the group mean ratio of 1.536, compared with patients with a preserved I-123 MIBG ratio. Maximum oxygen consumption was not predictive of time to cardiac transplant or death. CONCLUSIONS: In this study of patients with congestive heart failure resulting from dilated cardiomyopathy, a 15-minute heart-to-mediastinum ratio of I-123 MIBG activity provided more accurate prediction of cardiac transplantation or death than other standard clinical tests.

Infections in the heart transplant recipient.

The overall incidence of infection after transplantation has decreased with improved immunosuppressive agents, increased knowledge and use of prophylaxis, and better detection and treatment of infection. Nevertheless, infection continues to be a major cause of morbidity and mortality in heart transplant recipients. The knowledgeable nurse in any setting who cares for a transplant recipient must be aware of the lifelong susceptibility to common and opportunistic infections. The transplant recipient and his or her family must also be aware of the risks of early opportunistic infection. Infection is a lifelong concern for all persons on immunosuppressant medications, and the individual must learn appropriate precautions to reduce this risk. Hand washing and avoidance of infected individuals are the most important self-care actions that the transplant patient should adopt. Recipients must also learn to monitor for subtle signs of infection. The nurse is responsible for teaching self-care to patients and family members. Ultimately, a team effort by the patient, family, nurses, and physicians can reduce the risk of infection in this vulnerable population.

Carvedilol improves left ventricular function in heart failure patients with idiopathic dilated cardiomyopathy and a wide range of sympathetic nervous system function as measured by iodine 123 metaiodobenzylguanidine.

BACKGROUND: Carvedilol treatment reduces the mortality rate in patients with congestive heart failure. It is not known whether carvedilol treatment is effective in heart failure patients with substantial cardiac sympathetic nerve dysfunction. The goal of this study was to determine the effect of chronic carvedilol treatment in patients with cardiac sympathetic nerve dysfunction of varying severity. METHODS AND RESULTS: In 22 congestive heart failure patients with idiopathic cardiomyopathy, sympathetic nerve function was assessed before and after 7.2 +/- 2.7 months of carvedilol treatment with the use of iodine 123 metaiodobenzylguanidine (MIBG) imaging, radionuclide ventriculography, and transmyocardial norepinephrine sampling. Patients with relatively advanced impairment of cardiac sympathetic nerve function, as manifested by a baseline I-123 MIBG ratio lower than 1.40, had a statistically significant improvement in I-123 heart-mediastinum ratio with carvedilol treatment, from 1.26 +/- 0.12 to 1.39 +/- 0.20 (P =.004). Of 10 patients with a baseline I-123 MIBG ratio lower than 1.40, 9 had an increase in the heart-mediastinum ratio with carvedilol treatment. Left ventricular ejection fraction increased from 25.4% +/- 7.8% to 37.3% +/- 14.7% (P <.001), with no difference between patients with relatively advanced versus relatively preserved cardiac sympathetic nerve function. CONCLUSION: Most patients with congestive heart failure show a favorable response in left ventricular function to carvedilol treatment, regardless of the baseline level of cardiac sympathetic nervous system function, as assessed by neuronal imaging with I-123 MIBG. Patients with relatively advanced impairment of baseline I-123 MIBG uptake are most likely to show evidence of improved cardiac sympathetic nervous system function in response to carvedilol therapy.

Polymorphisms of the beta1-adrenergic receptor predict exercise capacity in heart failure.

BACKGROUND: Exercise performance in patients with congestive heart failure is partially dependent on cardiac beta1-adrenergic receptor (beta1AR) function. There are 2 common polymorphisms of the beta1AR gene that alter the encoded amino acids at positions 49 (Ser or Gly) and 389 (Gly or Arg) and alter receptor function in vitro. Their relevance to modification of cardiac function in heart failure is not known. METHODS: Exercise testing was performed in 263 patients with idiopathic or ischemic cardiomyopathy (left ventricular ejection fraction approximately 25%). Potential associations were sought between beta1AR genotypes and the primary outcome variables of peak oxygen consumption (VO2), heart rate response, and exercise time. RESULTS: The major determinants of exercise capacity were the polymorphisms at position 389, where patients homozygous for Gly389 had significantly lower peak VO2 compared with those with Arg389 (14.5 +/- 0.6 vs 17.7 +/- 0.4 mL/kg/min, P =.006), despite similar clinical characteristics including left ventricular ejection fraction. Consistent with a gene dose-response, heterozygosity was associated with an intermediate response (16.9 +/- 0.6 mL/kg/min, P <.05). When position 49 genotypes were included, a graded relationship between the 5 2-locus haplotypes and VO2 was found. Two haplotypes displayed the most divergent peak VO2: homozygous Gly389/Ser49, and homozygous Arg389/Gly49 carriers (14.4 +/- 0.5 vs 18.2 +/- 0.8 mL/kg/min, P =.001). Genotype did not predict the heart rate response. The above results were independent of beta-blocker or other medication use, left ventricular ejection fraction, beta2AR genotype, or other demographic and clinical characteristics. CONCLUSION: beta1AR polymorphisms are a significant determinant of exercise capacity in patients with congestive heart failure. Early identification, by genetic testing for these polymorphisms, of heart failure patients at risk for development of depressed exercise capacity may be useful for initiation of specific therapy tailored to genotype.

Detection of occult urinary tract infections in dogs with diabetes mellitus.

Dogs with diabetes mellitus may develop occult urinary tract infections. In this study, diabetic dogs with negative and positive bacterial urine cultures were compared. Records from 51 dogs with diabetes mellitus were reviewed at the University of Illinois. No difference was identified between the groups in urine specific gravity, pH, glucose, ketones, protein, red blood cells, white blood cells, or epithelial cells. Dogs with occult urinary tract infection did have an increased incidence of bacteriuria, but this was not a consistent finding. Therefore, the urine on all diabetic dogs should be cultured to accurately identify the presence or absence of bacterial urinary tract infections.

Pulmonary thromboembolism associated with Blastomyces dermatitidis in a dog.

An 8-year-old, male castrated golden retriever presented for cough and increased respiratory effort. Radiographs revealed an alveolar pattern in the right caudal lung lobe and an opacity at the carina suspected to be enlarged tracheobronchial lymph nodes. The disease progressed to involve the right middle lung lobe. Cytopathology of a fine-needle aspirate and bronchoalveolar lavage fluid were nondiagnostic. Surgical removal of the right caudal lung lobe and biopsy of the perihilar lymph nodes revealed pulmonary thromboembolism and reactive lymph nodes. The dog died several days postoperatively, and necropsy revealed diffuse pulmonary thromboembolism. Additionally, Blastomyces dermatitis organisms were identified in a pyogranulomatous mass surrounding the trachea near the carina. In an extensive literature search, no reports of pulmonary thromboembolism associated with blastomycosis were identified. It is suspected that the inflammation secondary to blastomycosis caused the thromboembolism.