Telesurgical Assessment: Using Smartphone Messaging to Efficiently Manage Postoperative Wounds.

Background: Telemedicine is an evolving field of interactions between physicians and patients remotely. Health care delivery, patient satisfaction, adherence, earlier diagnosis, increased access, and cost reduction are all areas that telemedicine has potential influence. One focus involves the use of photos in wound assessment. Today, many patients' smartphones can capture high-quality digital photographs, which can easily be transmitted. Postoperative patients are an ideal population for this, as they have a certain level of uncertainty with regard to the healing course, which can often lead to patients seeking out care in unnecessarily costly settings. These visits can lead to inefficient use of health care resources, especially when a telesurgical assessment (TSA) could provide appropriate care more efficiently. Objective: We present data collected from a series of patients who received a TSA to demonstrate the potential benefits of incorporating TSA into postoperative wound care. Methods/Clinical Presentation: Patients who underwent a procedure and contacted their surgeon within 2 weeks with concerns received a TSA, which included a discussion as well as photographs through smartphone. Their surgeon then determined further treatment steps, if any. Results: We experienced that 85% of patients did not require emergent treatment for their concerns, 46% were prescribed medications, whereas 39% of patients did not require any intervention. Conclusion: Our results show that TSAs alleviated patient concerns and provide resolutions, while saving resources and increasing satisfaction. Incorporating aspects of telemedicine into outpatient practice could be valuable, especially with postoperative wound checks.

Incisional Hernia After Percutaneous Endoscopic Gastrostomy Tube Placement: Importance of Avoiding the Linea Alba.

A gastrostomy tube passes from a patient's stomach through the abdominal wall and allows for direct enteral access. An alternative to an open gastrostomy, a percutaneous endoscopic gastrostomy (PEG) is typically favored because it is a less invasive option. However, a thorough understanding of the anatomy involved is paramount to prevent complications, regardless of what technique is chosen for placement. We present a case of an incisional hernia, which developed after the removal of a PEG tube placed through the midline of an abdominal wall, which is both a rare and avoidable complication. Placement of a PEG tube lateral to midline and avoiding the linea alba, an inherent weak point, will decrease the incidence of incisional hernias.

Peritoneal pocket hernia: A distinct cause of early postoperative small bowel obstruction and strangulation: A report of two cases following robotic herniorrhaphy.

Laparoscopic and robotic hernia surgery offers advantages over open herniorrhaphy including faster recover and lower wound infection but is associated with rare but serious complications such as visceral injury and intestinal obstruction. We describe two cases of small bowel obstruction with strangulation that occurred shortly after routine robotic hernia surgery. We define this rare type of strangulating internal hernia as a peritoneal pocket hernia and call attention to its diagnosis and management.

Operative bed recurrence of thyroid cancer: utility of a preoperative needle localization technique.

BACKGROUND: Surgical management of recurrent disease after total thyroidectomy and/or neck dissection for thyroid carcinoma remains a challenging clinical problem. Reoperation is associated with a significant increase in morbidity. Preoperative needle localization technique for non-palpable breast tumors has recently been extrapolated to head and neck surgery. We report on the use of preoperative ultrasound-guided needle localization for non-palpable recurrent operative bed disease as an intraoperative aid in resection. METHODS: Patients with thyroid carcinoma were identified from a retrospective database at a tertiary care center from 2011-2014. Inclusion criteria were history of thyroidectomy and/or neck dissection, non-palpable recurrent disease in the resection bed on surveillance, and ultrasound-guided needle localization of recurrent disease before resection. Perioperative data and outcomes were analyzed. RESULTS: Seventeen patients were identified using the inclusion criteria listed above. Median patient age was 46 years (53% male, 47% female). A total of 23 masses in the previous operative bed were needle-localized successfully with no major long-term sequelae from this technique. The recurrent laryngeal nerve was involved with tumor in six patients. Two patients, in whom the tumor surrounded the nerve circumferentially, experienced recurrent laryngeal nerve injuries. No patients experienced postoperative hypocalcemia. With a routine surveillance and a median follow-up of 558 days, sixteen of the patients remain with no evidence of disease. CONCLUSIONS: Preoperative ultrasound-guided needle localization of non-palpable recurrent operative bed disease after thyroidectomy and/or neck dissection is a potentially safe method to aid in resection and cure.

An Evaluation of Postoperative Complications and Cost After Short-Stay Thyroid Operations.

BACKGROUND: Concern for postoperative complications causing airway compromise has limited widespread acceptance of ambulatory thyroid surgery. We evaluated differences in outcomes and hospital costs in those monitored for a short stay of 6 h (SS), inpatient observation of 6-23 h (IO), or inpatient admission of >23 h (IA). METHODS: We retrospectively reviewed all patients undergoing thyroidectomy from 2006 to 2012. The incidence of postoperative hemorrhage, nerve dysfunction, and hypocalcemia were evaluated, as well as cost data comparing the SS and IO groups. RESULTS: Of 1447 thyroidectomies, 880 (60.8 %) were performed as SS, 401 (27.7 %) as IO, and 166 (11.5 %) as IA. Fewer patients in the SS group (59 %) underwent total thyroidectomy than IO (73 %) and IA (71 %; p < 0.01), and SS patients had smaller thyroid weights (27.9 g) compared with IO and IA (47.2 and 98.9 g, respectively; p < 0.01). Ten (0.69 %) patients developed hematomas requiring reoperation, five of the ten patients received antiplatelet or anticoagulant therapy perioperatively. Only one patient in the IA group bled within the 6- to 23-h period, and no patients with bleeding who were discharged at 6 h would have benefitted from 23-h observation. Twenty-four (1.66 %) recurrent laryngeal nerve injuries were identified, 16 with temporary neuropraxias. In addition, 24 (1.66 %) patients had symptomatic hypocalcemia, which was transient in 17 individuals. Financial data showed higher payments and lower costs associated with SS compared with IO. CONCLUSIONS: Selective SS thyroidectomy can be safe and cost effective, with few overall complications in patients undergoing more complex operations involving larger thyroids who were admitted to hospital.

A risk model to determine surgical treatment in patients with thyroid nodules with indeterminate cytology.

BACKGROUND: Thyroid nodules are present in 19-67 % of the population and have a 5-10 % risk of malignancy. Fine needle aspiration biopsies are indeterminate in 20-30 % of patients, often necessitating thyroid surgery for diagnosis. We hypothesized that developing a risk model incorporating factors associated with malignancy could help predict the risk of malignancy in patients with indeterminate thyroid nodules. METHODS: We identified 151 patients with a cytologic diagnosis of follicular neoplasm (Bethesda IV) who progressed to surgery. We retrospectively analyzed demographic, clinical, sonographic, and cytological variables in relation to thyroid carcinoma. RESULTS: Of 151 patients, 51 (33.8 %) had a final diagnosis of thyroid carcinoma. Papillary carcinoma was diagnosed in 34 patients (66.7 %), follicular carcinoma in 15 (29.4 %), and Hürthle cell carcinoma in 2 (3.9 %). On univariate analysis, younger age, male gender, tobacco use, larger nodule size, and calcifications on ultrasound, nuclear atypia on cytology, and suspicious frozen section were associated with the presence of malignancy. When determining odds ratios, four factors were most predictive of malignancy: nodule calcification [odds ratio (OR) 6.37, 95 % confidence interval (CI) 1.62-25.1, p < 0.01] and nodule size (OR 1.75, 95 % CI 1.19-2.57, p < 0.01) on ultrasound, nuclear atypia on cytology (OR 4.91, 95 % CI 1.90-12.66, p < 0.01), and tobacco use (OR 4.59, 95 % CI 1.30-16.27, p < 0.02). A multivariable model based on these four factors resulted in a c-statistic of 0.82. CONCLUSIONS: A multivariable model based on calcification, nodule size, nuclear atypia, and tobacco use may predict the risk of thyroid cancer requiring a total thyroidectomy in patients with thyroid nodules of indeterminate cytology.

The utility of lymph node mapping sonogram and thyroglobulin surveillance in post thyroidectomy papillary thyroid cancer patients.

BACKGROUND: The American Thyroid Association recommends lymph node mapping (LNM) ultrasonography 6-12 months after thyroidectomy for patients with papillary thyroid cancer (PTC). The yield of LNM over thyroglobulin (TG) screening is not well defined. We sought to investigate this relationship. METHODS: Post thyroidectomy LNM was performed on 163 patients with PTC. LNM was considered positive based on these criteria: Loss of fatty hilum (LOFH), microcalcifications, hypervascularity, architectural distortion, or short axis (>8 mm). Serum TG levels were compared to LNM and fine needle aspiration (FNA). RESULTS: Sixty-nine patients had suspicious LNM (42%) and 17 had PTC on FNA (25%). There were 135 suspicious lymph nodes described with malignant nodes found in 6 of 65 patients (9%) with LOFH, 13 of 18 patients (76%) with microcalcifications, 11 of 12 patients (92%) with hypervascularity, 16 of 28 patients (52%) with architectural distortion, and 4 of 7 patients (52%) with enlarged size on FNA. The positive predictive value of LNM was 0.34, increasing to 0.66 when LOFH was excluded. Among 152 patients with documented TG data, LNM identified cervical nodal metastasis in 4 patients with TG < 0.5 pg/mL (anti-TG antibody negative, thyroid-stimulating hormone suppressed). Of the 15 patients with positive anti-TG antibody, 3 with recurrence were found on LNM. CONCLUSION: LNM can detect recurrent PTC when TG level is undetectable, and LOFH is a low-yield sonographic characteristic.

Does nodule size predict compressive symptoms in patients with thyroid nodules?

BACKGROUND: Thyromegaly and thyroid nodules are known to cause compressive symptoms, but the exact relationship between nodule size and development of compressive symptoms is unclear. We sought to determine whether compressive symptoms are directly related to nodule size. METHODS: A retrospective analysis of 99 patients who underwent thyroidectomy by a single surgeon was performed. Patients were placed into one of two cohorts: those who experienced preoperative compressive symptoms (N=51) and those who did not (N=48). Compressive symptoms were defined as experiencing neck fullness, dysphagia, choking, or dyspnea. Nodule size, thyroid lobe size, and the presence of visible thyromegaly were compared between the two groups. RESULTS: Average nodule size in patients with compressive symptoms was 3.8 versus 2.2 cm in asymptomatic patients (P<0.0001). Average lobe diameter was 6.2 cm in patients with compressive symptoms versus 4.9 cm in asymptomatic patients (P<0.001). Visible thyromegaly was present in 65.2% of patients with compressive symptoms and 15.4% of asymptomatic patients (P<0.0001). The most common symptom was dysphagia, occurring in 80% of patients, followed by neck fullness (69%), choking (49%), and dyspnea (32%). Of patients who underwent surgery for compressive symptoms, 92.7% had improvement in their symptoms postoperatively. Of patients with a thyroid nodule greater than 1.5 cm, 97% showed improvement in symptoms postoperatively. CONCLUSIONS: Thyroid nodule size and lobe size appear to directly correlate with compressive symptoms. Of patients with compressive symptoms and a thyroid nodule >1.5 cm, 97% experienced improvement in symptoms postoperatively.

Carbonic anhydrase 4 and crystallin α-B immunoreactivity may distinguish benign from malignant thyroid nodules in patients with indeterminate thyroid cytology.

BACKGROUND: Thyroid nodules are present in 19%-67% of the population and carry a 5%-10% risk of malignancy. Unfortunately, fine-needle aspiration biopsies are indeterminate in 20%-30% of patients, often necessitating thyroid surgery for diagnosis. Numerous DNA microarray studies including a recently commercialized molecular classifier have helped to better distinguish benign from malignant thyroid nodules. Unfortunately, these assays often require probes for >100 genes, are expensive, and only available at a few laboratories. We sought to validate these DNA microarray assays at the protein level and determine whether simple and widely available immunohistochemical biomarkers alone could distinguish benign from malignant thyroid nodules. METHODS: A tissue microarray (TMA) composed of 26 follicular thyroid carcinomas (FTCs) and 53 follicular adenomas (FAs) from patients with indeterminate thyroid nodules was stained with 17 immunohistochemical biomarkers selected based on prior DNA microarray studies. Antibodies used included galectin 3, growth and differentiation factor 15, protein convertase 2, cluster of differentiation 44 (CD44), glutamic oxaloacetic transaminase 1 (GOT1), trefoil factor 3 (TFF3), Friedreich Ataxia gene (X123), fibroblast growth factor 13 (FGF13), carbonic anhydrase 4 (CA4), crystallin alpha-B (CRYAB), peptidylprolyl isomerase F (PPIF), asparagine synthase (ASNS), sodium channel, non-voltage gated, 1 alpha subunit (SCNN1A), frizzled homolog 1 (FZD1), tyrosine related protein 1 (TYRP1), E cadherin, type 1 (ECAD), and thyroid hormone receptor associated protein 220 (TRAP220). Of note, two of these biomarkers (GOT1 and CD44) are now used in the Afirma classifier assay. We chose to compare specifically FTC versus FA rather than include all histologic categories to create a more uniform immunohistochemical comparison. In addition, we have found that most papillary thyroid carcinoma could often be reasonably distinguished from benign disease by morphological cytology findings alone. RESULTS: Increased immunoreactivity of CRYAB was associated with thyroid malignancy (c-statistic, 0.644; negative predictive value [NPV], 0.90) and loss of immunoreactivity of CA4 was also associated with malignancy (c-statistic, 0.715; NPV, 0.90) in indeterminate thyroid specimens. The combination of CA4 and CRYAB for discriminating FTC from FA resulted in a better c-statistic of 0.75, sensitivity of 0.76, specificity of 0.59, positive predictive value (PPV) of 0.32, and NPV of 0.91. When comparing widely angioinvasive FTC from FA, the resultant c-statistic improved to 0.84, sensitivity of 0.75, specificity of 0.76, PPV of 0.11, and NPV of 0.99. CONCLUSIONS: Loss of CA4 and increase in CRYAB immunoreactivity distinguish FTC from FA in indeterminate thyroid nodules on a thyroid TMA with an NPV of 91%. Further studies in preoperative patient fine needle aspiration (FNAs) are needed to validate these results.

Diagnosing thyroid lymphoma: steroid administration may result in rapid improvement of dyspnea : a report of two cases.

INTRODUCTION: Thyroid nodules, whether benign or malignant, are slow growing masses. There are certain clinical situations where sudden rapid growth may occur and cause acute respiratory compromise secondary to tracheal compression. CASE PRESENTATION: Here we describe two patients with suddenly enlarging thyroid nodules, who developed acute respiratory compromise in the absence of tracheal compression. Their symptoms rapidly improved with administration of corticosteroids, and in subsequent workup, both were diagnosed as thyroid lymphoma. CONCLUSIONS: The potent effect of corticosteroids in the rapid improvement of respiratory compromise associated with thyroid lymphoma represents an important clinical finding. This opens the possibility for the favorable response to corticosteroid therapy to be regarded as a possible preliminary diagnostic tool for thyroid lymphoma in acute respiratory distress patients in the absence of tracheal compression. Subsequent retrospective studies are necessary to verify this hypothesis.

Is one benign fine needle aspiration enough?

BACKGROUND: Fine needle aspiration (FNA) is used to diagnose thyroid nodules, but the follow-up of benign FNA is unclear. We sought to determine whether routine repeat FNAs after initial benign FNA reduces false negatives. METHODS: We identified 265 patients who had at least one benign FNA that either progressed to surgery or had at least one repeat FNA. We reviewed their ultrasonography, FNA cytology, and surgical pathology. RESULTS: Of 127 patients with initial benign FNA that had surgery, 13 had a malignancy, yielding a 10.2% false-negative rate. Of 22 patients who had surgery after at least two benign FNAs, one had a malignancy, yielding a 4.5% false-negative rate. Initially benign cytology (Bethesda II) was upgraded to a cytology requiring surgical intervention (Bethesda IV-VI) in 7 of 129 (5.4%) patients after two FNAs. Suspicious features on ultrasound, including size >4 cm, calcifications, or increased vascularity were found in 90% of patients with a false-negative FNA. CONCLUSIONS: The overall false-negative rate of thyroid FNAs is 10.2%, which is reduced to 4.5% with a second benign FNA. Ninety percent of patients with a false-negative FNA had suspicious sonographic features. Reaspiration should be considered in patients with sonographically suspicious nodules.

Athlete's hernia--a true, early direct inguinal hernia: diagnosis, pathophysiology, and surgical treatment.

Athlete's hernia (AH) is an activity limiting condition that presents as chronic inguinal pain in elite athletes. The diagnosis involves a thorough history and physical examination and can be aided by ultrasound interrogation of the groin. Operative treatment with a direct tissue repair of the inguinal floor successfully alleviates symptoms and allows for full return to activity. A retrospective analysis of patients with the diagnosis of AH from January 1998 to May 2010 who underwent operative repair was reviewed. Patients were evaluated based on age, gender, sport, time to presentation, subjective and objective physical findings, imaging findings, operative findings, length of follow-up, and return to activity. Ninety-six patients (6 females) with a median age of 22.6 years were evaluated. In the majority of these patients, operative exploration revealed a wide external ring with separation of the fibers of the external oblique aponeurosis and an unprotected and bulging transverses abdominis aponeurosis, very akin to an early direct inguinal hernia. The mean initial follow-up time was 6 weeks at which point all but two of the patients were able to resume their full level of activity without restrictions. The diagnosis of AH, although somewhat elusive, can be easily established with a high degree of suspicion after doing a thorough history and physical exam augmented with ultrasonography. AH is equivalent to an early direct inguinal hernia found in young athletes and can be surgically corrected allowing return to full activity.

Calcitonin-negative neuroendocrine tumor of the thyroid: a distinct clinical entity.

BACKGROUND: Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor (NET) that arises from the parafollicular cells (C-cells) of the thyroid gland which produces calcitonin (CT) and is, therefore, a serum and immunohistochemical biomarker of MTC. Here, we describe a patient with another form of NET arising with the thyroid gland. PATIENT FINDINGS: This is a forty-year-old woman who underwent total thyroidectomy for a thyroid nodule that had features of an NET on fine needle aspiration. Her serum CT and carcinoembryonic antigen were normal. Surgical pathology showed a well-differentiated NET with immunohistochemical stains positive for markers of follicular cells (thyroglobulin and synaptophysin), positive for neuroendocrine markers (neuron specific enolase and chromogranin A), but negative for CT, the defining marker of MTC. CONCLUSIONS: We describe a rare case of a nonmedullary NET of the thyroid gland arising from thyroid follicular cells, not parafollicular cells. We suggest that calcitonin-negative neuroendocrine tumor of the thyroid gland (CNNETT) may be an entity that has not been recognized in the literature. This distinction between MTC and CNNETT may be important, as the treatment and prognosis may differ.

Routine second-opinion cytopathology review of thyroid fine needle aspiration biopsies reduces diagnostic thyroidectomy.

BACKGROUND: Follicular thyroid carcinoma cannot be distinguished reliably from benign follicular neoplasia by fine needle aspiration (FNA) biopsy. Given an estimated 20% risk of malignancy, many patients with indeterminate FNA biopsies require thyroidectomy for diagnosis. Some centers have shown significant discordance when a second pathologist evaluates the same FNA biopsy. We sought to determine whether routine second-opinion cytopathology reduces the need for diagnostic thyroidectomy, especially in patients with indeterminate FNA biopsies. METHODS: In all, 331 thyroid FNA biopsy specimens obtained from outside centers from 2004 to 2009 were reviewed at our institution. The FNA biopsy results were categorized into nondiagnostic (Bethesda I), benign (Bethesda II), indeterminate (follicular/Hurthle cell neoplasm, follicular/Hurthle cell lesion; Bethesda III & IV), and malignant (papillary or suspicious for papillary or other malignancy; Bethesda V and VI). Second-opinion cytology was compared with the initial opinion in 331 cases and with final operative pathology in the 250 patients who progressed to thyroidectomy. RESULTS: The average patient age was 51 with a predominant number of female (79%) participants. The overall cytology concordance for all 331 FNA biopsies was 66% (218/331). Concordance was highest at 86% (74/86) with malignant FNA biopsies. Concordance in the 129 patients with indeterminate FNA biopsies was only 37% (48/129). Indeterminate FNA biopsies were reread as nondiagnostic in 21% (27/129) of patients and as benign in 42% (54/129) of patients. Twenty-two patients with an indeterminate FNA biopsy reread as benign progressed to operative therapy for reasons other than cytology (eg, symptomatic nodule and radiation exposure/high risk) and were found to be benign in 95% (21/22) of patients on operative pathology for a 95% negative predictive value. An additional 11 patients with an indeterminate FNA reread as benign had follow-up FNA biopsies, each of which was benign. Indeterminate FNA biopsies on initial cytology had a malignancy rate of 13% (17/129) on operative pathology compared with 29% (14/48) for indeterminate FNA biopsies from second opinion. A second opinion improved FNA biopsy accuracy from 60% to 74%. Overall, second-opinion cytology of indeterminate FNA biopsies avoided diagnostic operation in 25% (32/129). CONCLUSION: Routine second opinion review of indeterminate thyroid FNA biopsies can potentially obviate the need for diagnostic thyroidectomy in 25% of patients without increases in false negatives.

SERCA inhibition limits the functional effects of cyclic GMP in both control and hypertrophic cardiac myocytes.

The negative functional effects of cyclic GMP are controlled by the sarcoplasmic reticulum calcium-ATPase (SERCA). The effects of cyclic GMP are blunted in cardiac hypertrophy. We tested the hypothesis that the interaction between cyclic GMP and SERCA would be reduced in hypertrophic cardiac myocytes. Myocytes were isolated from 7 control and 7 renal-hypertensive hypertrophic rabbits. Control and hypertrophic myocytes received 8-bromo-cGMP (8-Br-cGMP; 10(-7), 10(-6), 10(-5) mol/l), the SERCA blocker thapsigargin (10(-8) mol/l) followed by 8-Br-cGMP, or the SERCA blocker, cyclopiazonic acid (CPA; 10(-7) mol/l) followed by 8-Br-cGMP. Percent shortening and maximal rate of shortening and relaxation were recorded using a video edge detector. Changes in cytosolic Ca2+ were assessed in fura 2-loaded myocytes. In controls, 8-Br-cGMP caused a significant 36% decrease in percent shortening from 5.8 +/- 0.4 to 3.7 +/- 0.3%. Thapsigargin and CPA did not affect basal control or hypertrophic myocyte function. When 8-Br-cGMP was given following thapsigargin or CPA, the negative effects of 8-Br-cGMP on control myocyte function were reduced. In hypertrophic myocytes, 8-Br-cGMP caused a smaller but significant 17% decrease in percent shortening from 4.7 +/- 0.2 to 3.9 +/- 0.1%. When 8-Br-cGMP was given following thapsigargin or CPA, no significant changes occurred in hypertrophic cell function. Intracellular Ca2+ transients responded in a similar manner to changes in cell function in control and hypertrophic myocytes. These results show that the effects of cyclic GMP were reduced in hypertrophic myocytes, but this was not related to SERCA. In presence of SERCA inhibitors, the responses to cyclic GMP were blunted in hypertrophic as well as control myocytes.

Chronic nitric oxide synthase blockade desensitizes the heart to the negative metabolic effects of nitric oxide.

The consequences of chronic nitric oxide synthase (NOS) blockade on the myocardial metabolic and guanylyl cyclase stimulatory effects of exogenous nitric oxide (NO) were determined. Thirty-three anesthetized open-chest rabbits were randomized into four groups: control, NO donor S-nitroso-N-acetyl-penicillamine (SNAP, 10(-4 )M), NOS blocking agent N(G)-nitro-L-arginine methyl ester (L-NAME, 20 mg/kg/day) for 10 days followed by a 24 hour washout and L-NAME for 10 days followed by a 24 hour washout plus SNAP. Myocardial O(2) consumption was determined from coronary flow (microspheres) and O(2) extraction (microspectrophotometry). Cyclic GMP and guanylyl cyclase activity were determined by radioimmunoassay. There were no baseline metabolic, functional or hemodynamic differences between control and L-NAME treated rabbits. SNAP in controls caused a reduction in O(2) consumption (SNAP 5.9+/-0.6 vs. control 8.4+/-0.8 ml O(2)/min/100 g) and a rise in cyclic GMP (SNAP 18.3+/-3.8 vs. control 10.4+/-0.9 pmol/g). After chronic L-NAME treatment, SNAP caused no significant changes in O(2) consumption (SNAP 7.1+/-0.8 vs. control 6.4+/-0.7) or cyclic GMP (SNAP 14.2+/-1.8 vs. control 12.1+/-1.3). In controls, guanylyl cyclase activity was significantly stimulated by SNAP (216.7+/-20.0 SNAP vs. 34.4+/-2.5 pmol/mg/min base), while this increase was blunted after L-NAME (115.9+/-24.5 SNAP vs. 24.9+/-4.7 base). These results demonstrated that chronic NOS blockade followed by washout blunts the response to exogenous NO, with little effect on cyclic GMP or myocardial O(2) consumption. This was related to reduced guanylyl cyclase activity after chronic L-NAME. These results suggest that, unlike many receptor systems, the NO-cyclic GMP signal transduction system becomes downregulated upon chronic inhibition.

Negative inotropic effects of C-type natriuretic peptide are attenuated in hypertrophied ventricular myocytes associated with reduced cyclic GMP production.

BACKGROUND: We tested the hypothesis that the negative inotropic effects of C-type natriuretic peptide (CNP) would be diminished in renal hypertensive (one-kidney-one-clip, 1K1C) hypertrophic rabbit hearts and that this attenuated effect would be due either to decreased cyclic GMP production or to reduced signaling. MATERIAL AND METHODS: Using isolated control and 1K1C ventricular myocytes, cell shortening data (video edge detection) were collected: (1) at baseline and after CNP 10(-8,-7) M, followed by KT5823 (KT), a cyclic GMP-dependent protein kinase inhibitor; or (2) at baseline, following KT pre-treatment and subsequent CNP 10(-8,-7) M. In addition, cyclic GMP levels were determined by radioimmunoassay at baseline and CNP 10(-7) M. RESULTS: In control myocytes, CNP decreased percent shortening (5.7 +/- 0.4 versus 4.0 +/- 0.4% at 10(-7) M), maximal rate of shortening (58.7 +/- 5.1 versus 45.2 +/- 3.6 microm/sec) and maximal rate of relaxation (57.1 +/- 4.9 versus 44.1 +/- 3.4 microm/sec) in a concentration-dependent manner. These effects were attenuated by subsequent KT administration. CNP failed to produce these negative functional effects in 1K1C myocytes. When pre-treated with KT, CNP had no negative functional effect in either normal and 1K1C myocytes. Basal levels of cyclic GMP were similar in control versus 1K1C myocytes; however, CNP produced a significant rise in cyclic GMP level in control (63.6 +/- 7.8 versus 83.5 +/- 11.3 pmol/10(5) myocytes) but not in 1K1C (49.2 +/- 2.6 versus 52.7 +/- 5.6) myocytes. CONCLUSIONS: Thus, CNP acted through the cyclic GMP protein kinase in control myocytes. We conclude that in hypertrophic cardiac myocytes, the decreased effect of CNP was because of decreased production of cyclic GMP.