Clinical profiles of patients with surgically resected pheochromocytoma and paraganglioma.

BACKGROUND/AIMS: Pheochromocytoma and paraganglioma (PPGL) are catecholamine-producing tumors that can cause blood pressure (BP) elevation and cardiovascular complications. Clinical presentation of these tumors may be changed through widespread use of imaging studies, which enables detection of PPGLs before onset of symptoms. We investigated clinical profiles of patients with surgically resected PPGLs. METHODS: From 2005 to 2017, 111 consecutive patients with surgically resected PPGLs in two tertiary hospitals in Korea were studied. RESULTS: Mean age was 52 ± 16 years, 57 patients (51.4%) were male and 54 (48.6%) were hypertensive. Twenty-nine PPGLs (26.1%) were extra-adrenal paragangliomas. Sixteen (14.4%) and seven patients (6.3%) (Group 1, n = 23) were diagnosed during work-up of hypertension and transient cardiomyopathy respectively, and the remainder (Group 2, n = 88) were incidentalomas detected during routine abdominal imaging. Patients in the Group 1 were younger and more frequently symptomatic, and had higher BPs, heart rates and levels of urinary catecholamines than those in the Group 2. Paragangliomas were less frequent and secretion of epinephrine and metanephrine was more predominant in the Group 1 than in Group 2. After the surgical resections, 18.2% of patients still needed antihypertensive medications. CONCLUSION: Out of 111 patients with surgically resected PPGLs, 88 (79.3%) were diagnosed as incidentalomas. Seven patients presented with transient cardiomyopathy and 16 with hypertension. Tumor location and secretion of catecholamine may vary depending on the presence of symptoms.

Usefulness of Myocardial Longitudinal Strain in Prediction of Heart Failure in Patients with Successfully Reperfused Anterior Wall ST-segment Elevation Myocardial Infarction.

BACKGROUND AND OBJECTIVES: Acute myocardial infarction-related heart failure (HF) is associated with poor outcome. This study was designed to investigate the usefulness of global longitudinal strain (GLS), global circumferential strain (GCS) and mean longitudinal strain of left anterior descending artery territory (LSant) measured by 2-dimensional speckle tracking echocardiography (2D STE) in prediction of acute anterior wall ST-segment elevation myocardial infarction (ant-STEMI)-related HF. METHODS: A total of 171 patients with ant-STEMI who underwent successful primary coronary intervention and had available 2D STE data were enrolled. Patients were divided into 3 groups: in-hospital HF, post-discharge HF, and no-HF groups. RESULTS: In-hospital and post-discharge HF developed in 39 (22.8%) and 13 (7.6%) of patients, respectively and 113 patients (69.6%) remained without HF. Multivariate analysis showed that GLS was the only factor significantly associated with the development of in-hospital HF. For post-discharge HF, LSant was the only independent predictor. Other echocardiographic or laboratory parameters did not show independent association with the development of ant-STEMI-related HF. CONCLUSIONS: GLS is a powerful echocardiographic parameter related to development of in-hospital HF and LSant was significantly associated with post-discharge HF in patients with successfully reperfused ant-STEMI.

Relative Bradycardia in Scrub Typhus.

To investigate the relationship between heart rate and temperature, we examined 493 febrile patients with documented disease. These patients were diagnosed serologically and analyzed retrospectively: 337 (68.4%) responded to fever with increased heart rate < 10 beats/minute/°C (relative bradycardia [RB]), and 156 patients had a heart rate response ≥ 10 beats/minute/°C (general heart rate increase [GHRI]). The RB group had a higher median resting heart rate and lower heart rate at maximum temperature than the GHRI group. Despite differences in heart rate response, no significant differences were seen in clinical outcomes (acute kidney injury, systemic inflammatory response syndrome (SIRS), and death). We concluded that most patients with scrub typhus presented with RB. In scrub typhus infection, RB can be included as one of the clinical features for differential diagnosis from other infectious diseases.

Variants of Brugada Syndrome and Early Repolarization Syndrome: An Expanded Concept of J-Wave Syndrome.

BACKGROUND: The role of J-waves in the pathogenesis of ventricular fibrillation (VF) occurring in structurally normal hearts is important. METHODS: We evaluated 127 patients who received an implantable cardioverter-defibrillator (ICD) for Brugada syndrome (BS, n = 53), early repolarization syndrome (ERS, n = 24), and patients with unknown or deferred diagnosis (n = 50). Electrocardiography (ECG), clinical characteristics, and ICD data were analyzed. RESULTS: J-waves were found in 27/50 patients with VF of unknown/deferred diagnosis. The J-waves were reminiscent of those seen in BS or ERS, and this subgroup of patients was termed variants of ERS and BS (VEB). In 12 VEB patients, the J/ST/T-wave morphology was coved, although amplitudes were <0.2 mV. In 15 patients, noncoved-type J/ST/T-waves were present in the right precordial leads. In the remaining 23 patients, no J-waves were identified. VEB patients exhibited clinical characteristics similar to those of BS and ERS patients. Phenotypic transition and overlap were observed among patients with BS, ERS, and VEB. Twelve patients with BS had background inferolateral ER, while five ERS patients showed prominent right precordial J-waves. Patients with this transient phenotype overlap showed a significantly lower shock-free survival than the rest of the study patients. CONCLUSIONS: VEB patients demonstrate ECG phenotype similar to but distinct from those of BS and ERS. The spectral nature of J-wave morphology/distribution and phenotypic transition/overlap suggest a common pathophysiologic background in patients with VEB, BS, and ERS. Prognostic implication of these ECG variations requires further investigation.

ECG features and proarrhythmic potentials of therapeutic hypothermia.

OBJECTIVE: Hypothermia can induce ECG J waves. Recent studies suggest that J waves may be associated with ventricular fibrillation (VF) in patients with structurally normal hearts. However, little is known about the ECG features, clinical significance or arrhythmogenic potentials of therapeutic hypothermia (TH)-induced J waves. METHODS: We analysed ECGs from 240 patients who underwent TH at six major university hospitals in Korea between August 2010 and December 2013. The prevalence, amplitudes and distributions of the J waves and the development of malignant arrhythmia were analysed. RESULTS: The average patient body temperature was 33.5±1.0°C during TH. J waves were observed in 98 patients (40.8%). They were newly developed in 91 cases, and pre-existing J waves were augmented in seven patients. J waves during TH were primarily observed in leads II, III, aVF and V4-6. The average amplitude of the J waves was 0.239±0.152 mV. There were four VF events during TH. These events occurred in three patients who were finally diagnosed with Brugada syndrome, idiopathic VF or early repolarisation syndrome, respectively, and in one patient with non-cardiac aetiology (asphyxia). CONCLUSIONS: J waves were recorded in about 40% of the patients who received TH. They were most frequently observed in the inferior limb leads or lateral precordial leads. Life-threatening VF occurred only rarely (1.7%) during TH and were mainly observed in patients with primary arrhythmic disorder. Although a causal relationship between TH-induced J waves and VF remains unknown, administering TH to this potentially susceptible, high-risk population may require careful attention.

Rosuvastatin Reduces Blood Viscosity in Patients with Acute Coronary Syndrome.

BACKGROUND AND OBJECTIVES: Wall shear stress contributes to atherosclerosis progression and plaque rupture. There are limited studies for statin as a major contributing factor on whole blood viscosity (WBV) in patients with acute coronary syndrome (ACS). This study investigates the effect of statin on WBV in ACS patients. SUBJECTS AND METHODS: We prospectively enrolled 189 consecutive patients (mean age, 61.3±10.9 years; 132 males; ST-segment elevation myocardial infarction, n=52; non-ST-segment elevation myocardial infarction, n=84; unstable angina n=53). Patients were divided into two groups (group I: previous use of statins for at least 3 months, n=51; group II: statin-naïve patients, n=138). Blood viscosities at shear rates of 1 s-1 (diastolic blood viscosity; DBV) and 300 s-1 (systolic blood viscosity; SBV) were measured at baseline and one month after statin treatment. Rosuvastatin was administered to patients after enrollment (mean daily dose, 16.2±4.9 mg). RESULTS: Baseline WBV was significantly higher in group II ([SBV: group I vs group II, 40.8±5.9 mP vs. 44.2±7.4 mP, p=0.003], [DBV: 262.2±67.8 mP vs. 296.9±76.0 mP, p=0.002]). WBV in group II was significantly lower one month after statin treatment ([SBV: 42.0±4.7 mP, p=0.012, DBV: 281.4±52.6 mP, p=0.044]). However, low-density lipoprotein cholesterol level was not associated with WBV in both baseline (SBV: R2=0.074, p=0.326; DBV: R2=0.073, p=0.337) and after one month follow up (SBV: R2=0.104, p=0.265; DBV: R2=0.112, p=0.232). CONCLUSION: Previous statin medication is an important determinant in lowering WBV in patients with ACS. However, one month of rosuvastatin decreased WBV in statin-naïve ACS patients.

Cervical vagal nerve stimulation activates the stellate ganglion in ambulatory dogs.

BACKGROUND AND OBJECTIVES: Recent studies showed that, in addition to parasympathetic nerves, cervical vagal nerves contained significant sympathetic nerves. We hypothesized that cervical vagal nerve stimulation (VNS) may capture the sympathetic nerves within the vagal nerve and activate the stellate ganglion. MATERIALS AND METHODS: We recorded left stellate ganglion nerve activity (SGNA), left thoracic vagal nerve activity (VNA), and subcutaneous electrocardiogram in seven dogs during left cervical VNS with 30 seconds on-time and 30 seconds off time. We then compared the SGNA between VNS on and off times. RESULTS: Cervical VNS at moderate (0.75 mA) output induced large SGNA, elevated heart rate (HR), and reduced HR variability, suggesting sympathetic activation. Further increase of the VNS output to >1.5 mA increased SGNA but did not significantly increase the HR, suggesting simultaneous sympathetic and parasympathetic activation. The differences of integrated SGNA and integrated VNA between VNS on and off times (ΔSGNA) increased progressively from 5.2 mV-s {95% confidence interval (CI): 1.25-9.06, p=0.018, n=7} at 1.0 mA to 13.7 mV-s (CI: 5.97-21.43, p=0.005, n=7) at 1.5 mA. The difference in HR (ΔHR, bpm) between on and off times was 5.8 bpm (CI: 0.28-11.29, p=0.042, n=7) at 1.0 mA and 5.3 bpm (CI 1.92 to 12.61, p=0.122, n=7) at 1.5 mA. CONCLUSION: Intermittent cervical VNS may selectively capture the sympathetic components of the vagal nerve and excite the stellate ganglion at moderate output. Increasing the output may result in simultaneously sympathetic and parasympathetic capture.

Estimating sympathetic tone by recording subcutaneous nerve activity in ambulatory dogs.

INTRODUCTION: We tested the hypothesis that subcutaneous nerve activity (SCNA) of the thorax correlates with the stellate ganglion nerve activity (SGNA) and can be used to estimate the sympathetic tone. METHODS AND RESULTS: We implanted radio transmitters in 11 ambulatory dogs to record left SGNA, left thoracic vagal nerve activity (VNA), and left thoracic SCNA, including 3 with simultaneous video monitoring and nerve recording. Two additional dogs were studied under general anesthesia with apamin injected into the right stellate ganglion while the right SGNA and the right SCNA were recorded. There was a significant positive correlation between integrated SGNA (iSGNA) and integrated SCNA (iSCNA) in the first 7 ambulatory dogs, with correlation coefficient of 0.70 (95% confidence interval [CI] 0.61-0.84, P < 0.05 for each dog). Tachycardia episodes (heart rate exceeding 150 bpm for ≥3 seconds) were invariably preceded by SGNA and SCNA. There was circadian variation of both SCNA and SGNA. Crosstalk was ruled out because SGNA, VNA, and SCNA bursts had different timing and activation patterns. In an eighth dog, closely spaced bipolar subcutaneous electrodes also recorded SCNA, but with reduced signal to noise ratio. Video monitoring in additional 3 dogs showed that movement was not a cause of high frequency SCNA. The right SGNA correlated strongly with right SCNA and heart rate in 2 anesthetized dogs after apamin injection into the right stellate ganglion. CONCLUSIONS: SCNA recorded by bipolar subcutaneous electrodes correlates with the SGNA and can be used to estimate the sympathetic tone.

Electrocardiographic predictors of bradycardia-induced torsades de pointes in patients with acquired atrioventricular block.

BACKGROUND: Predictors of torsades de pointes (TdP) in bradyarrhythmia-induced acquired long QT syndrome are not well defined. OBJECTIVE: The purpose of this study was to search for electrocardiographic (ECG) TdP predictors in patients with acquired atrioventricular block (AVB) and QT prolongation. METHODS: We analyzed 12-lead ECGs from 20 patients (15 females, age 65.9 ± 15.6 years) with TdP episodes from among 898 AVB patients (2.2%) in 3 tertiary hospitals. The ECG repolarization parameters in TdP patients were compared with those of 80 age- and sex-matched control AVB patients with no TdP episodes. RESULTS: TdP was initiated by premature ventricular complexes with a long-short sequence of activation. The average cycle length of the long sequence was 1289.9 ± 228.9 ms and was 2.3 ± 0.6 times longer than the cycle length of the short sequence. TdP patients had a significantly longer mean QT interval (716.4 ± 98.9 ms vs 523.2 ± 91.3 ms, P = .001), mean T peak to end interval (334.2 ± 59.1 ms vs 144.0 ± 73.7 ms, P = .001) and a higher T peak to end interval/QT ratio (0.49 ± 0.09 vs 0.27 ± 0.11, P = .001) compared with non-TdP controls. TdP patients showed a higher prevalence of notched T waves in which T2 was at least 3 mm taller than T1 (45.0% vs 1.3%, P = .001), triphasic T waves (30.0% vs 1.3%, P = .001), reversed asymmetry (20.0% vs 0%, P = .001), and T-wave alternans (35.0% vs 0%, P = .001). An algorithm combining these morphologic parameters was able to differentiate TdP patients from non-TdP patients with high sensitivity (85.0%) and specificity (97.5%). CONCLUSION: An algorithm combining specific T-wave morphologies was useful for identifying patients with AVB who are at risk for developing TdP.

Autonomic nerve activity and blood pressure in ambulatory dogs.

BACKGROUND: The relationship between cardiac autonomic nerve activity and blood pressure (BP) changes in ambulatory dogs is unclear. OBJECTIVE: The purpose of this study was to test the hypotheses that simultaneous termination of stellate ganglion nerve activity (SGNA) and vagal nerve activity (VNA) predisposes to spontaneous orthostatic hypotension and that specific ß2-adrenoceptor blockade prevents the hypotensive episodes. METHODS: We used a radiotransmitter to record SGNA, VNA, and BP in eight ambulatory dogs. Video imaging was used to document postural changes. RESULTS: Of these eight dogs, five showed simultaneous sympathovagal discharges in which the minute-by-minute integrated SGNA correlated with integrated VNA in a linear pattern (group 1). In these dogs, abrupt termination of simultaneous SGNA-VNA at the time of postural changes (as documented by video imaging) was followed by abrupt (>20 mm Hg over four beats) drops in BP. Dogs without simultaneous on/off firing (group 2) did not have drastic drops in pressure. ICI-118,551 (ICI, a specific ß2-blocker) infused at 3 µg/kg/h for 7 days significantly increased BP from 126 mm Hg (95% confidence interval 118-133) to 133 mm Hg (95% confidence interval 125-141; P = .0001). The duration of hypotension (mean systolic BP <100 mm Hg) during baseline accounted for 7.1% of the recording. The percentage was reduced by ICI to 1.3% (P = .01). CONCLUSION: Abrupt simultaneous termination of SGNA-VNA was observed at the time of orthostatic hypotension in ambulatory dogs. Selective ß2-adrenoceptor blockade increased BP and reduced the duration of hypotension in this model.

Temporal variation and morphologic characteristics of J-waves in patients with early repolarisation syndrome.

OBJECTIVE: Electrocardiographic markers identifying malignant forms of early repolarisation (ER) from ER of normal variants are of prime clinical importance. We compared the ECG parameters of ER patterns in patients with early repolarisation syndrome (ERS) proximate to the ventricular fibrillation (VF) episodes, remote from the events and those with normal controls with ER. DESIGN: A retrospective, case-control study. SETTING: University hospital. PATIENTS: This study included 12 patients with ERS and 36 age-matched, gender-matched controls with ER. MAIN OUTCOME MEASURES: Dynamic change of J-wave. RESULTS: The highest amplitude of J-wave, sum of the J-wave amplitudes or the number of leads with ER showed a dramatic change during the perievent period. J-wave amplitudes (2.0±1.3 vs 4.0±1.7, p=0.004) and the number of leads with ER (3.3±1.7 vs 5.3±2.0, p=0.021) were significantly higher around the time of VF. In particular, the characteristic morphology of 'giant' (wide, >80 ms) J-waves were observed during the perievent period in 5/12 patients with ERS. However, there were no significant differences in the electrocardiographic parameters of ER pattern remote from VF events between the patients with ERS and normal control subjects with ER. CONCLUSIONS: Although the extent of and amplitude of J-wave or ST segment elevation (STE) increased significantly around VF episodes, the electrocardiographic parameters of ER remote from VF episodes were not significantly different from those of normal controls. The narrow time window of these ECG changes limits early detection of ER patients at risk of developing VF or sudden cardiac death.

Apamin-sensitive calcium-activated potassium currents in rabbit ventricles with chronic myocardial infarction.

INTRODUCTION: The apamin-sensitive small-conductance calcium-activated potassium current (IKAS ) is increased in heart failure. It is unknown if myocardial infarction (MI) is also associated with an increase of IKAS . METHODS AND RESULTS: We performed Langendorff perfusion and optical mapping in 6 normal hearts and 10 hearts with chronic (5 weeks) MI. An additional 6 normal and 10 MI hearts were used for patch clamp studies. The infarct size was 25% (95% confidence interval, 20-31) and the left ventricular ejection fraction was 50 (46-54). The rabbits did not have symptoms of heart failure. The action potential duration measured to 80% repolarization (APD80 ) in the peri-infarct zone (PZ) was 150 (142-159) milliseconds, significantly (P = 0.01) shorter than that in the normal ventricles (167 [158-177] milliseconds. The intracellular Ca transient duration was also shorter in the PZ (148 [139-157] milliseconds) than that in normal ventricles (168 [157-180] milliseconds; P = 0.017). Apamin prolonged the APD80 in PZ by 9.8 (5.5-14.1)%, which is greater than that in normal ventricles (2.8 [1.3-4.3]%, P = 0.006). Significant shortening of APD80 was observed at the cessation of rapid pacing in MI but not in normal ventricles. Apamin prevented postpacing APD80 shortening. Patch clamp studies showed that IKAS was significantly higher in the PZ cells (2.51 [1.55-3.47] pA/pF, N = 17) than in the normal cells (1.08 [0.36-1.80] pA/pF, N = 15, P = 0.019). CONCLUSION: We conclude that IKAS is increased in MI ventricles and contributes significantly to ventricular repolarization especially during tachycardia.

Elevated coronary whole blood viscosity in acute coronary syndrome patients.

OBJECTIVES: As most clinical studies measure whole blood viscosity (WBV) from peripheral samples, potential differences in WBV obtained from the coronary arteries are often ignored. This study investigated differences in WBV measured from coronary artery specimens in patients with and without acute coronary syndrome (ACS). METHODS AND RESULTS: Consecutive patients with chest pain who underwent diagnostic coronary angiography were divided into two groups [non-ACS (n = 16), ACS (n = 22)]. The ACS group consisted of unstable angina (n = 13) and acute myocardial infarction (n = 9) patients. Two blood samples were obtained from each patient at the both coronary artery ostia prior to coronary angiography. Low-shear and high-shear blood viscosities (BVs) were measured at shear rates of 1 and 300 s-1, respectively, by a scanning capillary tube viscometer (Bio-Visco Inc., South Korea). Both low-shear and high-shear BVs obtained from peripheral, left and right coronary arteries were not different in both groups. Mean coronary low-shear WBV values obtained in ACS group were 29.2% higher than those in non-ACS group (295.3 ± 87.2 mP vs. 228.5 ± 69.2 mP, p = 0.016). Mean coronary high-shear WBV values obtained in ACS group were 15.6% higher than those in non-ACS group (42.9 ± 10.0 mP vs. 37.1 ± 4.6 mP, p = 0.036). CONCLUSIONS: Direct measurement of WBV from the coronary artery showed no differences with peripheral samples. Future larger studies are needed to clarify our results.

Sympathetic nerve fibers and ganglia in canine cervical vagus nerves: localization and quantitation.

BACKGROUND: Cervical vagal nerve (CVN) stimulation may improve left ventricular ejection fraction in patients with heart failure. OBJECTIVES: To test the hypothesis that sympathetic structures are present in the CVN and to describe the location and quantitate these sympathetic components of the CVN. METHODS: We performed immunohistochemical studies of the CVN from 11 normal dogs and simultaneously recorded stellate ganglion nerve activity, left thoracic vagal nerve activity, and subcutaneous electrocardiogram in 2 additional dogs. RESULTS: A total of 28 individual nerve bundles were present in the CVNs of the first 11 dogs, with an average of 1.87±1.06 per dog. All CVNs contain tyrosine hydroxylase-positive (sympathetic) nerves, with a total cross-sectional area of 0.97±0.38 mm(2). The sympathetic nerves were nonmyelinated, typically located at the periphery of the nerve bundles and occupied 0.03%-2.80% of the CVN cross-sectional area. Cholineacetyltransferase-positive nerve fibers occupied 12.90%-42.86% of the CVN cross-sectional areas. Ten of 11 CVNs showed tyrosine hydroxylase and cholineacetyltransferase colocalization. In 2 dogs with nerve recordings, we documented heart rate acceleration during spontaneous vagal nerve activity in the absence of stellate ganglion nerve activity. CONCLUSIONS: Sympathetic nerve fibers are invariably present in the CVNs of normal dogs and occupy in average up to 2.8% of the cross-sectional area. Because sympathetic nerve fibers are present in the periphery of the CVNs, they may be susceptible to activation by electrical stimulation. Spontaneous activation of the sympathetic component of the vagal nerve may accelerate the heart rate.

Guggulsterone inhibits melanogenesis in B16 murine melanoma cells by downregulating tyrosinase expression.

In the present study, we investigated the effect of guggulsterone on melanogenesis in B16 melanoma cells and elucidated its possible mechanism of action. The effects of guggulsterone on melanogenesis were determined by assaying melanin synthesis and cellular tyrosinase activity in B16/F10 mouse melanoma cells. Guggulsterone dose-dependently inhibited isobutylmethylxanthine (IBMX)-induced melanogenesis and cellular tyrosinase activity with no cytotoxicity. Decreased melanin biosynthesis was accompanied by the reduced expression of melanogenesis-related genes, such as tyrosinase, microphthalmia-associated transcription factor, tyrosinase-related protein (TRP)-1 and TRP-2. Guggulsterone also inhibited α-melanocyte stimulating hormone- or forskolin-induced increases in melanogenesis, suggesting an action on the cAMP-dependent melanogenic pathway. Co-incubation with chenodeoxycholic acid, a well-known farnesoid-X receptor agonist, did not affect IBMX-induced melanogenesis. These results suggest that guggulsterone exerts a melanogenic inhibitory effect through the downregulation of tyrosinase expression.