Is exercise-related QT interval shortening with a peaked T wave a specific electrocardiographic finding of pheochromocytoma?

The QT interval is an indirect scale of the time between ventricular depolarization and repolarization. Both markedly-abnormal long and short QT intervals are associated with an increased risk for sudden cardiac death due to life-threatening ventricular arrhythmia [[1]Napolitano C. Bloise R. Monteforte N. Priori S.G. Sudden cardiac death and genetic ion channelopathies: long QT, Brugada, short QT, catecholaminergic polymorphic ventricular tachycardia, and idiopathic ventricular fibrillation.Circulation. 2012; 125: 2027-2034Crossref PubMed Scopus (111) Google Scholar]. Long QT syndrome (LQTS) is characterized by prolonged QT interval on the surface electrocardiogram (ECG) and is associated with malignant arrhythmia leading to syncope, cardiac arrest, and sudden death [[2]Moss A.J. Schwartz P.J. Crampton R.S. Tzivoni D. Locati E.H. MacCluer J. Hall W.J. Weitkamp L. Vincent G.M. Garson Jr., A. The long QT syndrome. Prospective longitudinal study of 328 families.Circulation. 1991; 84: 1136-1144Crossref PubMed Scopus (841) Google Scholar]. LQTS can be subclassified into congenital and acquired forms. Genetic testing can identify a mutation in 50–75% of clinically affected patients with congenital LQTS, as well as some patients with acquired LQTS [[3]Tester D.J. Will M.L. Haglund C.M. Ackerman M.J. Effect of clinical phenotype on yield of long QT syndrome genetic testing.J Am Coll Cardiol. 2006; 47: 764-768Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar]. Thirteen genetic forms of LQTS have been described, and the most prevalent forms are LQT1 and LQT2 (due to mutations in potassium channels), and LQT3 (due to a sodium channel mutation) [1Napolitano C. Bloise R. Monteforte N. Priori S.G. Sudden cardiac death and genetic ion channelopathies: long QT, Brugada, short QT, catecholaminergic polymorphic ventricular tachycardia, and idiopathic ventricular fibrillation.Circulation. 2012; 125: 2027-2034Crossref PubMed Scopus (111) Google Scholar, 4Liu L. Hayashi K. Kaneda T. Ino H. Fujino N. Uchiyama K. Konno T. Tsuda T. Kawashiri M.A. Ueda K. Higashikata T. Shuai W. Kupershmidt S. Higashida H. Yamagishi M. A novel mutation in the transmembrane nonpore region of the KCNH2 gene causes severe clinical manifestations of long QT syndrome.Heart Rhythm. 2013; 10: 61-67Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar]. The acquired form of LQTS is more common than the congenital form; risk factors include use of QT-prolonging drugs, hypokalemia, bradycardia, and genetic variations in ion channel genes [5Roden D.M. Viswanathan P.C. Genetics of acquired long QT syndrome.J Clin Invest. 2005; 115: 2025-2032Crossref PubMed Scopus (201) Google Scholar, 6Hayashi K. Shimizu M. Ino H. Yamaguchi M. Terai H. Hoshi N. Higashida H. Terashima N. Uno Y. Kanaya H. Mabuchi H. Probucol aggravates long QT syndrome associated with a novel missense mutation M124T in the N-terminus of HERG.Clin Sci (Lond). 2004; 107: 175-182Crossref PubMed Scopus (35) Google Scholar]. Short QT syndrome (SQTS) is characterized by abbreviated QT intervals and an increased susceptibility to arrhythmia and sudden death [[7]Gussak I. Brugada P. Brugada J. Wright R.S. Kopecky S.L. Chaitman B.R. Bjerregaard P. Idiopathic short QT interval: a new clinical syndrome?.Cardiology. 2000; 94: 99-102Crossref PubMed Scopus (551) Google Scholar]. We analyzed 12,149 ECGs that had been recorded at our hospital for cardiac examination and demonstrated that the QTc intervals of 2 standard deviations below the mean were 354 ms in males and 364 ms in females, respectively [[8]Funada A. Hayashi K. Ino H. Fujino N. Uchiyama K. Sakata K. Masuta E. Sakamoto Y. Tsubokawa T. Yamagishi M. Assessment of QT intervals and prevalence of short QT syndrome in Japan.Clin Cardiol. 2008; 31: 270-274Crossref PubMed Scopus (68) Google Scholar]. Therefore, QTc <350 ms for males and 360 ms for females should be considered a short QT interval. The hereditary short QT syndrome is a genetic syndrome and five different genes encoding the potassium and calcium channels have been implicated in the pathogenesis of SQTS [9Brugada R. Hong K. Dumaine R. Cordeiro J. Gaita F. Borggrefe M. Menendez T.M. Brugada J. Pollevick G.D. Wolpert C. Burashnikov E. Matsuo K. Wu Y.S. Guerchicoff A. Bianchi F. et al.Sudden death associated with short-QT syndrome linked to mutations in HERG.Circulation. 2004; 109: 30-35Crossref PubMed Scopus (699) Google Scholar, 10Bellocq C. van Ginneken A.C. Bezzina C.R. Alders M. Escande D. Mannens M.M. Baro I. Wilde A.A. Mutation in the KCNQ1 gene leading to the short QT-interval syndrome.Circulation. 2004; 109: 2394-2397Crossref PubMed Scopus (520) Google Scholar, 11Priori S.G. Pandit S.V. Rivolta I. Berenfeld O. Ronchetti E. Dhamoon A. Napolitano C. Anumonwo J. di Barletta M.R. Gudapakkam S. Bosi G. Stramba-Badiale M. Jalife J. A novel form of short QT syndrome (SQT3) is caused by a mutation in the KCNJ2 gene.Circ Res. 2005; 96: 800-807Crossref PubMed Scopus (532) Google Scholar, 12Antzelevitch C. Pollevick G.D. Cordeiro J.M. Casis O. Sanguinetti M.C. Aizawa Y. Guerchicoff A. Pfeiffer R. Oliva A. Wollnik B. Gelber P. Bonaros Jr., E.P. Burashnikov E. Wu Y. Sargent J.D. et al.Loss-of-function mutations in the cardiac calcium channel underlie a new clinical entity characterized by ST-segment elevation, short QT intervals, and sudden cardiac death.Circulation. 2007; 115: 442-449Crossref PubMed Scopus (745) Google Scholar]. Gain of function mutations in patients in the KCNH2 [[9]Brugada R. Hong K. Dumaine R. Cordeiro J. Gaita F. Borggrefe M. Menendez T.M. Brugada J. Pollevick G.D. Wolpert C. Burashnikov E. Matsuo K. Wu Y.S. Guerchicoff A. Bianchi F. et al.Sudden death associated with short-QT syndrome linked to mutations in HERG.Circulation. 2004; 109: 30-35Crossref PubMed Scopus (699) Google Scholar], KCNQ1 [[10]Bellocq C. van Ginneken A.C. Bezzina C.R. Alders M. Escande D. Mannens M.M. Baro I. Wilde A.A. Mutation in the KCNQ1 gene leading to the short QT-interval syndrome.Circulation. 2004; 109: 2394-2397Crossref PubMed Scopus (520) Google Scholar], and KCNJ2 [[11]Priori S.G. Pandit S.V. Rivolta I. Berenfeld O. Ronchetti E. Dhamoon A. Napolitano C. Anumonwo J. di Barletta M.R. Gudapakkam S. Bosi G. Stramba-Badiale M. Jalife J. A novel form of short QT syndrome (SQT3) is caused by a mutation in the KCNJ2 gene.Circ Res. 2005; 96: 800-807Crossref PubMed Scopus (532) Google Scholar] genes generate SQT1, SQT2, and SQT3 forms of SQTS. Loss of function missense mutations of the CACNA1C [[12]Antzelevitch C. Pollevick G.D. Cordeiro J.M. Casis O. Sanguinetti M.C. Aizawa Y. Guerchicoff A. Pfeiffer R. Oliva A. Wollnik B. Gelber P. Bonaros Jr., E.P. Burashnikov E. Wu Y. Sargent J.D. et al.Loss-of-function mutations in the cardiac calcium channel underlie a new clinical entity characterized by ST-segment elevation, short QT intervals, and sudden cardiac death.Circulation. 2007; 115: 442-449Crossref PubMed Scopus (745) Google Scholar] and CACNB2 [[12]Antzelevitch C. Pollevick G.D. Cordeiro J.M. Casis O. Sanguinetti M.C. Aizawa Y. Guerchicoff A. Pfeiffer R. Oliva A. Wollnik B. Gelber P. Bonaros Jr., E.P. Burashnikov E. Wu Y. Sargent J.D. et al.Loss-of-function mutations in the cardiac calcium channel underlie a new clinical entity characterized by ST-segment elevation, short QT intervals, and sudden cardiac death.Circulation. 2007; 115: 442-449Crossref PubMed Scopus (745) Google Scholar] genes encoding the α1 and β2b subunits of the L-type calcium channel give rise to SQT4 and SQT5, respectively. Meanwhile, several conditions are known as secondary causes of short QT interval: hyperkalemia, hypercalcemia, hyperthermia, acidosis, effect of catecholamine or acetylcholine, chronic fatigue syndrome, use of digitalis, and abbreviation of QT interval related to activation of KATP current (Table 1) [13Patel C. Yan G.X. Antzelevitch C. Short QT syndrome: from bench to bedside.Circ Arrhythm Electrophysiol. 2010; 3: 401-408Crossref PubMed Scopus (123) Google Scholar, 14Naschitz J. Fields M. Isseroff H. Sharif D. Sabo E. Rosner I. Shortened QT interval: a distinctive feature of the dysautonomia of chronic fatigue syndrome.J Electrocardiol. 2006; 39: 389-394Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar, 15Gomes J.A. Dhatt M.S. Akhtar M. Carambas C.R. Rubenson D.S. Damato A.N. Effects of digitalis on ventricular myocardial and His-Purkinje refractoriness and reentry in man.Am J Cardiol. 1978; 42: 931-938Abstract Full Text PDF PubMed Scopus (13) Google Scholar, 16Garberoglio L. Giustetto C. Wolpert C. Gaita F. Is acquired short QT due to digitalis intoxication responsible for malignant ventricular arrhythmias?.J Electrocardiol. 2007; 40: 43-46Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar].Table 1Secondary causes of short QT interval in clinical practice.HyperkalemiaHypercalcemiaHyperthermiaAcidosisEffect of catecholamineActivation of KAChParadoxical shortening of the QT intervalActivation of KATPChronic fatigue syndromeDigitalis Open table in a new tab In this issue of Journal of Cardiology Cases, Gungor et al. report the case of a MEN2 male patient with exercise-related QT interval shortening with a peaked T wave [[17]Gungor O. Ozeke O. Sayinalp S. Ertan C. Demir A.D. Ilicin G. Ozer C. Exercise-related QT interval shortening with a peaked T wave in a boy with MEN 2 syndrome.J Cardiol Cases. 2013; 7: e93-e96Abstract Full Text Full Text PDF Scopus (1) Google Scholar]. The resting ECG showed normal QTc interval of 394 ms. However, the patient complained of dizziness and flushing during the treadmill exercise test and then showed QTc shortening of 309 ms and slowing of the heart rate of 56 bpm at second minute of recovery phase. Then, the patient was diagnosed as having MEN2 by endocrine examination and computed tomography scan, and underwent bilateral open adrenalectomy and total thyroidectomy. Histological findings showed bilateral pheochromocytoma and medullary thyroid carcinoma. Because previous study of the QT interval in recovery after exercise reported that the 2nd percentiles for the QTc using the Bazett formula at 2 min recovery was 393 ms [[18]Berger W.R. Gow R.M. Kamberi S. Cheung M. Smith K.R. Davis A.M. The QT and corrected QT interval in recovery after exercise in children.Circ Arrhythm Electrophysiol. 2011; 4: 448-455Crossref PubMed Scopus (18) Google Scholar], the patient's QTc interval at 2 min recovery was obviously short. Several reasons were considered to explain the shortening of the QT interval with a peaked T wave after exercise in this patient. One explanation for this finding is augmentation of the sympathetic nerve activity. Several studies reported that the effect of catecholamine is one of the secondary causes of short QT interval [13Patel C. Yan G.X. Antzelevitch C. Short QT syndrome: from bench to bedside.Circ Arrhythm Electrophysiol. 2010; 3: 401-408Crossref PubMed Scopus (123) Google Scholar, 19Chinushi M. Sato A. Iijima K. Suzuki K. Hiroshi F. Izumi D. Watanabe H. Kanae H. Aizawa Y. Exercise-related QT interval shortening with a peaked T wave in a healthy boy with a family history of sudden cardiac death.Pacing Clin Electrophysiol. 2012; 35: e239-e242Crossref PubMed Scopus (4) Google Scholar, 20Kawataki M. Kashima T. Toda H. Tanaka H. Relation between QT interval and heart rate. Applications and limitations of Bazett's formula.J Electrocardiol. 1984; 17: 371-375Abstract Full Text PDF PubMed Scopus (93) Google Scholar]. Gungor et al. speculated that acute and massive catecholamine release caused a direct toxic effect on myocytes which resulted in these electrocardiographic changes [[17]Gungor O. Ozeke O. Sayinalp S. Ertan C. Demir A.D. Ilicin G. Ozer C. Exercise-related QT interval shortening with a peaked T wave in a boy with MEN 2 syndrome.J Cardiol Cases. 2013; 7: e93-e96Abstract Full Text Full Text PDF Scopus (1) Google Scholar]. The plasma catecholamine during exercise test in this patient was not measured but is thought to have increased, because a previous study reported that the post-exercise levels of epinephrine and the epinephrine/dopamine ratio were significantly higher in pheochromocytoma patients compared to healthy controls [[21]Telenius-Berg M. Adolfsson L. Berg B. Hamberger B. Nordenfelt I. Tibblin S. Welander G. Catecholamine release after physical exercise. A new provocative test for early diagnosis of pheochromocytoma in multiple endocrine neoplasia type 2.Acta Med Scand. 1987; 222: 351-359Crossref PubMed Scopus (13) Google Scholar]. Reexamination of treadmill exercise test after bilateral adrenalectomy is helpful in confirming association between pheochromocytoma and short QT interval with a peaked T wave. In contrast, conflicting studies were reported regarding whether catecholamine shortened absolute QT and corrected QT intervals: pheochromocytoma may induce QT prolongation [[22]Paulin F.L. Klein G.J. Gula L.J. Skanes A.C. Yee R. Krahn A.D. QT prolongation and monomorphic VT caused by pheochromocytoma.J Cardiovasc Electrophysiol. 2009; 20: 931-934Crossref PubMed Scopus (16) Google Scholar], and exogenously administered epinephrine and isoproterenol cause minor QTc prolongation in normal healthy individuals [[23]Magnano A.R. Talathoti N. Hallur R. Bloomfield D.M. Garan H. Sympathomimetic infusion and cardiac repolarization: the normative effects of epinephrine and isoproterenol in healthy subjects.J Cardiovasc Electrophysiol. 2006; 17: 983-989Crossref PubMed Scopus (52) Google Scholar]. The other explanation is deceleration-dependent shortening of QT interval [13Patel C. Yan G.X. Antzelevitch C. Short QT syndrome: from bench to bedside.Circ Arrhythm Electrophysiol. 2010; 3: 401-408Crossref PubMed Scopus (123) Google Scholar, 24Gussak I. Liebl N. Nouri S. Bjerregaard P. Zimmerman F. Chaitman B.R. Deceleration-dependent shortening of the QT interval: a new electrocardiographic phenomenon?.Clin Cardiol. 1999; 22: 124-126Crossref PubMed Scopus (21) Google Scholar]. Several reports showed patients with shortening of QT interval associated with a decrease in heart rate [24Gussak I. Liebl N. Nouri S. Bjerregaard P. Zimmerman F. Chaitman B.R. Deceleration-dependent shortening of the QT interval: a new electrocardiographic phenomenon?.Clin Cardiol. 1999; 22: 124-126Crossref PubMed Scopus (21) Google Scholar, 25Takahashi N. Ito M. Ishida S. Nakagawa M. Hara M. Saikawa T. Sakata T. Paradoxically shortened QT interval after a prolonged pause.Pacing Clin Electrophysiol. 1998; 21: 1476-1479Crossref PubMed Scopus (15) Google Scholar]. The patient in this study presented sinus bradycardia in recovery after exercise probably due to vasovagal reflex. Augmentation of the sympathetic nerve activity during exercise could cause excessive left ventricular contractions which resulted in vasovagal reflex thorough the left ventricular mechanoreceptor. Activation of the IKACh caused by parasympathetic stimuli to the heart could be associated with a shortening of the action potential duration. Interestingly, a loss of function mutation in the KCNJ5 gene which encodes the IKACh channel subunit Kir3.4 was recently identified in congenital long QT syndrome [[26]Yang Y. Liang B. Liu J. Li J. Grunnet M. Olesen S.P. Rasmussen H.B. Ellinor P.T. Gao L. Lin X. Li L. Wang L. Xiao J. Liu Y. Zhang S. et al.Identification of a Kir3.4 mutation in congenital long QT syndrome.Am J Hum Genet. 2010; 86: 872-880Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar]. Finally, it is important that gene analysis should be performed to test whether the patient has congenital short QT syndrome or not, and to detect mutations in the RET proto-oncogene which is a major gene responsible for MEN2. Transient peaked T waves and shortening of QT interval during exercise stress testing in this issue are interesting findings and may provide an early clue for undiagnosed pheochromocytoma. It is necessary to elucidate the detailed mechanism and accumulate more pheochromocytoma patients with similar ECG changes, although careful monitoring of hemodynamics is needed when treadmill exercise test is performed for pheochromocytoma patients. Exercise-related QT interval shortening with a peaked T wave in a boy with MEN 2 syndromeJournal of Cardiology CasesVol. 7Issue 4PreviewMultiple endocrine neoplasia 2 (MEN 2) is a hereditary syndrome associated with medullary thyroid carcinoma, pheochromocytoma (PCC), and hyperparathyroidism. PCCs in patients with MEN 2 are usually found in the adrenals after the manifestation of medullary thyroid cancer and are commonly bilateral and hormonally active. Unfortunately, a diagnosis of MEN 2 or PCC often is delayed until after the patient has developed an advanced MEN 2-related tumor. We present unusual electrocardiographic changes on exercise testing in MEN 2 syndrome.