Correspondence Surgical Declaration of Independence
To the Editor: After reading Dr. Herbert Fred’s “Medical Education on the Brink,”1 I was inspired to start a revolution in surgical education. He ended his essay with the following recommendation: “. . . raise the bar of performance in all training programs to a distinctly higher level, with excellence as the perpetual goal.” To their credit, influential members of the American College of Surgeons 2 reviewed the current state of surgical education and concluded: • “During the past decade, the failure rate on the American Board of Surgery’s oral exam has climbed steadily from 16% to 28%.” • “This is a scary situation.” • “We have a problem. . . . we have to stop being bullied by naïve, public, politically driven agendas and by some of our own graybeard pundits . . . and once again take over the control of educating our successors.” After reading this, I came across an article on the increasing failure rate in internal medicine, then yet another on the American Board of Thoracic Surgery’s oral board examination: the failure rate on that exam has doubled between 2000 and 2011 (from 14.4% to 28.1%).3 I believe that educational demand on resident physicians in all specialties has loosened, and many of my colleagues share this view. Rigorous knowledge of human pathology has been subordinated to respect for the residents’ self-esteem. This might well turn out doctors who feel great about knowing nothing. My generation produced some weird people. Many were politically incorrect. But they were characters with character! They could dig out a necrotic colon at 3 am. They could control exsanguinating hemorrhage after leaving their anniversary parties. They could crack a chest and save a gunshot-wound victim, then regale the resident with a few Halsted and Billroth anecdotes. I suppose that most of my surgical heroes, if they were in the current system, would be referred to various well-being committees for gender and cultural counseling. They might be suspended or have their privileges amended. But they had all passed their boards and could do their jobs. As this 4th of July approached, I began to view Dr. Fred’s remarks as a call to arms for a revival of classic medical education. Coming from Massachusetts, I felt that I could take some liberties in rewriting the origTexas Heart Institute Journal
inal call-to-arms document, the Declaration of Independence. So one Saturday afternoon, I carefully reviewed that document. I decided that classically educated surgeons (and by extension, all classically educated physicians) should declare their independence from far-removed governing bodies that hinder growth and prosperity. There now exists a Declaration of Surgical Independence. Just send a note to SurgicalIndependence@ gmail.com and I will send you a copy. I hope that the Declaration, in some small way, will “raise the bar of performance in all training programs to a distinctly higher level.” Leo A. Gordon, MD, FACS, Los Angeles, California
References 1. Fred HL. Medical education on the brink: 62 years of frontline observations and opinions. Tex Heart Inst J 2012;39(3): 322-9. 2. Jancin B. Surgical educators flag training deficits. ACS Surgery News 2013;9(5):1,8. Available from: http://www.acssurgerynews.com/fileadmin/content_pdf/sn/past_issues/ sn201305.pdf [cited 2013 Aug 8]. 3. Wendling P. Thoracic surgery board failures up since 2006. ACS Surgery News 2013;9(7):23. Available from: http:// www.acssurgerynews.com/fileadmin/content_pdf/sn/past_ issues/Surg_July2013_Lores.pdf [cited 2013 Aug 8].
Historical Remarks on the Original Trendelenburg Operation for Massive Pulmonary Embolism
To the Editor: We read with interest the story from Dr. Medins1 about his volunteer medical work during the 1970s in Africa. He described his emergent removal of shrapnel from the bifurcation of a patient’s pulmonary artery (PA) “via the old-fashioned Trendelenburg procedure. . . . The aorta was clamped, the pulmonary artery incised at its bifurcation, the shrapnel removed, and the pulmonary artery closed—all in 5 minutes. The patient survived.”1 This accomplishment by Dr. Medins—without benefit of hypothermia or a heart-lung machine—is laudable indeed. However, in the original account by Trendelenburg,2 he did not report clamping the aorta when removing thromboembolic clots from his patients with massive pulmonary embolism. Instead of 633
cross-clamping the main PA, he looped a rubber tube behind the aorta and the main PA through the transverse sinus, compressing the pulmonary conus from behind to reveal the clots and optimize their removal.2 From what we could determine, neither the aorta nor the main PA was clamped during any old-fashioned Trendelenburg procedure (TP) reported from 1908 through 1957.2-6 The description by Dr. Medins might influence some to believe that the original TP was a valuable or practicable operation. In actuality, when the TP was used to treat pulmonary embolism, the outcomes were usually fatal.2-6 Trendelenburg’s own patients did not survive the procedure.2,6 Thereafter, 20 more unsuccessful attempts were reported.6 In March 1924, Kirschner (Trendelenburg’s pupil) reported the f irst successful outcome.7 During the next decade, only 3 more successes were documented, all in Europe.6 In 1934, Edward Churchill noted the dampened enthusiasm for the TP at his hospital after 10 consecutive failures.3 Through 1957, approximately 300 total procedures yielded a dozen survivors at most.4-6 Despite Trendelenburg’s intent, the procedure was hazardous, technically difficult, and perhaps performed too late—the patients were often in advanced cardiogenic shock or dying states. The challenge was to balance their precarious clinical course with the timing of the operation.3 Churchill endorsed postponing the TP until the patient was nearing death but cautioned that unnecessary delay would decrease the chance of success: “At times . . . the procedure could perhaps be more properly termed an immediate postmortem examination than a surgical operation.” 3 In this regard, the TP cannot compare with modern open surgical pulmonary embolectomy.
Giovanni Saeed, MD, Department of Cardiovascular Surgery, Rainer Gradaus, MD, PhD, Jörg Neuzner, MD, PhD, Department of Internal Medicine II and Cardiology, Klinikum Kassel GmbH, Kassel, Germany
References 1. Medins G. The Trendelenburg procedure revisited. Tex Heart Inst J 2013;40(3):371. 2. Trendelenburg F. Ueber die operative Behandlung der Embolie der Lungenarterie. Arch Klin Chir 1908;86(3):686-700. 3. Churchill ED. The mechanism of death in massive pulmonary embolism with comments on the Trendelenburg operation. Surg Gynecol Obstet 1934;59:513-7. 4. McFadden PM, Ochsner JL. Aggressive approach to pulmonary embolectomy for massive acute pulmonary embolism: a historical and contemporary perspective. Mayo Clin Proc 2010;85(9):782-4.
634
5. Sabiston DC Jr. Trendelenburg’s classic work on the operative treatment of pulmonary embolism. Ann Thorac Surg 1983; 35(5):570-4. 6. Bottcher W, Kruger A. The history of surgery in pulmonary embolism [in German]. Z Herz- Thorax- Gefaβchir 2006; 20(4):162-73. 7. Kirschner MB. Ein durch die Trendelenburgsche Operation geheilter Fall von Embolie der Art. pulmonalis [in German]. Arch Klin Chir 1924;133:312-59.
Cardiac Manifestations of Mitochondrial Disorders
To the Editor: With interest, we read the review about mitochondrial cardiomyopathy by Meyers and colleagues.1 We have the following comments and concerns. The authors provided a comprehensive overview of the cardiac manifestations of mitochondrial disorders. In addition to the cardiac abnormalities listed in their Table I, pulmonary artery hypertension should be mentioned. It can occur as an isolated phenotypic feature in nonsyndromic and syndromic mitochondrial disorders.2 Two syndromic disorders that manifest themselves with pulmonary artery hypertension are HUPRA syndrome (hyperuricemia, pulmonary hypertension, renal failure in infancy, and alkalosis), caused by mutations in SARS2, which encodes the mitochondrial seryl-tRNA synthetase2; and MELAS syndrome (mitochondrial encephalopathy with lactic acidosis and stroke-like episodes), caused by mutations in the tRNALeu gene. In nonsyndromic disorders, pulmonary artery hypertension has been described in association with mutations in the NFU1, tRNAGlu, and COX7B genes.3 Another cardiac abnormality occasionally associated with mitochondrial disorders is arterial hypertension.4 Arterial hypertension, described in syndromic and nonsyndromic mitochondrial conditions, can be caused by mutations in mitochondrial DNA (mtDNA) or nuclear DNA (nDNA)-located genes.4 Maternal arterial hypertension has been associated with the cytochrome b 15059G>A mtDNA mutation4 and the ribosomal RNA 1555A>G mutation. Arterial hypertension has also been found in those who carry SLC25A4 or SDHD mutations. A rare cardiac manifestation of mitochondrial disease is a patent foramen ovale. It has been found in patients with MELAS syndrome and in those who carry mutations in the DNA2 or BSCL2 genes.5 Patients with mtDNA depletion syndrome or tRNALeu mutations can also develop ventricular septal defects. A further point that we want to mention is that cardiomyopathy in mitochondrial disorders occurs not Volume 40, Number 5, 2013
only in syndromic conditions but also in the nonsyndromic forms, and much more frequently. Nonsyndromic disorders often go undetected for years, because of their nonspecific clinical manifestations and slow progression. Only when patients develop acute cardiac symptoms might they undergo thorough investigations that reveal the underlying defect. Finally, there is no evidence that coenzyme Q, L-carnitine, creatine phosphate, thiamine, riboflavin, vitamin C, vitamin E, idebeneone, or dihydrolipoate is therapeutically beneficial for cardiac manifestations of mitochondrial disorders, and heart transplantation must be mentioned as a treatment for intractable heart failure caused by mitochondrial dilative cardiomyopathy. Heart transplantation has been successfully performed in patients carrying tRNAIle mutations 6 and in mtDNA depletion syndrome. Overall, mitochondrial cardiac disease is even more variable than described. Despite the absence of causal treatments, effective symptomatic measures should be applied, particularly for mitochondrial cardiomyopathy.
Josef Finsterer, MD, PhD, Krankenanstalt Rudolfstiftung, Vienna, Austria; and Sinda Zarrouk-Mahjoub, PhD, Laboratory of Biochemistry, UR “Human Nutrition and Metabolic Disorders,” Faculty of Medicine, Monastir, Tunisia
References 1. Meyers DE, Basha HI, Koenig MK. Mitochondrial cardiomyopathy: pathophysiology, diagnosis, and management. Tex Heart Inst J 2013;40(4):385-94. 2. Belostotsky R, Ben-Shalom E, Rinat C, Becker-Cohen R, Feinstein S, Zeligson S, et al. Mutations in the mitochondrial seryl-tRNA synthetase cause hyperuricemia, pulmonary hypertension, renal failure in infancy and alkalosis, HUPRA syndrome. Am J Hum Genet 2011;88(2):193-200. 3. Indrieri A, van Rahden VA, Tiranti V, Morleo M, Iaconis D, Tammaro R, et al. Mutations in COX7B cause microphthalmia with linear skin lesions, an unconventional mitochondrial disease. Am J Hum Genet 2012;91(5):942-9. 4. Sobenin IA, Chistiakov DA, Sazonova MA, Ivanova MM, Bobryshev YV, Orekhov AN, Postnov AY. Association of the level of heteroplasmy of the 15059G>A mutation in the MTCYB mitochondrial gene with essential hypertension. World J Cardiol 2013;5(5):132-40. 5. Rahman OU, Khawar N, Khan MA, Ahmed J, Khattak K, Al-Aama JY, et al. Deletion mutation in BSCL2 gene underlies congenital generalized lipodystrophy in a Pakistani family. Diagn Pathol 2013;8:78. 6. Giordano C, Perli E, Orlandi M, Pisano A, Tuppen HA, He L, et al. Cardiomyopathies due to homoplasmic mitochondrial tRNA mutations: morphologic and molecular features. Hum Pathol 2013;44(7):1262-70.
Texas Heart Institute Journal
This letter was referred to Dr. Deborah E. Meyers and colleagues, who reply in this manner: We appreciate the thoughtful response of Finsterer and Zarrouk-Mahjoub to our article on cardiac manifestations of mitochondrial disorders.1 Their letter emphasizes the increasingly recognized role that mitochondrial dysregulation probably plays in a broad range of cardiovascular and age-related disorders. Finsterer and Zarrouk-Mahjoub point out that pulmonary artery hypertension (PAH) should have been included in our Table I, which lists common clinical manifestations of mitochondrial disorders. They cite 2 reports of rare syndromes to support this view. The first syndrome, HUPRA (hyperuricemia, PAH, renal failure in infancy, alkalosis), has been observed in infants and is associated with a mutation in the SARS2 gene, which encodes mitochondrial seryl-tRNA synthetase.2,3 The 2nd rare syndrome cited is microphthalmia with linear skin lesions (MLS); it has been associated with both holocytochrome c-type synthase (HCCS), which encodes a crucial participant in the respiratory chain, and COX7B mutations.4 A panoply of congenital cardiac abnormalities is observed in MLS; PAH has been described in several cases only. The most notable aspect of these 2 reports is not the association with PAH, but the fact that both HUPRA and MLS represent true developmental phenotypes associated with mitochondrial genetic abnormalities. This is entirely distinct from the manner in which classical mitochondrial disorders are usually characterized: as a progressive postnatal organ-failure syndrome that manifests itself in multiple organs and systems. We concur with Finsterer and Zarrouk-Mahjoub that nonsyndromic PAH can be considered broadly in terms of mitochondrial dysregulation. A recent review of metabolism and bioenergetics in the right ventricle and pulmonary vasculature cited evidence that mitochondrial-metabolic abnormalities have been identified in PAH.5 Notable abnormalities in pyruvate-dehydrogenase-kinase–mediated inhibition of pyruvate dehydrogenase resulted in a “glycolytic shift” that could be detected early in the clinical course of PAH. This shift reduced contractility in the right ventricle, and the pulmonary vasculature cells became hyperproliferative and apoptosis-resistant. In our article, we attempted to stress that energy deficiency is both a cause and an effect of disease. There is always the lurking question of whether an identified mitochondrial abnormality is the cause or effect of common disease processes. Finsterer and Zarrouk-Mahjoub note that hypertension, which is a highly polygenic condition influenced by the environment, is occasionally associated with mitochondrial disorders. They cite a report by Sobenin and colleagues,6 who observed altered heteroplasmy levels of G15059G>A in patients with hypertension com635
pared with normotensive control subjects. Confounding this observation is the demonstration of similarly altered levels of heteroplasmy (the ratio of wild-type to mutant mtDNA) in older patients (in whom hypertension is common) and in patients with hypertriglyceridemia. Further weakening the association is that heteroplasmy levels are known to be altered in a range of chronic diseases including atherosclerosis, Alzheimer’s disease, and diabetes mellitus. Again, the question arises: is demonstrating an association by itself adequate to implicate a mitochondrial abnormality as causative? We agree that abnormalities of bioenergetics are increasingly recognized as major culprits in cardiomyopathy in both inherited and acquired cardiac disease. In our article,1 we made the specific point that “mitochondria are a crucial platform for energy transduction, cell signaling, and cell-death pathways even in the absence of underlying mitochondrial disease.” We also mentioned transplantation as a potential therapy for selected patients who have mitochondrial cardiomyopathies, although international experience with this approach is limited. Care would need to be paid to the “mitochondrial stress management” strategies in the peri-transplant period that we outlined. Transplantation would constitute a substantial physiologic stress for a mitochondrial-disorder patient. Although no large, multicenter, randomized, controlled trials have established mortality benef its in treating mitochondrial disorders, there seems to be a benefit from using coenzyme Q, L-carnitine, creatine phosphate, thiamine, and riboflavin in combination as part of a “mitochondrial cocktail” during crisis.7 The data are limited, but it will be interesting to see whether such medications in combination can have a synergistic effect on respiratory chain function during crisis, because most studies have involved individual drugs and stable patients with mitochondrial disorders. No well-defined dosage has been established, and individual responses to such medications can differ because of genetic differences in mitochondrial metabolism. We hope that by delineating what is known, what is not known, and what is controversial regarding available clinical management strategies, we can promote increasing recognition of mitochondrial disorders and thoughtful management, based on current knowledge.
References 1. Meyers DE, Basha HI, Koenig MK. Mitochondrial cardiomyopathy: pathophysiology, diagnosis, and management. Tex Heart Inst J 2013;40(4):385-94. 2. Rivera H, Martin-Hernandez E, Delmiro A, Garcia-Silva MT, Quijada-Fraile P, Muley R, et al. A new mutation in the gene encoding mitochondrial seryl-tRNA synthetase as a cause of HUPRA syndrome. BMC Nephrol 2013;14(1):195. 3. Belostotsky R, Ben-Shalom E, Rinat C, Becker-Cohen R, Feinstein S, Zeligson S, et al. Mutations in the mitochondrial seryl-tRNA synthetase cause hyperuricemia, pulmonary hypertension, renal failure in infancy and alkalosis, HUPRA syndrome. Am J Hum Genet 2011;88(2):193-200. 4. Indrieri A, van Rahden VA, Tiranti V, Morleo M, Iaconis D, Tammaro R, et al. Mutations in COX7B cause microphthalmia with linear skin lesions, an unconventional mitochondrial disease. Am J Hum Genet 2012;91(5):942-9. 5. Archer SL, Fang YH, Ryan JJ, Piao L. Metabolism and bioenergetics in the right ventricle and pulmonary vasculature in pulmonary hypertension. Pulm Circ 2013;3(1):144-52. 6. Sobenin IA, Chistiakov DA, Sazonova MA, Ivanova MM, Bobryshev YV, Orekhov AN, Postnov AY. Association of the level of heteroplasmy of the 15059G>A mutation in the MTCYB mitochondrial gene with essential hypertension. World J Cardiol 2013;5(5):132-40. 7. Vahdat KK, Ilias-Basha H, Tung PP, Memon NB, Hall AC, Koenig MK, Meyers DE. Ventricular arrhythmias and acute left ventricular dysfunction as a primary and life-threatening manifestation of a mitochondrial crisis: a novel management strategy. J Cardiol Cases 2012;6(2):e35-8.
Letters to the Editor should be no longer than 2 double-spaced typewritten pages and should generally contain no more than 6 references. They should be signed, with the expectation that the letters will be published if appropriate. The right to edit all correspondence in accordance with Journal style is reserved by the editors.
Deborah E. Meyers, MD, FACC, Texas Heart Institute, Houston, Texas; Haseeb Ilias Basha, MD, Michigan State University, Flint, Michigan; Mary Kay Koenig, MD, The University of Texas Medical School at Houston, Houston, Texas
636
Volume 40, Number 5, 2013
To the Editor: After reading Dr. Herbert Fred’s “Medical Education on the Brink,”1 I was inspired to start a revolution in surgical education. He ended his essay with the following recommendation: “. . . raise the bar of performance in all training programs to a distinctly higher level, with excellence as the perpetual goal.” To their credit, influential members of the American College of Surgeons 2 reviewed the current state of surgical education and concluded: • “During the past decade, the failure rate on the American Board of Surgery’s oral exam has climbed steadily from 16% to 28%.” • “This is a scary situation.” • “We have a problem. . . . we have to stop being bullied by naïve, public, politically driven agendas and by some of our own graybeard pundits . . . and once again take over the control of educating our successors.” After reading this, I came across an article on the increasing failure rate in internal medicine, then yet another on the American Board of Thoracic Surgery’s oral board examination: the failure rate on that exam has doubled between 2000 and 2011 (from 14.4% to 28.1%).3 I believe that educational demand on resident physicians in all specialties has loosened, and many of my colleagues share this view. Rigorous knowledge of human pathology has been subordinated to respect for the residents’ self-esteem. This might well turn out doctors who feel great about knowing nothing. My generation produced some weird people. Many were politically incorrect. But they were characters with character! They could dig out a necrotic colon at 3 am. They could control exsanguinating hemorrhage after leaving their anniversary parties. They could crack a chest and save a gunshot-wound victim, then regale the resident with a few Halsted and Billroth anecdotes. I suppose that most of my surgical heroes, if they were in the current system, would be referred to various well-being committees for gender and cultural counseling. They might be suspended or have their privileges amended. But they had all passed their boards and could do their jobs. As this 4th of July approached, I began to view Dr. Fred’s remarks as a call to arms for a revival of classic medical education. Coming from Massachusetts, I felt that I could take some liberties in rewriting the origTexas Heart Institute Journal
inal call-to-arms document, the Declaration of Independence. So one Saturday afternoon, I carefully reviewed that document. I decided that classically educated surgeons (and by extension, all classically educated physicians) should declare their independence from far-removed governing bodies that hinder growth and prosperity. There now exists a Declaration of Surgical Independence. Just send a note to SurgicalIndependence@ gmail.com and I will send you a copy. I hope that the Declaration, in some small way, will “raise the bar of performance in all training programs to a distinctly higher level.” Leo A. Gordon, MD, FACS, Los Angeles, California
References 1. Fred HL. Medical education on the brink: 62 years of frontline observations and opinions. Tex Heart Inst J 2012;39(3): 322-9. 2. Jancin B. Surgical educators flag training deficits. ACS Surgery News 2013;9(5):1,8. Available from: http://www.acssurgerynews.com/fileadmin/content_pdf/sn/past_issues/ sn201305.pdf [cited 2013 Aug 8]. 3. Wendling P. Thoracic surgery board failures up since 2006. ACS Surgery News 2013;9(7):23. Available from: http:// www.acssurgerynews.com/fileadmin/content_pdf/sn/past_ issues/Surg_July2013_Lores.pdf [cited 2013 Aug 8].
Historical Remarks on the Original Trendelenburg Operation for Massive Pulmonary Embolism
To the Editor: We read with interest the story from Dr. Medins1 about his volunteer medical work during the 1970s in Africa. He described his emergent removal of shrapnel from the bifurcation of a patient’s pulmonary artery (PA) “via the old-fashioned Trendelenburg procedure. . . . The aorta was clamped, the pulmonary artery incised at its bifurcation, the shrapnel removed, and the pulmonary artery closed—all in 5 minutes. The patient survived.”1 This accomplishment by Dr. Medins—without benefit of hypothermia or a heart-lung machine—is laudable indeed. However, in the original account by Trendelenburg,2 he did not report clamping the aorta when removing thromboembolic clots from his patients with massive pulmonary embolism. Instead of 633
cross-clamping the main PA, he looped a rubber tube behind the aorta and the main PA through the transverse sinus, compressing the pulmonary conus from behind to reveal the clots and optimize their removal.2 From what we could determine, neither the aorta nor the main PA was clamped during any old-fashioned Trendelenburg procedure (TP) reported from 1908 through 1957.2-6 The description by Dr. Medins might influence some to believe that the original TP was a valuable or practicable operation. In actuality, when the TP was used to treat pulmonary embolism, the outcomes were usually fatal.2-6 Trendelenburg’s own patients did not survive the procedure.2,6 Thereafter, 20 more unsuccessful attempts were reported.6 In March 1924, Kirschner (Trendelenburg’s pupil) reported the f irst successful outcome.7 During the next decade, only 3 more successes were documented, all in Europe.6 In 1934, Edward Churchill noted the dampened enthusiasm for the TP at his hospital after 10 consecutive failures.3 Through 1957, approximately 300 total procedures yielded a dozen survivors at most.4-6 Despite Trendelenburg’s intent, the procedure was hazardous, technically difficult, and perhaps performed too late—the patients were often in advanced cardiogenic shock or dying states. The challenge was to balance their precarious clinical course with the timing of the operation.3 Churchill endorsed postponing the TP until the patient was nearing death but cautioned that unnecessary delay would decrease the chance of success: “At times . . . the procedure could perhaps be more properly termed an immediate postmortem examination than a surgical operation.” 3 In this regard, the TP cannot compare with modern open surgical pulmonary embolectomy.
Giovanni Saeed, MD, Department of Cardiovascular Surgery, Rainer Gradaus, MD, PhD, Jörg Neuzner, MD, PhD, Department of Internal Medicine II and Cardiology, Klinikum Kassel GmbH, Kassel, Germany
References 1. Medins G. The Trendelenburg procedure revisited. Tex Heart Inst J 2013;40(3):371. 2. Trendelenburg F. Ueber die operative Behandlung der Embolie der Lungenarterie. Arch Klin Chir 1908;86(3):686-700. 3. Churchill ED. The mechanism of death in massive pulmonary embolism with comments on the Trendelenburg operation. Surg Gynecol Obstet 1934;59:513-7. 4. McFadden PM, Ochsner JL. Aggressive approach to pulmonary embolectomy for massive acute pulmonary embolism: a historical and contemporary perspective. Mayo Clin Proc 2010;85(9):782-4.
634
5. Sabiston DC Jr. Trendelenburg’s classic work on the operative treatment of pulmonary embolism. Ann Thorac Surg 1983; 35(5):570-4. 6. Bottcher W, Kruger A. The history of surgery in pulmonary embolism [in German]. Z Herz- Thorax- Gefaβchir 2006; 20(4):162-73. 7. Kirschner MB. Ein durch die Trendelenburgsche Operation geheilter Fall von Embolie der Art. pulmonalis [in German]. Arch Klin Chir 1924;133:312-59.
Cardiac Manifestations of Mitochondrial Disorders
To the Editor: With interest, we read the review about mitochondrial cardiomyopathy by Meyers and colleagues.1 We have the following comments and concerns. The authors provided a comprehensive overview of the cardiac manifestations of mitochondrial disorders. In addition to the cardiac abnormalities listed in their Table I, pulmonary artery hypertension should be mentioned. It can occur as an isolated phenotypic feature in nonsyndromic and syndromic mitochondrial disorders.2 Two syndromic disorders that manifest themselves with pulmonary artery hypertension are HUPRA syndrome (hyperuricemia, pulmonary hypertension, renal failure in infancy, and alkalosis), caused by mutations in SARS2, which encodes the mitochondrial seryl-tRNA synthetase2; and MELAS syndrome (mitochondrial encephalopathy with lactic acidosis and stroke-like episodes), caused by mutations in the tRNALeu gene. In nonsyndromic disorders, pulmonary artery hypertension has been described in association with mutations in the NFU1, tRNAGlu, and COX7B genes.3 Another cardiac abnormality occasionally associated with mitochondrial disorders is arterial hypertension.4 Arterial hypertension, described in syndromic and nonsyndromic mitochondrial conditions, can be caused by mutations in mitochondrial DNA (mtDNA) or nuclear DNA (nDNA)-located genes.4 Maternal arterial hypertension has been associated with the cytochrome b 15059G>A mtDNA mutation4 and the ribosomal RNA 1555A>G mutation. Arterial hypertension has also been found in those who carry SLC25A4 or SDHD mutations. A rare cardiac manifestation of mitochondrial disease is a patent foramen ovale. It has been found in patients with MELAS syndrome and in those who carry mutations in the DNA2 or BSCL2 genes.5 Patients with mtDNA depletion syndrome or tRNALeu mutations can also develop ventricular septal defects. A further point that we want to mention is that cardiomyopathy in mitochondrial disorders occurs not Volume 40, Number 5, 2013
only in syndromic conditions but also in the nonsyndromic forms, and much more frequently. Nonsyndromic disorders often go undetected for years, because of their nonspecific clinical manifestations and slow progression. Only when patients develop acute cardiac symptoms might they undergo thorough investigations that reveal the underlying defect. Finally, there is no evidence that coenzyme Q, L-carnitine, creatine phosphate, thiamine, riboflavin, vitamin C, vitamin E, idebeneone, or dihydrolipoate is therapeutically beneficial for cardiac manifestations of mitochondrial disorders, and heart transplantation must be mentioned as a treatment for intractable heart failure caused by mitochondrial dilative cardiomyopathy. Heart transplantation has been successfully performed in patients carrying tRNAIle mutations 6 and in mtDNA depletion syndrome. Overall, mitochondrial cardiac disease is even more variable than described. Despite the absence of causal treatments, effective symptomatic measures should be applied, particularly for mitochondrial cardiomyopathy.
Josef Finsterer, MD, PhD, Krankenanstalt Rudolfstiftung, Vienna, Austria; and Sinda Zarrouk-Mahjoub, PhD, Laboratory of Biochemistry, UR “Human Nutrition and Metabolic Disorders,” Faculty of Medicine, Monastir, Tunisia
References 1. Meyers DE, Basha HI, Koenig MK. Mitochondrial cardiomyopathy: pathophysiology, diagnosis, and management. Tex Heart Inst J 2013;40(4):385-94. 2. Belostotsky R, Ben-Shalom E, Rinat C, Becker-Cohen R, Feinstein S, Zeligson S, et al. Mutations in the mitochondrial seryl-tRNA synthetase cause hyperuricemia, pulmonary hypertension, renal failure in infancy and alkalosis, HUPRA syndrome. Am J Hum Genet 2011;88(2):193-200. 3. Indrieri A, van Rahden VA, Tiranti V, Morleo M, Iaconis D, Tammaro R, et al. Mutations in COX7B cause microphthalmia with linear skin lesions, an unconventional mitochondrial disease. Am J Hum Genet 2012;91(5):942-9. 4. Sobenin IA, Chistiakov DA, Sazonova MA, Ivanova MM, Bobryshev YV, Orekhov AN, Postnov AY. Association of the level of heteroplasmy of the 15059G>A mutation in the MTCYB mitochondrial gene with essential hypertension. World J Cardiol 2013;5(5):132-40. 5. Rahman OU, Khawar N, Khan MA, Ahmed J, Khattak K, Al-Aama JY, et al. Deletion mutation in BSCL2 gene underlies congenital generalized lipodystrophy in a Pakistani family. Diagn Pathol 2013;8:78. 6. Giordano C, Perli E, Orlandi M, Pisano A, Tuppen HA, He L, et al. Cardiomyopathies due to homoplasmic mitochondrial tRNA mutations: morphologic and molecular features. Hum Pathol 2013;44(7):1262-70.
Texas Heart Institute Journal
This letter was referred to Dr. Deborah E. Meyers and colleagues, who reply in this manner: We appreciate the thoughtful response of Finsterer and Zarrouk-Mahjoub to our article on cardiac manifestations of mitochondrial disorders.1 Their letter emphasizes the increasingly recognized role that mitochondrial dysregulation probably plays in a broad range of cardiovascular and age-related disorders. Finsterer and Zarrouk-Mahjoub point out that pulmonary artery hypertension (PAH) should have been included in our Table I, which lists common clinical manifestations of mitochondrial disorders. They cite 2 reports of rare syndromes to support this view. The first syndrome, HUPRA (hyperuricemia, PAH, renal failure in infancy, alkalosis), has been observed in infants and is associated with a mutation in the SARS2 gene, which encodes mitochondrial seryl-tRNA synthetase.2,3 The 2nd rare syndrome cited is microphthalmia with linear skin lesions (MLS); it has been associated with both holocytochrome c-type synthase (HCCS), which encodes a crucial participant in the respiratory chain, and COX7B mutations.4 A panoply of congenital cardiac abnormalities is observed in MLS; PAH has been described in several cases only. The most notable aspect of these 2 reports is not the association with PAH, but the fact that both HUPRA and MLS represent true developmental phenotypes associated with mitochondrial genetic abnormalities. This is entirely distinct from the manner in which classical mitochondrial disorders are usually characterized: as a progressive postnatal organ-failure syndrome that manifests itself in multiple organs and systems. We concur with Finsterer and Zarrouk-Mahjoub that nonsyndromic PAH can be considered broadly in terms of mitochondrial dysregulation. A recent review of metabolism and bioenergetics in the right ventricle and pulmonary vasculature cited evidence that mitochondrial-metabolic abnormalities have been identified in PAH.5 Notable abnormalities in pyruvate-dehydrogenase-kinase–mediated inhibition of pyruvate dehydrogenase resulted in a “glycolytic shift” that could be detected early in the clinical course of PAH. This shift reduced contractility in the right ventricle, and the pulmonary vasculature cells became hyperproliferative and apoptosis-resistant. In our article, we attempted to stress that energy deficiency is both a cause and an effect of disease. There is always the lurking question of whether an identified mitochondrial abnormality is the cause or effect of common disease processes. Finsterer and Zarrouk-Mahjoub note that hypertension, which is a highly polygenic condition influenced by the environment, is occasionally associated with mitochondrial disorders. They cite a report by Sobenin and colleagues,6 who observed altered heteroplasmy levels of G15059G>A in patients with hypertension com635
pared with normotensive control subjects. Confounding this observation is the demonstration of similarly altered levels of heteroplasmy (the ratio of wild-type to mutant mtDNA) in older patients (in whom hypertension is common) and in patients with hypertriglyceridemia. Further weakening the association is that heteroplasmy levels are known to be altered in a range of chronic diseases including atherosclerosis, Alzheimer’s disease, and diabetes mellitus. Again, the question arises: is demonstrating an association by itself adequate to implicate a mitochondrial abnormality as causative? We agree that abnormalities of bioenergetics are increasingly recognized as major culprits in cardiomyopathy in both inherited and acquired cardiac disease. In our article,1 we made the specific point that “mitochondria are a crucial platform for energy transduction, cell signaling, and cell-death pathways even in the absence of underlying mitochondrial disease.” We also mentioned transplantation as a potential therapy for selected patients who have mitochondrial cardiomyopathies, although international experience with this approach is limited. Care would need to be paid to the “mitochondrial stress management” strategies in the peri-transplant period that we outlined. Transplantation would constitute a substantial physiologic stress for a mitochondrial-disorder patient. Although no large, multicenter, randomized, controlled trials have established mortality benef its in treating mitochondrial disorders, there seems to be a benefit from using coenzyme Q, L-carnitine, creatine phosphate, thiamine, and riboflavin in combination as part of a “mitochondrial cocktail” during crisis.7 The data are limited, but it will be interesting to see whether such medications in combination can have a synergistic effect on respiratory chain function during crisis, because most studies have involved individual drugs and stable patients with mitochondrial disorders. No well-defined dosage has been established, and individual responses to such medications can differ because of genetic differences in mitochondrial metabolism. We hope that by delineating what is known, what is not known, and what is controversial regarding available clinical management strategies, we can promote increasing recognition of mitochondrial disorders and thoughtful management, based on current knowledge.
References 1. Meyers DE, Basha HI, Koenig MK. Mitochondrial cardiomyopathy: pathophysiology, diagnosis, and management. Tex Heart Inst J 2013;40(4):385-94. 2. Rivera H, Martin-Hernandez E, Delmiro A, Garcia-Silva MT, Quijada-Fraile P, Muley R, et al. A new mutation in the gene encoding mitochondrial seryl-tRNA synthetase as a cause of HUPRA syndrome. BMC Nephrol 2013;14(1):195. 3. Belostotsky R, Ben-Shalom E, Rinat C, Becker-Cohen R, Feinstein S, Zeligson S, et al. Mutations in the mitochondrial seryl-tRNA synthetase cause hyperuricemia, pulmonary hypertension, renal failure in infancy and alkalosis, HUPRA syndrome. Am J Hum Genet 2011;88(2):193-200. 4. Indrieri A, van Rahden VA, Tiranti V, Morleo M, Iaconis D, Tammaro R, et al. Mutations in COX7B cause microphthalmia with linear skin lesions, an unconventional mitochondrial disease. Am J Hum Genet 2012;91(5):942-9. 5. Archer SL, Fang YH, Ryan JJ, Piao L. Metabolism and bioenergetics in the right ventricle and pulmonary vasculature in pulmonary hypertension. Pulm Circ 2013;3(1):144-52. 6. Sobenin IA, Chistiakov DA, Sazonova MA, Ivanova MM, Bobryshev YV, Orekhov AN, Postnov AY. Association of the level of heteroplasmy of the 15059G>A mutation in the MTCYB mitochondrial gene with essential hypertension. World J Cardiol 2013;5(5):132-40. 7. Vahdat KK, Ilias-Basha H, Tung PP, Memon NB, Hall AC, Koenig MK, Meyers DE. Ventricular arrhythmias and acute left ventricular dysfunction as a primary and life-threatening manifestation of a mitochondrial crisis: a novel management strategy. J Cardiol Cases 2012;6(2):e35-8.
Letters to the Editor should be no longer than 2 double-spaced typewritten pages and should generally contain no more than 6 references. They should be signed, with the expectation that the letters will be published if appropriate. The right to edit all correspondence in accordance with Journal style is reserved by the editors.
Deborah E. Meyers, MD, FACC, Texas Heart Institute, Houston, Texas; Haseeb Ilias Basha, MD, Michigan State University, Flint, Michigan; Mary Kay Koenig, MD, The University of Texas Medical School at Houston, Houston, Texas
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Volume 40, Number 5, 2013
