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Six months of Sildenafil therapy improves heart rate recovery in patients with heart failure
International Journal of Cardiology 136 (2009) 341 – 367 www.elsevier.com/locate/ijcard
Letters to the Editor
Six months of Sildenafil therapy improves heart rate recovery in patients with heart failure Marco Guazzi a,⁎, Ross Arena b , Sherry Pinkstaff b , Maurizio D. Guazzi c a
University of Milano, San Paolo Hospital, Cardiopulmonary Laboratory, Cardiology Division, University of Milano, San Paolo Hospital, Milano, Italy b Departments of Physiology and Physical Therapy, Virginia Commonwealth University, Health Sciences Campus, Richmond, Virginia, USA c Institute of Cardiology, University of Milano, Milano, Italy Received 8 January 2008; accepted 26 April 2008 Available online 29 July 2008
Abstract Previous research has demonstrated an increase in large vessel stiffness in patients with heart failure (HF). Furthermore, heart rate recovery (HRR) may be negatively impacted by increased arterial stiffness secondary to altered baroreceptor discharge. The purpose of the present study was to determine if chronic phosphodiesterase 5 (PDE5) inhibition with Sildenafil, previously shown to improve arterial stiffness, favorably impacts HRR in patients with HF. Forty male subjects (age: 65.3 ± 7.3 years, baseline ejection fraction: 37.1 ± 7.4%, 15 non-ischemic HF/25 ischemic HF) participated in this study. Subjects received Sildenafil (25 mg, 3 times/day) for six months. Symptomlimited exercise testing was performed at baseline and six months with a lower extremity ergometer. Heart rate recovery was defined as HR at maximal exercise minus HR at 1 min recovery. No adverse effects were reported throughout the study period. Paired t-testing revealed that HRR was significantly improved following six months of Sildenafil therapy (baseline: 17.5 ± 3.5 bpm vs. Post: 20.6 ± 3.2 bpm). The results of the present study indicate that chronic Sildenafil therapy significantly increases HRR, an important prognostic marker, in patients with HF. A plausible mechanism for the improvement of HRR is the previously demonstrated impact Sildenafil has on arterial stiffness and therefore baroreceptor function. © 2008 Elsevier Ireland Ltd. All rights reserved. Keywords: Arterial stiffness; Baroreceptor; Autonomic tone
1 . Introduction Numerous variables obtained from exercise testing provide important clinical information in patients with heart failure (HF). In particular, a number of investigations have found ventilatory efficiency and aerobic capacity to be highly prognostic in the HF population [1]. Moreover, aerobic capacity and/or ventilatory efficiency have been shown to respond favorably to numerous interventions [2,3]. Aside from variables exclusively obtained from ventilatory expired ⁎ Corresponding author. Associate Professor, Department of Physical Therapy, Box 980224, Virginia Commonwealth University, Health Sciences Campus, Richmond, VA 23298-0224, USA. Tel.: +804 828 0234; fax: +804 828 8111. E-mail address: [email protected] (R. Arena).
gas analysis, several other traditional exercise testing variables have demonstrated prognostic, and therefore clinical, value. Among the host of potential variables, heat rate recovery (HRR), has demonstrated significant predictive value in patients with HF [4]. This easily calculated HR response also appears to add predictive value to other established exercise test variables such as ventilatory efficiency [5]. In addition, a recent investigation by Myers et al. [6] demonstrated that HRR significantly increases following exercise training in a group of patients with HF. We are, however, unaware of additional investigations examining the impact of various interventions on HRR. Chronic phosphodiesterase 5 (PDE5) inhibition with Sildenafil has previously been shown to improve arterial stiffness [7–10]. Given the link between HRR and arterial stiffness [11] we hypothesize that Sildenafil will likewise improve HRR.
342
Letters to the Editor
2 . Subjects and methods Forty male subjects diagnosed with HF (age: 65.3 ± 7.3 years, baseline ejection fraction: 37.1 ± 7.4%, 15 nonischemic HF/25 ischemic HF) participated in this study. Subjects received Sildenafil (25 mg, 3 times/day) for six months. Optimal medical treatment with ACE-inhibitors and beta-blockers was achieved prior to study initiation. Ninetythree percent, 88% and 88% were on a stable does of an ACE inhibitor, diuretic and beta-blocker, respectively. Symptomlimited exercise testing was performed at baseline and six months with a lower extremity ergometer. The exercise protocol consisted of increases in workload at a rate of 10 W/min to maximal exertion. Heart rate recovery was defined as HR at maximal exercise minus HR at 1 min into recovery. All subjects performed the same cool-down procedures consisting of pedaling against zero-load for 20 s followed by continued monitoring while the patient was in the seated position. Peak respiratory exchange ratio and HR were also determined to ensure consistent subject effort between exercise tests. 3 . Results and discussion No adverse effects were reported throughout the study period and all subjects successfully completed the protocol. Peak respiratory exchange ratio (1.10 ± 0.04 vs. 1.10 ± 0.04, p= 0.25) and HR (139.4 ± 7.5 bpm vs. 140.2 ± 7.0 bpm, p= 0.09) were not significantly different between the baseline and postintervention exercise test, indicating comparable effort. Heart rate recovery was, however, significantly higher following six months of Sildenafil therapy (17.5 ± 3.5 bpm vs. 20.6 ± 3.2 bpm, p b 0.001). The improvement in HRR is illustrated in Fig. 1. Our group has previously demonstrated that chronic Sildenafil therapy significantly improves aerobic capacity and ventilatory efficiency in patients with HF [3]. To our knowledge, this is the first investigation examining the effect of Sildenafil on HRR. Our results demonstrate this important
Fig. 1. Change in HRR following six months of Sildenafil.
marker of cardiovascular health and prognosis is significantly improved following a pharmacologic intervention. While the exact mechanisms influencing HRR have yet to be elucidated, parasympathetic reactivation appears to be a primary factor [12]. Furthermore, the degree of large artery compliance may significantly influence HR control following exercise by altering the level of baroreceptor sensitivity (i.e. greater arterial compliance = greater baroreceptor discharge and HR reduction post post-exercise) [13]. Previous research has also demonstrated a significant correlation between HRR and arterial stiffness in apparently healthy subjects [11]. It is therefore plausible to suspect interventions that improve arterial stiffness, such as Sildenafil [8–10], would likewise increase HRR through an increase in baroreceptor sensitivity. The results of the present study support this hypothesis. The fact that we did not assess changes in arterial stiffness in the present investigation is certainly a limitation. Improvements in arterial stiffness following the use of Sildenafil has have been previously reported in patients with HF [8] as well as subjects diagnosed with hypertension [10], erectile dysfunction [9] and coronary artery disease [7]. Furthermore, there is a sound physiologic rationale linking arterial stiffness and HRR. Future research should, however, be directed towards directly assessing the correlation between changes in arterial stiffness and HRR following Sildenafil use in patients with HF. In conclusion, our results demonstrate Sildenafil improves HRR as well as other exercise test variables (previous investigation [3]) in patients with HF. Previous research has also shown that HRR provides an accurate, non-invasive, reflection of cardiovascular health and possesses prognostic value. Given the potential clinical importance of HRR, the use of this variable to assess the response to treatment in HF should be considered. References [1] Arena R, Myers J, Abella J, et al. Development of a ventilatory classification system in patients with heart failure. Circulation 2007;115:2410–7. [2] Myers J, Dziekan G, Goebbels U, Dubach P. Influence of high-intensity exercise training on the ventilatory response to exercise in patients with reduced ventricular function. Med Sci Sports Exerc 1999;31:929–37. [3] Guazzi M, Samaja M, Arena R, Vicenzi M, Guazzi MD. Long-term use of sildenafil in the therapeutic management of heart failure. J Am Coll Cardiol 2007;50:2136–44. [4] Lipinski MJ, Vetrovec GW, Gorelik D, Froelicher VF. The importance of heart rate recovery in patients with heart failure or left ventricular systolic dysfunction. J Card Fail 2005;11:624–30. [5] Arena R, Guazzi M, Myers J, Peberdy MA. Prognostic value of heart rate recovery in patients with heart failure. Am Heart J 2006;151:851. [6] Myers J, Hadley D, Oswald U, et al. Effects of exercise training on heart rate recovery in patients with chronic heart failure. Am Heart J 2007;153:1056–63. [7] Vlachopoulos C, Hirata K, O'Rourke MF. Effect of sildenafil on arterial stiffness and wave reflection. Vasc Med 2003;8:243–8. [8] Hirata K, Adji A, Vlachopoulos C, O'Rourke MF. Effect of sildenafil on cardiac performance in patients with heart failure. Am J Cardiol 2005;96:1436–40. [9] Shigemura K, Arakawa S, Kamidono S, Nakano Y, Fujisawa M. Effect of sildenafil on arterial stiffness, as assessed by pulse wave velocity, in patients with erectile dysfunction. Int J Urol 2006;13:956–9.
Letters to the Editor [10] Mahmud A, Hennessy M, Feely J. Effect of sildenafil on blood pressure and arterial wave reflection in treated hypertensive men. J Hum Hypertens 2001;15:707–13. [11] Fei DY, Arena R, Arrowood JA, Kraft KA. Relationship between arterial stiffness and heart rate recovery in apparently healthy adults. Vasc Health Risk Manag 2005;1:85–9.
343
[12] Imai K, Sato H, Hori M, et al. Vagally mediated heart rate recovery after exercise is accelerated in athletes but blunted in patients with chronic heart failure. J Am Coll Cardiol 1994;24:1529–35. [13] Sa CR, Pannier B, Benetos A, et al. Association between high heart rate and high arterial rigidity in normotensive and hypertensive subjects. J Hypertens 1997;15:1423–30.
0167-5273/$ - see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2008.04.061
Cardiac and neurologic involvement in McLeod syndrome Josef Finsterer a,⁎ Claudia Stöllberger b b
a Krankenanstalt Rudolfstiftung, Austria Medical Department, Krankenanstalt Rudolfstiftung, Vienna, Austria
Received 8 January 2008; accepted 26 April 2008 Available online 25 July 2008
Keywords: Cardiac involvement; Genetics; Acanthocytosis; Chorea; Myocardium; Neuromuscular disorders
With interest we read the article by Oechslin et al. on the cardiologic and neurologic findings in 7 patients with genetically confirmed McLeod syndrome [1]. The authors concluded that cardiac involvement in McLeod syndrome may manifest as cardiomyopathy and that these patients require regular cardiologic follow-up investigations [1]. The study raises concerns. Table 1 shows that only six of the seven patients were neurologically investigated. Were the six patients seen by a neurologist or by the treating cardiologist? Why did the seventh patient not also undergo neurological investigations? Only two of six patients (33%) developed weakness or wasting, despite a mean age of 45 years. In a recent study on 10 patients, however, 80% developed weakness and wasting within a mean observational period of 15 years [2]. How to explain this discrepancy? All seven patients showed elevated creatine-kinase (CK) values. Recently, however, it has been shown that only 40% of the patients exhibit non-specific myopathic changes on muscle biopsy, whereas 100% exhibit neurogenic changes due to axonal neuropathy [2]. Which was the cause of CKelevation in the presented patients? Was a cerebral or cardiac cause or the presence of a macro-CK or mitochondrial CK excluded? If attributable exclusively to skeletal muscle damage, did the presented patients more frequently show myopathic changes as compared to previous findings? Were nerve conduction studies carried out to look for axonal ⁎ Corresponding author. Postfach 20 1180 Vienna, Austria, Europe. Tel.: +43 1 71165 92085; fax: +43 1 4781711. E-mail address: [email protected] (J. Finsterer).
neuropathy? How many of the seven patients underwent muscle biopsy? Which were the results? Were histopathological investigations of any skeletal muscle carried out in patient IV-5 who underwent autopsy? How many had undergone general anesthesia so far? Were any complications during general anesthesia reported in any of the seven? Had any of the patients developed rhabdomyolysis so far? Central nervous system manifestations in McLeod syndrome not only include chorea, psychiatric disorders, or cognitive impairment but also seizures [2]. How many of the included patients had developed epilepsy? Were imaging studies of the cerebrum carried out in any of the patients? Did any of the seven patients experience a stroke since two had an atrial septal aneurysm and one an apical left ventricular diverticulum [3]? Which was the definition of the latter finding? Diagnosis of cardiomyopathy requires the exclusion of coronary heart disease by coronary angiography. Did any of the patients report anginal chest pain? How many had undergone coronary angiography? Did at least the patient with cardiomyopathy undergo coronary angiography? Which were the results? The authors state that patients with McLeod syndrome and cardiomyopathy are at risk for sudden cardiac death. On the contrary, sudden cardiac death has been only rarely reported in McLeod syndrome [1,2,4]. Which ECG abnormalities were assessed? How many patients showed ST- or T-wave abnormalities, tall QRScomplexes, or QT-prolongation?
Letters to the Editor
Six months of Sildenafil therapy improves heart rate recovery in patients with heart failure Marco Guazzi a,⁎, Ross Arena b , Sherry Pinkstaff b , Maurizio D. Guazzi c a
University of Milano, San Paolo Hospital, Cardiopulmonary Laboratory, Cardiology Division, University of Milano, San Paolo Hospital, Milano, Italy b Departments of Physiology and Physical Therapy, Virginia Commonwealth University, Health Sciences Campus, Richmond, Virginia, USA c Institute of Cardiology, University of Milano, Milano, Italy Received 8 January 2008; accepted 26 April 2008 Available online 29 July 2008
Abstract Previous research has demonstrated an increase in large vessel stiffness in patients with heart failure (HF). Furthermore, heart rate recovery (HRR) may be negatively impacted by increased arterial stiffness secondary to altered baroreceptor discharge. The purpose of the present study was to determine if chronic phosphodiesterase 5 (PDE5) inhibition with Sildenafil, previously shown to improve arterial stiffness, favorably impacts HRR in patients with HF. Forty male subjects (age: 65.3 ± 7.3 years, baseline ejection fraction: 37.1 ± 7.4%, 15 non-ischemic HF/25 ischemic HF) participated in this study. Subjects received Sildenafil (25 mg, 3 times/day) for six months. Symptomlimited exercise testing was performed at baseline and six months with a lower extremity ergometer. Heart rate recovery was defined as HR at maximal exercise minus HR at 1 min recovery. No adverse effects were reported throughout the study period. Paired t-testing revealed that HRR was significantly improved following six months of Sildenafil therapy (baseline: 17.5 ± 3.5 bpm vs. Post: 20.6 ± 3.2 bpm). The results of the present study indicate that chronic Sildenafil therapy significantly increases HRR, an important prognostic marker, in patients with HF. A plausible mechanism for the improvement of HRR is the previously demonstrated impact Sildenafil has on arterial stiffness and therefore baroreceptor function. © 2008 Elsevier Ireland Ltd. All rights reserved. Keywords: Arterial stiffness; Baroreceptor; Autonomic tone
1 . Introduction Numerous variables obtained from exercise testing provide important clinical information in patients with heart failure (HF). In particular, a number of investigations have found ventilatory efficiency and aerobic capacity to be highly prognostic in the HF population [1]. Moreover, aerobic capacity and/or ventilatory efficiency have been shown to respond favorably to numerous interventions [2,3]. Aside from variables exclusively obtained from ventilatory expired ⁎ Corresponding author. Associate Professor, Department of Physical Therapy, Box 980224, Virginia Commonwealth University, Health Sciences Campus, Richmond, VA 23298-0224, USA. Tel.: +804 828 0234; fax: +804 828 8111. E-mail address: [email protected] (R. Arena).
gas analysis, several other traditional exercise testing variables have demonstrated prognostic, and therefore clinical, value. Among the host of potential variables, heat rate recovery (HRR), has demonstrated significant predictive value in patients with HF [4]. This easily calculated HR response also appears to add predictive value to other established exercise test variables such as ventilatory efficiency [5]. In addition, a recent investigation by Myers et al. [6] demonstrated that HRR significantly increases following exercise training in a group of patients with HF. We are, however, unaware of additional investigations examining the impact of various interventions on HRR. Chronic phosphodiesterase 5 (PDE5) inhibition with Sildenafil has previously been shown to improve arterial stiffness [7–10]. Given the link between HRR and arterial stiffness [11] we hypothesize that Sildenafil will likewise improve HRR.
342
Letters to the Editor
2 . Subjects and methods Forty male subjects diagnosed with HF (age: 65.3 ± 7.3 years, baseline ejection fraction: 37.1 ± 7.4%, 15 nonischemic HF/25 ischemic HF) participated in this study. Subjects received Sildenafil (25 mg, 3 times/day) for six months. Optimal medical treatment with ACE-inhibitors and beta-blockers was achieved prior to study initiation. Ninetythree percent, 88% and 88% were on a stable does of an ACE inhibitor, diuretic and beta-blocker, respectively. Symptomlimited exercise testing was performed at baseline and six months with a lower extremity ergometer. The exercise protocol consisted of increases in workload at a rate of 10 W/min to maximal exertion. Heart rate recovery was defined as HR at maximal exercise minus HR at 1 min into recovery. All subjects performed the same cool-down procedures consisting of pedaling against zero-load for 20 s followed by continued monitoring while the patient was in the seated position. Peak respiratory exchange ratio and HR were also determined to ensure consistent subject effort between exercise tests. 3 . Results and discussion No adverse effects were reported throughout the study period and all subjects successfully completed the protocol. Peak respiratory exchange ratio (1.10 ± 0.04 vs. 1.10 ± 0.04, p= 0.25) and HR (139.4 ± 7.5 bpm vs. 140.2 ± 7.0 bpm, p= 0.09) were not significantly different between the baseline and postintervention exercise test, indicating comparable effort. Heart rate recovery was, however, significantly higher following six months of Sildenafil therapy (17.5 ± 3.5 bpm vs. 20.6 ± 3.2 bpm, p b 0.001). The improvement in HRR is illustrated in Fig. 1. Our group has previously demonstrated that chronic Sildenafil therapy significantly improves aerobic capacity and ventilatory efficiency in patients with HF [3]. To our knowledge, this is the first investigation examining the effect of Sildenafil on HRR. Our results demonstrate this important
Fig. 1. Change in HRR following six months of Sildenafil.
marker of cardiovascular health and prognosis is significantly improved following a pharmacologic intervention. While the exact mechanisms influencing HRR have yet to be elucidated, parasympathetic reactivation appears to be a primary factor [12]. Furthermore, the degree of large artery compliance may significantly influence HR control following exercise by altering the level of baroreceptor sensitivity (i.e. greater arterial compliance = greater baroreceptor discharge and HR reduction post post-exercise) [13]. Previous research has also demonstrated a significant correlation between HRR and arterial stiffness in apparently healthy subjects [11]. It is therefore plausible to suspect interventions that improve arterial stiffness, such as Sildenafil [8–10], would likewise increase HRR through an increase in baroreceptor sensitivity. The results of the present study support this hypothesis. The fact that we did not assess changes in arterial stiffness in the present investigation is certainly a limitation. Improvements in arterial stiffness following the use of Sildenafil has have been previously reported in patients with HF [8] as well as subjects diagnosed with hypertension [10], erectile dysfunction [9] and coronary artery disease [7]. Furthermore, there is a sound physiologic rationale linking arterial stiffness and HRR. Future research should, however, be directed towards directly assessing the correlation between changes in arterial stiffness and HRR following Sildenafil use in patients with HF. In conclusion, our results demonstrate Sildenafil improves HRR as well as other exercise test variables (previous investigation [3]) in patients with HF. Previous research has also shown that HRR provides an accurate, non-invasive, reflection of cardiovascular health and possesses prognostic value. Given the potential clinical importance of HRR, the use of this variable to assess the response to treatment in HF should be considered. References [1] Arena R, Myers J, Abella J, et al. Development of a ventilatory classification system in patients with heart failure. Circulation 2007;115:2410–7. [2] Myers J, Dziekan G, Goebbels U, Dubach P. Influence of high-intensity exercise training on the ventilatory response to exercise in patients with reduced ventricular function. Med Sci Sports Exerc 1999;31:929–37. [3] Guazzi M, Samaja M, Arena R, Vicenzi M, Guazzi MD. Long-term use of sildenafil in the therapeutic management of heart failure. J Am Coll Cardiol 2007;50:2136–44. [4] Lipinski MJ, Vetrovec GW, Gorelik D, Froelicher VF. The importance of heart rate recovery in patients with heart failure or left ventricular systolic dysfunction. J Card Fail 2005;11:624–30. [5] Arena R, Guazzi M, Myers J, Peberdy MA. Prognostic value of heart rate recovery in patients with heart failure. Am Heart J 2006;151:851. [6] Myers J, Hadley D, Oswald U, et al. Effects of exercise training on heart rate recovery in patients with chronic heart failure. Am Heart J 2007;153:1056–63. [7] Vlachopoulos C, Hirata K, O'Rourke MF. Effect of sildenafil on arterial stiffness and wave reflection. Vasc Med 2003;8:243–8. [8] Hirata K, Adji A, Vlachopoulos C, O'Rourke MF. Effect of sildenafil on cardiac performance in patients with heart failure. Am J Cardiol 2005;96:1436–40. [9] Shigemura K, Arakawa S, Kamidono S, Nakano Y, Fujisawa M. Effect of sildenafil on arterial stiffness, as assessed by pulse wave velocity, in patients with erectile dysfunction. Int J Urol 2006;13:956–9.
Letters to the Editor [10] Mahmud A, Hennessy M, Feely J. Effect of sildenafil on blood pressure and arterial wave reflection in treated hypertensive men. J Hum Hypertens 2001;15:707–13. [11] Fei DY, Arena R, Arrowood JA, Kraft KA. Relationship between arterial stiffness and heart rate recovery in apparently healthy adults. Vasc Health Risk Manag 2005;1:85–9.
343
[12] Imai K, Sato H, Hori M, et al. Vagally mediated heart rate recovery after exercise is accelerated in athletes but blunted in patients with chronic heart failure. J Am Coll Cardiol 1994;24:1529–35. [13] Sa CR, Pannier B, Benetos A, et al. Association between high heart rate and high arterial rigidity in normotensive and hypertensive subjects. J Hypertens 1997;15:1423–30.
0167-5273/$ - see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2008.04.061
Cardiac and neurologic involvement in McLeod syndrome Josef Finsterer a,⁎ Claudia Stöllberger b b
a Krankenanstalt Rudolfstiftung, Austria Medical Department, Krankenanstalt Rudolfstiftung, Vienna, Austria
Received 8 January 2008; accepted 26 April 2008 Available online 25 July 2008
Keywords: Cardiac involvement; Genetics; Acanthocytosis; Chorea; Myocardium; Neuromuscular disorders
With interest we read the article by Oechslin et al. on the cardiologic and neurologic findings in 7 patients with genetically confirmed McLeod syndrome [1]. The authors concluded that cardiac involvement in McLeod syndrome may manifest as cardiomyopathy and that these patients require regular cardiologic follow-up investigations [1]. The study raises concerns. Table 1 shows that only six of the seven patients were neurologically investigated. Were the six patients seen by a neurologist or by the treating cardiologist? Why did the seventh patient not also undergo neurological investigations? Only two of six patients (33%) developed weakness or wasting, despite a mean age of 45 years. In a recent study on 10 patients, however, 80% developed weakness and wasting within a mean observational period of 15 years [2]. How to explain this discrepancy? All seven patients showed elevated creatine-kinase (CK) values. Recently, however, it has been shown that only 40% of the patients exhibit non-specific myopathic changes on muscle biopsy, whereas 100% exhibit neurogenic changes due to axonal neuropathy [2]. Which was the cause of CKelevation in the presented patients? Was a cerebral or cardiac cause or the presence of a macro-CK or mitochondrial CK excluded? If attributable exclusively to skeletal muscle damage, did the presented patients more frequently show myopathic changes as compared to previous findings? Were nerve conduction studies carried out to look for axonal ⁎ Corresponding author. Postfach 20 1180 Vienna, Austria, Europe. Tel.: +43 1 71165 92085; fax: +43 1 4781711. E-mail address: [email protected] (J. Finsterer).
neuropathy? How many of the seven patients underwent muscle biopsy? Which were the results? Were histopathological investigations of any skeletal muscle carried out in patient IV-5 who underwent autopsy? How many had undergone general anesthesia so far? Were any complications during general anesthesia reported in any of the seven? Had any of the patients developed rhabdomyolysis so far? Central nervous system manifestations in McLeod syndrome not only include chorea, psychiatric disorders, or cognitive impairment but also seizures [2]. How many of the included patients had developed epilepsy? Were imaging studies of the cerebrum carried out in any of the patients? Did any of the seven patients experience a stroke since two had an atrial septal aneurysm and one an apical left ventricular diverticulum [3]? Which was the definition of the latter finding? Diagnosis of cardiomyopathy requires the exclusion of coronary heart disease by coronary angiography. Did any of the patients report anginal chest pain? How many had undergone coronary angiography? Did at least the patient with cardiomyopathy undergo coronary angiography? Which were the results? The authors state that patients with McLeod syndrome and cardiomyopathy are at risk for sudden cardiac death. On the contrary, sudden cardiac death has been only rarely reported in McLeod syndrome [1,2,4]. Which ECG abnormalities were assessed? How many patients showed ST- or T-wave abnormalities, tall QRScomplexes, or QT-prolongation?