Editorial Comment Cardiology 2014;129:25–27 DOI: 10.1159/000363283
Received: April 28, 2014 Accepted: April 28, 2014 Published online: June 25, 2014
Non-Dipping Heart Rate, Microalbuminuria and Thrombocytosis in Type 2 Diabetes Mellitus: Can We Connect the Dots? Bharat K. Kantharia Memorial Hermann Hospital and Heart and Vascular Institute, Houston, Tex., USA
© 2014 S. Karger AG, Basel 0008–6312/14/1291–0025$39.50/0 E-Mail [email protected] www.karger.com/crd
Pertinent to the study, the cohort consisted of 179 patients (60% male) with T2DM and proliferative retinopathy. These patients with long-standing DM underwent extensive investigations, including 24-hour ambulatory BP monitoring, urinary albumin-creatinine ratio, and tests for peripheral neuropathy, peripheral vascular disease, insulin resistance and active inflammation. Surprisingly, information on whether or not investigations such as ECGs, echocardiograms, stress tests and Holter monitoring were performed in these high-risk patients for associated CV disorders is lacking. The main finding of the study is that patients with non-dipping HR independently had a significantly higher logarithmic albumin-creatinine ratio and higher platelet counts. The authors conclude that non-dipping HR might give an indication of underlying generalized atherosclerosis in diabetic patients [5]. ‘Non-dipping BP’ and ‘non-dipping HR’ are defined when, during sleep, there is lack of a nocturnal drop by 10–20% of their average respective values during the daytime, wakeful period. Because the sympathetic and parasympathetic inputs during wakefulness and sleep are different, both non-dipping BP and non-dipping HR may provide information regarding ANS dysfunction. Such information may not concur with each other as HR is less dependent than BP on physical exercise. Thus, HR data may provide different insights compared to other tests and methodologies, e.g. HR variability. The most practiBharat K. Kantharia, MD, FRCP, FAHA, FACC, FESC, FHRS 5616 Jackson Street, Unit 2315 Houston, TX 77030 (USA) E-Mail bkantharia @ yahoo.com
Downloaded by: Univ. of Michigan, Taubman Med.Lib. 198.143.32.1 - 7/4/2015 11:24:55 AM
Many studies have shown a significant association between heart rate (HR) and cardiovascular (CV) and allcause mortality in the general population and individuals with various diseases [1–3]. Described by simple numbers, HR and blood pressure (BP) are in fact determined by a complex interplay of sympathetic and parasympathetic components of the autonomic nervous system (ANS) on the cardiac electrical system, baroreceptors, vascular tone, endothelial function and cardiac contractility in response to different stimuli in physiological and pathological conditions. Many abnormalities of HR and BP are observed in diabetes mellitus (DM), whether type 1 or type 2 (T2DM), due to its propensity to cause cardiac autonomic neuropathy (CAN). Given the complex problem of CAN, the CAN Subcommittee of the Toronto Consensus Panel on Diabetic Neuropathy has published a consensus document which discusses epidemiology, guidelines on definitions and staging, standardization of diagnostic criteria, and therapeutic approach, etc. [4]. The question of whether ANS dysfunction in diabetics is merely a marker or causative factor to target end-organ damage (TOD), including retinopathy, nephropathy and CV complications, has continued to stimulate research interest. To that end, the study relating microalbuminuria, high platelet counts and non-dipping HR in patients with T2DM by Magri et al. [5] in this issue of Cardiology is a welcome addition to an already existing pool of studies.
26
Cardiology 2014;129:25–27 DOI: 10.1159/000363283
and autonomic neuropathy had higher MPV. Higher MPV was also seen in patients with microvascular complications, such as retinopathy and microalbuminuria [15]. Higher platelet count as an independent predictor of diabetic nephropathy in T2DM has also been shown previously by Magri et al. [16]. Associations of higher MPV and various parameters of HR variability, including mean HR, low frequency band, and low frequency/high frequency ratio after acute myocardial infarction, reflective of sympathovagal imbalance with dominant sympathetic activity, have also been reported [17]. DM is a dreadful disease that affects millions of people worldwide. After so much ongoing multi-level research, we have not yet completely understood the pathophysiologies of numerous diabetes-related disease processes, such as atherosclerosis, angiogenesis, endothelial dysfunction, apoptosis and immunomodulation, and the list goes on! For example, pertaining to the study by Magri et al. [5], how can we effectively tie in the findings of the ‘non-dipping’ HR to retinopathy, nephropathy and TOD? How does non-dipping HR stimulate atherogenesis? Is ‘non-dipping’ HR all due to an overacting sympathetic system? Why do the parasympathetic dominance forces fail? Like many, as a clinician who wishes to have a comprehensive approach not just to treat what has already manifested, but also to prevent much that is at the subclinical level, I constantly wonder if there is any way we can effectively connect the dots that we already know and the ones that we will discover in the future.
Conflict of Interest None.
References
1 Kannel WB, Kannel C, Paffenbarger RS Jr, et al: Heart rate and cardiovascular mortality: the Framingham Study. Am Heart J 1987;113: 1489–1494. 2 Gillman MW, Kannel WB, Belanger A, et al: Influence of heart rate on mortality among persons with hypertension: the Framingham Study. Am Heart J 1993;125:1148–1154. 3 Fox K, Borer JS, Camm AJ, et al: Resting heart rate in cardiovascular disease. J Am Coll Cardiol 2007;50:823–830. 4 Spallone V, Ziegler D, Freeman R, et al: Cardiovascular autonomic neuropathy in diabetes: clinical impact, assessment, diagnosis, and management. Diabetes Metab Res Rev 2011;27:639–653.
Kantharia
Downloaded by: Univ. of Michigan, Taubman Med.Lib. 198.143.32.1 - 7/4/2015 11:24:55 AM
cal method to assess non-dipping BP and HR is by 24hour ambulatory BP monitoring recordings. The association of non-dipping BP with a higher incidence of TOD and CV complications is well known [6]. Its ominous role in the development of TOD in diabetic patients is evident in a study by Torbjörnsdotter et al. [7], in which normoalbuminuric patients with T2DM who had non-dipping BP were found to have significantly more basement membrane thickness and larger mesangial matrix volume fraction by electron microscopic examination of renal biopsies, and higher long-term glomerular filtration rate. Interestingly, positive correlations were found not only between HR with BP, but also between HR and basement membrane thickness, mesangial matrix volume fraction, and mean previous filtration fraction [7]. This strengthens the notion that non-dipping HR is a direct causal factor in the development of nephropathy and other TOD in patients with DM. In a study by Ben-Dov et al. [8], non-dipping HR showed significant links with several clinical variables, namely age, gender, obesity, hypertension and diabetes. Importantly, all-cause mortality analysis according to the deciles of different HR showed a very strong linear relationship only for HR dip, with a hazard ratio of 2.67 (1.31–5.47) for the lowest versus highest decile [8]. Besides all-cause mortality, non-dipping HR has also been shown to increase CV disease events, such as stroke, myocardial infarction and sudden cardiac death [9, 10]. In a study by Eguchi et al. [10], in which non-dipping HR was shown to increase CV events (hazard ratio 2.37, 95% CI 1.22–4.62), 44% of the study cohort in fact had T2DM, and the relationship of non-dipping HR to increased CV events was not dependent on non-dipping BP or the status of DM. Utilizing conventional cardiac autonomic reflex testing and HR variability parameters in patients with T2DM, CAN has also been shown to correlate with microalbuminuria and low glomerular filtration rate [11–13]. It has also been suggested that variability of BP and HR with ‘dipping’ and ‘non-dipping’ traits may be partially under genetic control and that genetic loci could be mapped by linkage analysis [14]. As regards to platelets, the relationship of their absolute number, volume and function to ANS and DM is enormously complex. In a large cohort of patients with and without T2DM, Kodiatte et al. [15] found a higher mean platelet count and mean platelet volume (MPV) in the diabetic group. Elevated MPV was found to have a strong positive correlation with glycosylated hemoglobin and blood sugar levels. Additionally, 62% of T2DM patients who had TOD, CV complications, and peripheral
Association of Non-Dipping HR and Microalbuminuria
10 Eguchi K, Hoshide S, Ishikawa J, et al: Nocturnal nondipping of heart rate predicts cardiovascular events in hypertensive patients. J Hypertens 2009;27:2265–2270. 11 Moran A, Palmas W, Field L, et al: Cardiovascular autonomic neuropathy is associated with microalbuminuria in older patients with type 2 diabetes. Diabetes Care 2004; 27: 972– 977. 12 Smulders YM, Jager A, Gerritsen J, et al: Cardiovascular autonomic function is associated with (micro-)albuminuria in elderly Caucasian subjects with impaired glucose tolerance or type 2 diabetes: the Hoorn Study. Diabetes Care 2000;23:1369–1374. 13 Tahrani AA, Dubb K, Raymond NT, et al: Cardiac autonomic neuropathy predicts renal function decline in patients with type 2 diabetes: a cohort study. Diabetologia 2014; 57: 1249–1256.
14 Fava C, Burri P, Almgren A, et al: Dipping and variability of blood pressure and heart rate at night are heritable traits. Am J Hypertens 2005;18:1402–1407. 15 Kodiatte TA, Manikyam UK, Rao SB, et al: Mean platelet volume in type 2 diabetes mellitus. J Lab Physicians 2012;4:5–9. 16 Magri CJ, Calleja N, Buhagiar G, et al: Factors associated with diabetic nephropathy in subjects with proliferative retinopathy. Int Urol Nephrol 2012;44:197–206. 17 Ozdemir O, Soylu M, Alyan O, et al: Association between mean platelet volume and autonomic nervous system functions: increased mean platelet volume reflects sympathetic overactivity. Exp Clin Cardiol 2004; 9: 243– 247.
Cardiology 2014;129:25–27 DOI: 10.1159/000363283
27
Downloaded by: Univ. of Michigan, Taubman Med.Lib. 198.143.32.1 - 7/4/2015 11:24:55 AM
5 Magri CJ, Xuereb RG, Fava S: Non-dipping heart rate and microalbuminuria in type 2 diabetes mellitus. Cardiology 2014;129:28–35. 6 Krzych ŁJ, Bochenek A: Blood pressure variability: epidemiological and clinical issues. Cardiol J 2013;20:112–120. 7 Torbjörnsdotter TB, Jaremko GA, Berg UB: Nondipping and its relation to glomerulopathy and hyperfiltration in adolescents with type 1 diabetes. Diabetes Care 2004; 27: 510– 516. 8 Ben-Dov IZ, Kark JD, Ben-Ishay D, et al: Blunted heart rate dip during sleep and allcause mortality. Arch Intern Med 2007; 167: 2116–2121. 9 Verdecchia P, Schillaci G, Borgioni C, et al: Adverse prognostic value of a blunted circadian rhythm of heart rate in essential hypertension. J Hypertens 1998;16:1335–1343.
Received: April 28, 2014 Accepted: April 28, 2014 Published online: June 25, 2014
Non-Dipping Heart Rate, Microalbuminuria and Thrombocytosis in Type 2 Diabetes Mellitus: Can We Connect the Dots? Bharat K. Kantharia Memorial Hermann Hospital and Heart and Vascular Institute, Houston, Tex., USA
© 2014 S. Karger AG, Basel 0008–6312/14/1291–0025$39.50/0 E-Mail [email protected] www.karger.com/crd
Pertinent to the study, the cohort consisted of 179 patients (60% male) with T2DM and proliferative retinopathy. These patients with long-standing DM underwent extensive investigations, including 24-hour ambulatory BP monitoring, urinary albumin-creatinine ratio, and tests for peripheral neuropathy, peripheral vascular disease, insulin resistance and active inflammation. Surprisingly, information on whether or not investigations such as ECGs, echocardiograms, stress tests and Holter monitoring were performed in these high-risk patients for associated CV disorders is lacking. The main finding of the study is that patients with non-dipping HR independently had a significantly higher logarithmic albumin-creatinine ratio and higher platelet counts. The authors conclude that non-dipping HR might give an indication of underlying generalized atherosclerosis in diabetic patients [5]. ‘Non-dipping BP’ and ‘non-dipping HR’ are defined when, during sleep, there is lack of a nocturnal drop by 10–20% of their average respective values during the daytime, wakeful period. Because the sympathetic and parasympathetic inputs during wakefulness and sleep are different, both non-dipping BP and non-dipping HR may provide information regarding ANS dysfunction. Such information may not concur with each other as HR is less dependent than BP on physical exercise. Thus, HR data may provide different insights compared to other tests and methodologies, e.g. HR variability. The most practiBharat K. Kantharia, MD, FRCP, FAHA, FACC, FESC, FHRS 5616 Jackson Street, Unit 2315 Houston, TX 77030 (USA) E-Mail bkantharia @ yahoo.com
Downloaded by: Univ. of Michigan, Taubman Med.Lib. 198.143.32.1 - 7/4/2015 11:24:55 AM
Many studies have shown a significant association between heart rate (HR) and cardiovascular (CV) and allcause mortality in the general population and individuals with various diseases [1–3]. Described by simple numbers, HR and blood pressure (BP) are in fact determined by a complex interplay of sympathetic and parasympathetic components of the autonomic nervous system (ANS) on the cardiac electrical system, baroreceptors, vascular tone, endothelial function and cardiac contractility in response to different stimuli in physiological and pathological conditions. Many abnormalities of HR and BP are observed in diabetes mellitus (DM), whether type 1 or type 2 (T2DM), due to its propensity to cause cardiac autonomic neuropathy (CAN). Given the complex problem of CAN, the CAN Subcommittee of the Toronto Consensus Panel on Diabetic Neuropathy has published a consensus document which discusses epidemiology, guidelines on definitions and staging, standardization of diagnostic criteria, and therapeutic approach, etc. [4]. The question of whether ANS dysfunction in diabetics is merely a marker or causative factor to target end-organ damage (TOD), including retinopathy, nephropathy and CV complications, has continued to stimulate research interest. To that end, the study relating microalbuminuria, high platelet counts and non-dipping HR in patients with T2DM by Magri et al. [5] in this issue of Cardiology is a welcome addition to an already existing pool of studies.
26
Cardiology 2014;129:25–27 DOI: 10.1159/000363283
and autonomic neuropathy had higher MPV. Higher MPV was also seen in patients with microvascular complications, such as retinopathy and microalbuminuria [15]. Higher platelet count as an independent predictor of diabetic nephropathy in T2DM has also been shown previously by Magri et al. [16]. Associations of higher MPV and various parameters of HR variability, including mean HR, low frequency band, and low frequency/high frequency ratio after acute myocardial infarction, reflective of sympathovagal imbalance with dominant sympathetic activity, have also been reported [17]. DM is a dreadful disease that affects millions of people worldwide. After so much ongoing multi-level research, we have not yet completely understood the pathophysiologies of numerous diabetes-related disease processes, such as atherosclerosis, angiogenesis, endothelial dysfunction, apoptosis and immunomodulation, and the list goes on! For example, pertaining to the study by Magri et al. [5], how can we effectively tie in the findings of the ‘non-dipping’ HR to retinopathy, nephropathy and TOD? How does non-dipping HR stimulate atherogenesis? Is ‘non-dipping’ HR all due to an overacting sympathetic system? Why do the parasympathetic dominance forces fail? Like many, as a clinician who wishes to have a comprehensive approach not just to treat what has already manifested, but also to prevent much that is at the subclinical level, I constantly wonder if there is any way we can effectively connect the dots that we already know and the ones that we will discover in the future.
Conflict of Interest None.
References
1 Kannel WB, Kannel C, Paffenbarger RS Jr, et al: Heart rate and cardiovascular mortality: the Framingham Study. Am Heart J 1987;113: 1489–1494. 2 Gillman MW, Kannel WB, Belanger A, et al: Influence of heart rate on mortality among persons with hypertension: the Framingham Study. Am Heart J 1993;125:1148–1154. 3 Fox K, Borer JS, Camm AJ, et al: Resting heart rate in cardiovascular disease. J Am Coll Cardiol 2007;50:823–830. 4 Spallone V, Ziegler D, Freeman R, et al: Cardiovascular autonomic neuropathy in diabetes: clinical impact, assessment, diagnosis, and management. Diabetes Metab Res Rev 2011;27:639–653.
Kantharia
Downloaded by: Univ. of Michigan, Taubman Med.Lib. 198.143.32.1 - 7/4/2015 11:24:55 AM
cal method to assess non-dipping BP and HR is by 24hour ambulatory BP monitoring recordings. The association of non-dipping BP with a higher incidence of TOD and CV complications is well known [6]. Its ominous role in the development of TOD in diabetic patients is evident in a study by Torbjörnsdotter et al. [7], in which normoalbuminuric patients with T2DM who had non-dipping BP were found to have significantly more basement membrane thickness and larger mesangial matrix volume fraction by electron microscopic examination of renal biopsies, and higher long-term glomerular filtration rate. Interestingly, positive correlations were found not only between HR with BP, but also between HR and basement membrane thickness, mesangial matrix volume fraction, and mean previous filtration fraction [7]. This strengthens the notion that non-dipping HR is a direct causal factor in the development of nephropathy and other TOD in patients with DM. In a study by Ben-Dov et al. [8], non-dipping HR showed significant links with several clinical variables, namely age, gender, obesity, hypertension and diabetes. Importantly, all-cause mortality analysis according to the deciles of different HR showed a very strong linear relationship only for HR dip, with a hazard ratio of 2.67 (1.31–5.47) for the lowest versus highest decile [8]. Besides all-cause mortality, non-dipping HR has also been shown to increase CV disease events, such as stroke, myocardial infarction and sudden cardiac death [9, 10]. In a study by Eguchi et al. [10], in which non-dipping HR was shown to increase CV events (hazard ratio 2.37, 95% CI 1.22–4.62), 44% of the study cohort in fact had T2DM, and the relationship of non-dipping HR to increased CV events was not dependent on non-dipping BP or the status of DM. Utilizing conventional cardiac autonomic reflex testing and HR variability parameters in patients with T2DM, CAN has also been shown to correlate with microalbuminuria and low glomerular filtration rate [11–13]. It has also been suggested that variability of BP and HR with ‘dipping’ and ‘non-dipping’ traits may be partially under genetic control and that genetic loci could be mapped by linkage analysis [14]. As regards to platelets, the relationship of their absolute number, volume and function to ANS and DM is enormously complex. In a large cohort of patients with and without T2DM, Kodiatte et al. [15] found a higher mean platelet count and mean platelet volume (MPV) in the diabetic group. Elevated MPV was found to have a strong positive correlation with glycosylated hemoglobin and blood sugar levels. Additionally, 62% of T2DM patients who had TOD, CV complications, and peripheral
Association of Non-Dipping HR and Microalbuminuria
10 Eguchi K, Hoshide S, Ishikawa J, et al: Nocturnal nondipping of heart rate predicts cardiovascular events in hypertensive patients. J Hypertens 2009;27:2265–2270. 11 Moran A, Palmas W, Field L, et al: Cardiovascular autonomic neuropathy is associated with microalbuminuria in older patients with type 2 diabetes. Diabetes Care 2004; 27: 972– 977. 12 Smulders YM, Jager A, Gerritsen J, et al: Cardiovascular autonomic function is associated with (micro-)albuminuria in elderly Caucasian subjects with impaired glucose tolerance or type 2 diabetes: the Hoorn Study. Diabetes Care 2000;23:1369–1374. 13 Tahrani AA, Dubb K, Raymond NT, et al: Cardiac autonomic neuropathy predicts renal function decline in patients with type 2 diabetes: a cohort study. Diabetologia 2014; 57: 1249–1256.
14 Fava C, Burri P, Almgren A, et al: Dipping and variability of blood pressure and heart rate at night are heritable traits. Am J Hypertens 2005;18:1402–1407. 15 Kodiatte TA, Manikyam UK, Rao SB, et al: Mean platelet volume in type 2 diabetes mellitus. J Lab Physicians 2012;4:5–9. 16 Magri CJ, Calleja N, Buhagiar G, et al: Factors associated with diabetic nephropathy in subjects with proliferative retinopathy. Int Urol Nephrol 2012;44:197–206. 17 Ozdemir O, Soylu M, Alyan O, et al: Association between mean platelet volume and autonomic nervous system functions: increased mean platelet volume reflects sympathetic overactivity. Exp Clin Cardiol 2004; 9: 243– 247.
Cardiology 2014;129:25–27 DOI: 10.1159/000363283
27
Downloaded by: Univ. of Michigan, Taubman Med.Lib. 198.143.32.1 - 7/4/2015 11:24:55 AM
5 Magri CJ, Xuereb RG, Fava S: Non-dipping heart rate and microalbuminuria in type 2 diabetes mellitus. Cardiology 2014;129:28–35. 6 Krzych ŁJ, Bochenek A: Blood pressure variability: epidemiological and clinical issues. Cardiol J 2013;20:112–120. 7 Torbjörnsdotter TB, Jaremko GA, Berg UB: Nondipping and its relation to glomerulopathy and hyperfiltration in adolescents with type 1 diabetes. Diabetes Care 2004; 27: 510– 516. 8 Ben-Dov IZ, Kark JD, Ben-Ishay D, et al: Blunted heart rate dip during sleep and allcause mortality. Arch Intern Med 2007; 167: 2116–2121. 9 Verdecchia P, Schillaci G, Borgioni C, et al: Adverse prognostic value of a blunted circadian rhythm of heart rate in essential hypertension. J Hypertens 1998;16:1335–1343.
