Korean Circ J.  2016 Jul;46(4):456-467. 10.4070/kcj.2016.46.4.456.

Systemic Hemodynamic Atherothrombotic Syndrome and Resonance Hypothesis of Blood Pressure Variability: Triggering Cardiovascular Events

• Kario K

• KMID: 2344419
• DOI: http://doi.org/10.4070/kcj.2016.46.4.456

Abstract

Blood pressure (BP) exhibits different variabilities and surges with different time phases, from the shortest beat-by-beat to longest yearly changes. We hypothesized that the synergistic resonance of these BP variabilites generates an extraordinarily large dynamic surge in BP and triggers cardiovascular events (the resonance hypothesis). The power of pulses is transmitted to the peripheral sites without attenuation by the large arteries, in individuals with stiffened arteries. Thus, the effect of a BP surge on cardiovascular risk would be especially exaggerated in high-risk patients with vascular disease. Based on this concept, our group recently proposed a new theory of systemic hemodynamic atherothromboltic syndrome (SHATS), a vicious cycle of hemodynamic stress and vascular disease that advances organ damage and triggers cardiovascular disease. Clinical phenotypes of SHATS are large-artery atherothombotic diseases such as stroke, coronary artery disease, and aortic and pheripheral artery disease; small-artery diseases, and microcirculation-related disease such as vascular cognitive dysfunction, heart failure, and chronic kidney disease. The careful consideration of BP variability and vascular diseases such as SHATS, and the early detection and management of SHATS, will achieve more effective individualized cardiovascular protection. In the near future, information and communication technology-based 'anticipation medicine' predicted by the changes of individual BP values could be a promising approach to achieving zero cardiovascular events.

Keyword

Hypertension; Masked hypertension; Blood pressure; Remote sensing technology

MeSH Terms

Arteries
Blood Pressure*
Cardiovascular Diseases
Coronary Artery Disease
Heart Failure
Hemodynamics*
Humans
Hypertension
Masked Hypertension
Phenotype
Remote Sensing Technology
Renal Insufficiency, Chronic
Stroke
Vascular Diseases

Figure

• 

  Fig. 1 Information and communication technology (ICT)-based assessment of different types of BP variability and vascular damage in SHATS. ABPM: ambulatory blood pressure monitoring, BPM: blood pressure monitoring, SD: standard deviation, BP: blood pressure, SHATS: systemic hemodynamic atherothrombotic syndrome. Kario K., Hypertension 2015; 65:1163-9.

• 

  Fig. 2 The synergistic resonance hypothesis of BP variability. ABPM: ambulatory blood pressure monitoring, BPM: blood pressure monitoring, CV: cardiovascular, BRS: baroreceptor sensitivity. Kario K, Am J Hypertens 2016; 29:14-6.

• 

  Fig. 3 Concept of systemic hemodynamic atherothrombotic syndrome (SHATS). The SHATS is a disease condition that accelerates the risk of organ damage and cardiovascular events via a vicious cycle of hemodynamic stress and vascular disease. AI: augmentation index., ECG: electrocardiography, BNP: B-type natriuretic peptide, NT-ProBNP: N-Terminal-ProBNP, UACR: urinary albumin/creatinine ratio, PWV: pulse wave velocity, CAVI: cardio ankle vascular index, ABI: ankle-brachial index, FMD: flow-mediated dilatation. Kario K., Nature Review Nephrol 2013;9:726-38.

• 

  Fig. 4 Prevalence of MRI-detected silent cerebral infarcts and incidence of stroke events during a 42-month period, in elderly hypertensive patients with or without morning surge in blood pressure — the Jichi Medical University ABPM Study, Wave 1. *Matching for age and 24-hr systolic BP. Kario K. et al., Circulation 2003;107:1401-6.

• 

  Fig. 5 Ethnic differences in the degree of morning BP surge: the ARTEMIS study (811 Japanese and 2,887 Caucasians). Hoshide S. et al., Hypertension 2015;66:750-6.

• 

  Fig. 6 On-treatment morning home and office BP values and cardiovascular events in medicated hypertensive patients (the HONEST Study). Kario K. et al., Hypertension 2014; 64: 989-96.

• 

  Fig. 7 On-treatment BP and coronary artery disease (CAD) vs. stroke risk: Hazard ratio* HONEST Study (21,591 hypertensives patients were followed for >2 yr). *Adjusted for sex, age, family history of cardiovascular disease (CVD), dyslipidemia, diabetes mellitus, chronic kidney disease, history of CVD, and smoking status. Kario K. et al., J Am Coll Cardiol 2016;67:1519-27.

• 

  Fig. 8 Ambulatory BP definitions by 24-hr clock. Kario K. et al., Hypertension 2015; 66:1130-7.

• 

  Fig. 9 Differential time-dependent ambulatory systolic BP reduction 6-month after RDN (pooled data of SYMPLICITY HTN-J+3). RDN: renal denervation. Kario K. et al., Hypertension 2015; 66:1130-7.

• 

  Fig. 10A Morning systolic BP reduction 6 months after RDN (pooled data of SYMPLICITY HTN-J+3). BP: blood pressure, RDN: renal denervation. Kario K. et al., Hypertension 2015;66:1130-7.

• 

  Fig. 10B Nighttime systolic BP reduction 6 months after RDN (pooled data of SYMPLICITY HTN-J+3). BP: blood pressure, RDN: renal denervation. Kario K. et al., Hypertension 2015;66:1130-7.

• 

  Fig. 11 Hypothesis of 'perfect' 24-h BP control by renal denervation in resistant hypertension. BP: blood pressure. Kario K., Essential Manual of 24-hour Blood Pressure Management from Morning to Nocturnal Hypertension. London, UK; Wiley-Blackwell; 2015. p. 1-138.

Reference

1. Lawes CM, Bennett DA, Parag V, et al. Asia Pacific Cohort Studies Collaboration. Blood pressure indices and cardiovascular disease in the Asia Pacific region: a pooled analysis. Hypertension. 2003; 42:69–75.

2. Ueshima H, Sekikawa A, Miura K, et al. Cardiovascular disease and risk factors in Asia: a selected review. Circulation. 2008; 118:2702–2709.

3. Hoshide S, Wang J, Park SH, et al. Treatment considerations of clinical physician on hypertension management in Asia. Curr Hypertens Rev. 2016; 12:164–168.

4. Park JB, Kario K, Wang JG. Systolic hypertension: an increasing clinical challenge in Asia. Hypertens Res. 2015; 38:227–236.

5. Shimamoto K, Ando K, Fujita T, et al. Japanese Society of Hypertension Committee for Guidelines for the Management of Hypertension. The Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH 2014). Hypertens Res. 2014; 37:253–390.

6. Kario K. Essential manual of 24-hour blood pressure management from morning to nocturnal hypertension. London, UK: Wiley-Blackwell;2015. p. 1–138.

7. Pickering TG, Shimbo D, Haas D. Ambulatory blood-pressure monitoring. N Engl J Med. 2006; 354:2368–2374.

8. O'Brien E, Parati G, Stergiou G, et al. European Society of Hypertension Working Group on Blood Pressure Monitoring. European Society of Hypertension position paper on ambulatory blood pressure monitoring. J Hypertens. 2013; 31:1731–1768.

9. Imai Y, Ohkubo T, Sakuma M, et al. Predictive power of screening blood pressure, ambulatory blood pressure and blood pressure measured at home for overall and cardiovascular mortality: a prospective observation in a cohort from Ohasama, northern Japan. Blood Press Monit. 1996; 1:251–254.

10. Kario K, Shimada K, Schwartz JE, Matsuo T, Hoshide S, Pickering TG. Silent and clinically overt stroke in older Japanese subjects with white-coat and sustained hypertension. J Am Coll Cardiol. 2001; 38:238–245.

11. Kario K, Pickering TG, Umeda Y, et al. Morning surge in blood pressure as a predictor of silent and clinical cerebrovascular disease in elderly hypertensives: a prospective study. Circulation. 2003; 107:1401–1406.

12. Clement DL, De Buyzere ML, De Bacquer DA, et al. Office versus Ambulatory Pressure Study Investigators. Prognostic value of ambulatory blood-pressure recordings in patients with treated hypertension. N Engl J Med. 2003; 348:2407–2415.

13. Ohkubo T, Kikuya M, Metoki H, et al. Prognosis of "masked" hypertension and "white-coat" hypertension detected by 24-h ambulatory blood pressure monitoring 10-year follow-up from the Ohasama study. J Am Coll Cardiol. 2005; 46:508–515.

14. Kario K, Okura A, Okawara Y, Tomitani N, Ikemoto T, Hoshide S. Impact of introducing catheter-based renal denervation into Japan for hypertension management: Estimation of number of target patients and clinical relevance of ambulatory blood pressure reduction. Curr Hypertens Rev. 2016; 12:156–163.

15. Parati G, Ochoa JE, Lombardi C, Bilo G. Assessment and management of blood-pressure variability. Nat Rev Cardiol. 2013; 10:143–155.

16. Kario K. Prognosis in relation to blood pressure variability: Pro side of the argument. Hypertension. 2015; 65:1163–1169.

17. Kario K. New insight of morning blood pressure surge into the triggers of cardiovascular disease-synergistic resonance of blood pressure variability. Am J Hypertens. 2016; 29:14–16.

18. Kario K. Orthostatic hypertension-a new haemodynamic cardiovascular risk factor. Nat Rev Nephrol. 2013; 9:726–738.

19. Kario K. Proposal of a new strategy for ambulatory blood pressure profile-based management of resistant hypertension in the era of renal denervation. Hypertens Res. 2013; 36:478–484.

20. Kario K. Systemic hemodynamic atherothrombotic syndrome: a blind spot in the current management of hypertension. J Clin Hypertens (Greenwich). 2015; 17:328–331.

21. Kario K. Morning surge in blood pressure: a phenotype of systemic hemodynamic atherothrombotic syndrome. Am J Hypertens. 2015; 28:7–9.

22. Kario K, Hamasaki H. Nocturnal Blood Pressure Surge Behind Morning Surge in Obstructive Sleep apnea syndrome: another phenotype of systemic hemodynamic atherothrombotic syndrome. J Clin Hypertens (Greenwich). 2015; 17:682–685.

23. Kikuya M, Ohkubo T, Metoki H, et al. Day by-day variability of blood pressure and heart rate at home as a novel predictor of prognosis: the Ohasama study. Hypertension. 2008; 52:1045–1050.

24. Rothwell PM, Howard SC, Dolan E, et al. Prognostic significance of visit-to-visit variability, maximum systolic blood pressure, and episodic hypertension. Lancet. 2010; 375:895–905.

25. Matsui Y, Ishikawa J, Eguchi K, Shibasaki S, Shimada K, Kario K. Maximum value of home blood pressure: a novel indicator of target organ damage in hypertension. Hypertension. 2011; 57:1087–1093.

26. Muntner P, Shimbo D, Tonelli M, Reynolds K, Arnett DK, Oparil S. The relationship between visit-to-visit variability in systolic blood pressure and all-cause mortality in the general population: findings from NHANES III, 1988 to 1994. Hypertension. 2011; 57:160–166.

27. Matsui Y, O'Rourke MF, Hoshide S, Ishikawa J, Shimada K, Kario K. Combined effect of angiotensin II receptor blocker and either a calcium channel blocker or diuretic on day-by-day variability of home blood pressure: the Japan Combined Treatment With Olmesartan and a Calcium-Channel Blocker Versus Olmesartan and Diuretics Randomized Efficacy Study. Hypertension. 2012; 59:1132–1138.

28. Eguchi K, Hoshide S, Schwartz JE, Shimada K, Kario K. Visit-to-visit and ambulatory blood pressure variability as predictors of incident cardiovascular events in patients with hypertension. Am J Hypertens. 2012; 25:962–968.

29. Nagai M, Hoshide S, Ishikawa J, Shimada K, Kario K. Visit-to-visit blood pressure variations: new independent determinants for cognitive function in the elderly at high risk of cardiovascular disease. J Hypertens. 2012; 30:1556–1563.

30. Nagai M, Hoshide S, Nishikawa M, Shimada K, Kario K. Sleep duration and insomnia in the elderly: associations with blood pressure variability and carotid artery remodeling. Am J Hypertens. 2013; 26:981–989.

31. Nagai M, Kario K. Visit-to-visit blood pressure variability, silent cerebral injury, and risk of stroke. Am J Hypertens. 2013; 26:1369–1376.

32. Yokota K, Fukuda M, Matsui Y, Hoshide S, Shimada K, Kario K. Impact of visit-to-visit variability of blood pressure on deterioration of renal function in patients with non-diabetic chronic kidney disease. Hypertens Res. 2013; 36:151–157.

33. Kawai T, Ohishi M, Ito N, et al. Alteration of vascular function is an important factor in the correlation between visit-to-visit blood pressure variability and cardiovascular disease. J Hypertens. 2013; 31:1387–1395.

34. Kawai T, Ohishi M, Kamide K, et al. Differences between daytime and nighttime blood pressure variability regarding systemic atherosclerotic change and renal function. Hypertens Res. 2013; 36:232–239.

35. Fukui M, Ushigome E, Tanaka M, et al. Home blood pressure variability on one occasion is a novel factor associated with arterial stiffness in patients with type 2 diabetes. Hypertens Res. 2013; 36:219–225.

36. Endo K, Kario K, Koga M, et al. Impact of early blood pressure variability on stroke outcomes after thrombolysis: the SAMURAI rt-PA Registry. Stroke. 2013; 44:816–818.

37. Tanaka E, Koga M, Kobayashi J, et al. Blood pressure variability on antihypertensive therapy in acute intracerebral hemorrhage: the Stroke Acute Management with Urgent Risk-factor Assessment and Improvement-intracerebral hemorrhage study. Stroke. 2014; 45:2275–2279.

38. Wei FF, Li Y, Zhang L, et al. Beat-to-beat, reading-to-reading, and day-to-day blood pressure variability in relation to organ damage in untreated Chinese. Hypertension. 2014; 63:790–796.

39. Nagai M, Hoshide S, Nishikawa M, Masahisa S, Kario K. Visit-to-visit blood pressure variability in the elderly: associations with cognitive impairment and carotid artery remodeling. Atherosclerosis. 2014; 233:19–26.

40. Palatini P, Reboldi G, Beilin LJ, et al. Added predictive value of nighttime blood pressure variability for cardiovascular events and mortality: the Ambulatory Blood Pressure-International Study. Hypertension. 2014; 64:487–493.

41. Kagitani H, Hoshide S, Kario K. Optimal indicators of home BP variability in perimenopausal women and associations with albuminuria and reproducibility: The J-HOT home BP study. Am J Hypertens. 2015; 28:586–594.

42. Rakugi H, Ogihara T, Saruta T, et al. Preferable effects of olmesartan/calcium channel blocker to olmesartan/diuretic on blood pressure variability in very elderly hypertension: COLM study subanalysis. J Hypertens. 2015; 33:2165–2172.

43. Shibasaki S, Hoshide S, Eguchi K, Ishikawa J, Kario K. Japan Morning Surge-Home Blood Pressure (J-HOP) Study Group. Increase trend in home blood pressure on a single occasion is associated With B-type natriuretic peptide and the estimated glomerular filtration rate. Am J Hypertens. 2015; 28:1098–1105.

44. Liu Z, Zhao Y, Zhang H, et al. Excessive variability in systolic blood pressure that is self-measured at home exacerbates the progression of brain white matter lesions and cognitive impairment in the oldest old. Hypertens Res. 2016; 39:245–253.

45. Kario K, Tomitani N, Matsumoto Y, et al. Research and development of information and communication technology-based home blood pressure monitoring from morning to nocturnal hypertension. Ann Glob Health. 2016; 82:254–273.

46. Kario K, Eguchi K, Nakagawa Y, Motai K, Shimada K. Relationship between extreme dippers and orthostatic hypertension in elderly hypertensive patients. Hypertension. 1998; 31:77–82.

47. Kario K, Eguchi K, Hoshide S, et al. U-curve relationship between orthostatic blood pressure change and silent cerebrovascular disease in elderly hypertensives: orthostatic hypertension as a new cardiovascular risk factor. J Am Coll Cardiol. 2002; 40:133–141.

48. Kario K. Orthostatic hypertension: a measure of blood pressure variation for predicting cardiovascular risk. Circ J. 2009; 73:1002–1007.

49. Ito S, Nagasawa T, Abe M, Mori T. Strain vessel hypothesis: a viewpoint for linkage of albuminuria and cerebro-cardiovascular risk. Hypertens Res. 2009; 32:115–121.

50. Metoki H, Ohkubo T, Kikuya M, Asayama K, Obara T, Hashimoto J, Totsune K, Hoshi H, Satoh H, Imai Y. Prognostic significance for stroke of a morning pressor surge and a nocturnal blood pressure decline: the Ohasama study. Hypertension. 2006; 47:149–154.

51. Nakase T, Yoshioka S, Sasaki M, Suzuki A. Clinical evaluation of lacunar infarction and branch atheromatous disease. J Stroke Cerebrovasc Dis. 2013; 22:406–412.

52. Kario K, Pickering TG. Blood pressure variability in elderly patients. Lancet. 2000; 355:1645–1646.

53. Matsui Y, Eguchi K, Shibasaki S, et al. Japan morning Surge-1 Study Group. Impact of arterial stiffness reduction on urinary albumin excretion during antihypertensive treatment: the Japan morning Surge-1 study. J Hypertens. 2010; 28:1752–1760.

54. Kario K. Morning surge in blood pressure and cardiovascular risk – evidence and perspectives. Hypertension. 2010; 56:765–773.

55. Li Y, Thijs L, Hansen TW, et al. International Database on Ambulatory Blood Pressure Monitoring in Relation to Cardiovascular Outcomes Investigators. Prognostic value of the morning blood pressure surge in 5645 subjects from 8 populations. Hypertension. 2010; 55:1040–1048.

56. Luo Y, Wang YL, Wu YB, et al. Association between the rate of the morning surge in blood pressure and cardiovascular events and stroke. Chin Med J (Engl). 2013; 126:510–514.

57. Verdecchia P, Angeli F, Mazzotta G, et al. Day-night dip and early-morning surge in blood pressure in hypertension: prognostic implications. Hypertension. 2012; 60:34–42.

58. Bombelli M, Fodri D, Toso E, et al. Relationship among morning blood pressure surge, 24-hour blood pressure variability, and cardiovascular outcomes in a white population. Hypertension. 2014; 64:943–950.

59. Hoshide S, Kario K, de la Sierra A, et al. Ethnic differences in the degree of morning blood pressure surge and in its determinants between Japanese and European hypertensive subjects: data from the ARTEMIS study. Hypertension. 2015; 66:750–756.

60. Kario K. Caution for winter morning surge in blood pressure: a possible link with cardiovascular risk in the elderly. Hypertension. 2006; 47:139–140.

61. Murakami S, Otsuka K, Kubo Y, et al. Repeated ambulatory monitoring reveals a Monday morning surge in blood pressure in a community-dwelling population. Am J Hypertens. 2004; 17:1179–1183.

62. Kario K. Clinician's manual on early morning risk management in hypertension. London, UK: Science Press;2004. p. 1–68.

63. Kario K, Ishikawa J, Pickering TG, et al. Morning hypertension: the strongest independent risk factor for stroke in elderly hypertensive patients. Hypertens Res. 2006; 29:581–587.

64. Kario K, Eguchi K, Umeda Y, et al. Morning surge in blood pressure as a predictor of silent and clinical cerebrovascular disease in elderly hypertensives: response. Circulation. 2003; 108:e72–e73.

65. Hoshide S, Kario K, Yano Y, et al. J-HOP study group. Association of morning and evening blood pressure at home with asymptomatic organ damage in the J-HOP Study. Am J Hypertens. 2014; 27:939–947.

66. Kario K, Saito I, Kushiro T, et al. Home blood pressure and cardiovascular outcomes in patients during antihypertensive therapy: primary results of HONEST, a large-scale prospective, real-world observational study. Hypertension. 2014; 64:989–996.

67. Kario K. Benefits of strict blood-pressure lowering in hypertension. Nat Rev Cardiol. 2016; 13:125–126.

68. Kario K, Saito I, Kushiro T, et al. Morning home blood pressure is a strong predictor of coronary artery disease. J Am Coll Cardiol. 2016; 67:1519–1527.

69. Panza JA, Epstein SE, Quyyumi AA. Circadian variation in vascular tone and its relation to alpha-sympathetic vasoconstrictor activity. N Engl J Med. 1991; 325:986–990.

70. Kario K, Pickering TG, Hoshide S, et al. Morning blood pressure surge and hypertensive cerebrovascular disease: role of the alpha adrenergic sympathetic nervous system. Am J Hypertens. 2004; 17:668–675.

71. Kario K, Matsui Y, Shibasaki S, et al. Japan Morning Surge-1 (JMS-1) Study Group. Japan Morning Surge-1 (JMS-1) Study Group. An alpha-adrenergic blocker titrated by self-measured blood pressure recordings lowered blood pressure and microalbuminuria in patients with morning hypertension: the Japan Morning Surge-1 Study. J Hypertens. 2008; 26:1257–1265.

72. Krum H, Schlaich MP, Sobotka PA, et al. Percutaneous renal denervation in patients with treatment-resistant hypertension: final 3-year report of the Symplicity HTN-1 study. Lancet. 2014; 383:622–629.

73. Esler MD, Krum H, Schlaich M, et al. Symplicity HTN-2 Investigators. Renal sympathetic denervation for treatment of drug-resistant hypertension: one-year results from the Symplicity HTN-2 randomized, controlled trial. Circulation. 2012; 126:2976–2982.

74. Hering D, Lambert EA, Marusic P, et al. Substantial reduction in single sympathetic nerve firing after renal denervation in patients with resistant hypertension. Hypertension. 2013; 61:457–464.

75. Schlaich MP, Sobotka PA, Krum H, Lambert E, Esler MD. Renal sympathetic-nerve ablation for uncontrolled hypertension. N Engl J Med. 2009; 361:932–934.

76. Kario K, Ogawa H, Okumura K, et al. SYMPLICITY HTN-Japan Investigators. SYMPLICITY HTN-Japan—first randomized controlled trial of catheterbased renal denervation in Asian patients. Circ J. 2015; 79:1222–1229.

77. Bhatt DL, Kandzari DE, O'Neill WW, et al. SYMPLICITY HTN-3 Investigators. A controlled trial of renal denervation for resistant hypertension. N Engl J Med. 2014; 370:1393–1401.

78. Kario K, Bhatt DL, Brar S, Cohen SA, Fahy M, Bakris GL. Effect of Catheter-Based Renal Denervation on Morning and Nocturnal Blood Pressure: Insights From SYMPLICITY HTN-3 and SYMPLICITY HTN-Japan. Hypertension. 2015; 66:1130–1137.

79. Kario K. Obstructive sleep apnea syndrome and hypertension: ambulatory blood pressure. Hypertens Res. 2009; 32:428–432.

80. Shirasaki O, Kuwabara M, Saito M, Tagami K, Washiya S, Kario K. Development and clinical application of a new technique for detecting 'sleep blood pressure surges' in sleep apnea patients based on a variable desaturation threshold. Hypertens Res. 2011; 34:922–928.

81. Kario K, Kuwabara M, Hoshide S, Nagai M, Shimpo M. Effects of nighttime single-dose administration of vasodilating vs. sympatholytic antihypertensive agents on sleep blood pressure in hypertensive patients with sleep apnea syndrome. J Clin Hypertens (Greenwich). 2014; 16:459–466.

82. Kuwabara M, Kario K. Development of a triggered nocturnal blood pressure monitoring which detects nighttime blood pressure surges in sleep apnea syndrome. Curr Hypertens Rev. 2016; 12:27–31.

83. Yoshida T, Kuwabara M, Hoshide S, Kario K. Recurrence of stroke caused by nocturnal hypoxia-induced blood pressure surge in a young adult male with severe obstructive sleep apnea syndrome. J Am Soc Hypertens. 2016; 10:201–204.

84. Kario K, Ikemoto T, Kuwabara M, Ishiyama H, Saito K, Hoshide S. Catheter-based renal denervation reduces hypoxia-triggered nocturnal blood pressure peak in obstructive sleep apnea syndrome. J Clin Hypertens (Greenwich). 2015; [in press].

85. Kario K, Bhatt DL, Kandzari DE, et al. Impact of renal denervation on patients with obstructive sleep apnea and resistant hypertension: insights from the SYMPLICITY HTN-3 trial. Circ J. 2016; 80:1404–1412.

86. Kim BK, Böhm M, Mahfoud F, et al. Renal denervation for treatment of uncontrolled hypertension in an Asian population: results from the Global SYMPLICITY Registry in South Korea (GSR Korea). J Hum Hypertens. 2016; 30:315–321.

87. Kandzari D, Kario K, Mahfoud F, et al. The SPYRAL HTN global clinical trial program: rationale and design for studies of renal denervation in the absence (SPYRAL HTN OFF-MED) and presence (SPYRAL HTN ON-MED) of antihypertensive medications. Am Heart J. 2016; 171:82–91.