Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

A pathophysiological compass to personalize antianginal drug treatment

Nature Reviews Cardiology volume 18, pages 838–852 (2021)Cite this article

Subjects

Abstract

Myocardial ischaemia results from coronary macrovascular or microvascular dysfunction compromising the supply of oxygen and nutrients to the myocardium. The underlying pathophysiological processes are manifold and encompass atherosclerosis of epicardial coronary arteries, vasospasm of large or small vessels and microvascular dysfunction — the clinical relevance of which is increasingly being appreciated. Myocardial ischaemia can have a broad spectrum of clinical manifestations, together denoted as chronic coronary syndromes. The most common antianginal medications relieve symptoms by eliciting coronary vasodilatation and modulating the determinants of myocardial oxygen consumption, that is, heart rate, myocardial wall stress and ventricular contractility. In addition, cardiac substrate metabolism can be altered to alleviate ischaemia by modulating the efficiency of myocardial oxygen use. Although a universal agreement exists on the prognostic importance of lifestyle interventions and event prevention with aspirin and statin therapy, the optimal antianginal treatment for patients with chronic coronary syndromes is less well defined. The 2019 guidelines of the ESC recommend a personalized approach, in which antianginal medications are tailored towards an individual patient’s comorbidities and haemodynamic profile. Although no antianginal medication improves survival, their efficacy for reducing symptoms profoundly depends on the underlying mechanism of the angina. In this Review, we provide clinicians with a rationale for when to use which compound or combination of drugs on the basis of the pathophysiology of the angina and the mode of action of antianginal medications.

Key points

  • Antianginal therapies improve coronary vascular oxygen supply to the ischaemic myocardium; reduce heart rate, myocardial work and oxygen consumption; or optimize the energetic efficiency of cardiomyocytes.

  • So far, neither drugs nor interventions that reduce ischaemia prolong survival in patients with chronic coronary syndromes.

  • Although current guidelines recommend β-blockers and calcium-channel blockers as first-line therapy, no evidence exists that these agents are superior to second-line therapies.

  • We provide a compass for the use of antianginal compounds in patients with chronic coronary syndromes that is tailored towards their haemodynamic status, left ventricular function and comorbidities.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: The haemodynamics of coronary blood flow.
Fig. 2: Cardiac mechano-energetic coupling in the normal and ischaemic heart.
Fig. 3: Modes of action of antianginal drugs, influencing oxygen consumption or supply.
Fig. 4: Mechanisms of nitrate-induced vasodilatation.
Fig. 5: Modulating cardiac metabolism to treat angina.
Fig. 6: Antianginal compass.

References

  1. Crea, F., Camici, P. G. & Bairey Merz, C. N. Coronary microvascular dysfunction: an update. Eur. Heart J. 35, 1101–1111 (2014).

    PubMed  Google Scholar 

  2. Knuuti, J. et al. 2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes. Eur. Heart J. 41, 407–477 (2019).

    Google Scholar 

  3. Boden, W. E. et al. Optimal medical therapy with or without PCI for stable coronary disease. N. Engl. J. Med. 356, 1503–1516 (2007).

    CAS  PubMed  Google Scholar 

  4. BARI 2D Study Group. et al. A randomized trial of therapies for type 2 diabetes and coronary artery disease. N. Engl. J. Med. 360, 2503–2515 (2009).

    Google Scholar 

  5. Xaplanteris, P. et al. Five-year outcomes with PCI guided by fractional flow reserve. N. Engl. J. Med. 379, 250–259 (2018).

    PubMed  Google Scholar 

  6. Maron, D. J. et al. Initial invasive or conservative strategy for stable coronary disease. N. Engl. J. Med. 382, 1395–1407 (2020).

    PubMed  PubMed Central  Google Scholar 

  7. Dargie, H. J., Ford, I. & Fox, K. M. Total Ischaemic Burden European Trial (TIBET). Effects of ischaemia and treatment with atenolol, nifedipine SR and their combination on outcome in patients with chronic stable angina. The TIBET Study Group. Eur. Heart J. 17, 104–112 (1996).

    CAS  PubMed  Google Scholar 

  8. Rehnqvist, N. et al. Effects of metoprolol vs verapamil in patients with stable angina pectoris. The Angina Prognosis Study in Stockholm (APSIS). Eur. Heart J. 17, 76–81 (1996).

    CAS  PubMed  Google Scholar 

  9. Pepine, C. J. et al. A calcium antagonist vs a non-calcium antagonist hypertension treatment strategy for patients with coronary artery disease. The International Verapamil-Trandolapril Study (INVEST): a randomized controlled trial. JAMA 290, 2805–2816 (2003).

    CAS  PubMed  Google Scholar 

  10. Nissen, S. E. et al. Effect of antihypertensive agents on cardiovascular events in patients with coronary disease and normal blood pressure: the CAMELOT study: a randomized controlled trial. JAMA 292, 2217–2225 (2004).

    CAS  PubMed  Google Scholar 

  11. Poole-Wilson, P. A. et al. Effect of long-acting nifedipine on mortality and cardiovascular morbidity in patients with stable angina requiring treatment (ACTION trial): randomised controlled trial. Lancet 364, 849–857 (2004).

    CAS  PubMed  Google Scholar 

  12. Morrow, D. A. et al. Effects of ranolazine on recurrent cardiovascular events in patients with non-ST-elevation acute coronary syndromes: the MERLIN-TIMI 36 randomized trial. JAMA 297, 1775–1783 (2007).

    CAS  PubMed  Google Scholar 

  13. Fox, K., Ford, I., Steg, P. G., Tendera, M. & Ferrari, R. Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomised, double-blind, placebo-controlled trial. Lancet 372, 807–816 (2008).

    CAS  PubMed  Google Scholar 

  14. Bangalore, S., Parkar, S. & Messerli, F. H. Long-acting calcium antagonists in patients with coronary artery disease: a meta-analysis. Am. J. Med. 122, 356–365 (2009).

    CAS  PubMed  Google Scholar 

  15. Fox, K. et al. Ivabradine in stable coronary artery disease without clinical heart failure. N. Engl. J. Med. 371, 1091–1099 (2014).

    PubMed  Google Scholar 

  16. Weisz, G. et al. Ranolazine in patients with incomplete revascularisation after percutaneous coronary intervention (RIVER-PCI): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet 387, 136–145 (2016).

    CAS  PubMed  Google Scholar 

  17. Sorbets, E. et al. β-blockers, calcium antagonists, and mortality in stable coronary artery disease: an international cohort study. Eur. Heart J. 40, 1399–1407 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Ferrari, R. et al. Efficacy and safety of trimetazidine after percutaneous coronary intervention (ATPCI): a randomised, double-blind, placebo-controlled trial. Lancet 396, 830–838 (2020).

    PubMed  Google Scholar 

  19. Nakamura, Y., Moss, A. J., Brown, M. W., Kinoshita, M. & Kawai, C. Long-term nitrate use may be deleterious in ischemic heart disease: a study using the databases from two large-scale postinfarction studies. Multicenter Myocardial Ischemia Research Group. Am. Heart J. 138, 577–585 (1999).

    CAS  PubMed  Google Scholar 

  20. Glasser, S. P. et al. Is randomization to placebo safe? Risk in placebo-controlled angina trials: angina risk meta-analysis. Cardiology 120, 174–181 (2011).

    CAS  PubMed  Google Scholar 

  21. Takahashi, J. et al. Prognostic impact of chronic nitrate therapy in patients with vasospastic angina: multicentre registry study of the Japanese coronary spasm association. Eur. Heart J. 36, 228–237 (2015).

    CAS  PubMed  Google Scholar 

  22. Fox, K. A. A., Metra, M., Morais, J. & Atar, D. The myth of ‘stable’ coronary artery disease. Nat. Rev. Cardiol. 17, 9–21 (2020).

    CAS  PubMed  Google Scholar 

  23. Patrono, C. & Baigent, C. Role of aspirin in primary prevention of cardiovascular disease. Nat. Rev. Cardiol. 16, 675–686 (2019).

    PubMed  Google Scholar 

  24. Adhyaru, B. B. & Jacobson, T. A. Safety and efficacy of statin therapy. Nat. Rev. Cardiol. 15, 757–769 (2018).

    CAS  PubMed  Google Scholar 

  25. Nordestgaard, B. G., Nicholls, S. J., Langsted, A., Ray, K. K. & Tybjærg-Hansen, A. Advances in lipid-lowering therapy through gene-silencing technologies. Nat. Rev. Cardiol. 15, 261–272 (2018).

    CAS  PubMed  Google Scholar 

  26. Sabatine, M. S. PCSK9 inhibitors: clinical evidence and implementation. Nat. Rev. Cardiol. 16, 155–165 (2019).

    CAS  PubMed  Google Scholar 

  27. Patti, G. et al. Prevention of atherothrombotic events in patients with diabetes mellitus: from antithrombotic therapies to new-generation glucose-lowering drugs. Nat. Rev. Cardiol. 16, 113–130 (2019).

    CAS  PubMed  Google Scholar 

  28. Bassenge, E. & Heusch, G. Endothelial and neuro-humoral control of coronary blood flow in health and disease. Rev. Physiol. Biochem. Pharmacol. 116, 77–165 (1990).

    CAS  PubMed  Google Scholar 

  29. Goodwill, A. G., Dick, G. M., Kiel, A. M. & Tune, J. D. Regulation of coronary blood flow. Compr. Physiol. 7, 321–382 (2017).

    PubMed  PubMed Central  Google Scholar 

  30. Levy, B. I., Heusch, G. & Camici, P. G. The many faces of myocardial ischemia and angina. Cardiovasc. Res. 115, 1460–1470 (2019).

    CAS  PubMed  Google Scholar 

  31. Heusch, G. Heart rate in the pathophysiology of coronary blood flow and myocardial ischaemia: benefit from selective bradycardic agents. Br. J. Pharmacol. 153, 1589–1601 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Mosher, P., Ross, J. Jr, McFate, P. A. & Shaw, R. F. Control of coronary blood flow by an autoregulatory mechanism. Circ. Res. 14, 250–259 (1964).

    CAS  PubMed  Google Scholar 

  33. Deussen, A., Ohanyan, V., Jannasch, A., Yin, L. & Chilian, W. Mechanisms of metabolic coronary flow regulation. J. Mol. Cell Cardiol. 52, 794–801 (2012).

    CAS  PubMed  Google Scholar 

  34. Bassenge, E. & Busse, R. Endothelial modulation of coronary tone. Prog. Cardiovasc. Dis. 30, 349–380 (1988).

    CAS  PubMed  Google Scholar 

  35. Heusch, G. The paradox of alpha-adrenergic coronary vasoconstriction revisited. J. Mol. Cell Cardiol. 51, 16–23 (2011).

    CAS  PubMed  Google Scholar 

  36. Beckman, J. S. & Koppenol, W. H. Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly. Am. J. Physiol. 271, C1424–C1437 (1996).

    CAS  PubMed  Google Scholar 

  37. Kälsch, H. et al. Are air pollution and traffic noise independently associated with atherosclerosis: the Heinz Nixdorf Recall Study. Eur. Heart J. 35, 853–860 (2014).

    PubMed  Google Scholar 

  38. Landmesser, U. et al. Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension. J. Clin. Invest. 111, 1201–1209 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Münzel, T. et al. Impact of oxidative stress on the heart and vasculature: part 2 of a 3-part series. J. Am. Coll. Cardiol. 70, 212–229 (2017).

    PubMed  PubMed Central  Google Scholar 

  40. Thijssen, D. H. J. et al. Expert consensus and evidence-based recommendations for the assessment of flow-mediated dilation in humans. Eur. Heart J. 40, 2534–2547 (2019).

    PubMed  Google Scholar 

  41. Mills, I. et al. Adaptive responses of coronary circulation and myocardium to chronic reduction in perfusion pressure and flow. Am. J. Physiol. Heart Circ. Physiol. 266, H447–H457 (1994).

    CAS  Google Scholar 

  42. Sorop, O. et al. Functional and structural adaptations of coronary microvessels distal to a chronic coronary artery stenosis. Circ. Res. 102, 795–803 (2008).

    CAS  PubMed  Google Scholar 

  43. Heusch, G. & Deussen, A. The effects of cardiac sympathetic nerve stimulation on the perfusion of stenotic coronary arteries in the dog. Circ. Res. 53, 8–15 (1983).

    CAS  PubMed  Google Scholar 

  44. Aversano, T. & Becker, L. C. Persistence of coronary vasodilator reserve despite functionally significant flow reduction. Am. J. Physiol. 248, H403–H411 (1985).

    CAS  PubMed  Google Scholar 

  45. Canty, J. M. & Klocke, F. J. Reduced regional myocardial perfusion in the presence of pharmacologic vasodilator reserve. Circulation 71, 370–377 (1985).

    PubMed  Google Scholar 

  46. Heusch, G., Guth, B. D., Seitelberger, R. & Ross, J. Jr. Attenuation of exercise-induced myocardial ischemia in dogs with recruitment of coronary vasodilator reserve by nifedipine. Circulation 75, 482–490 (1987).

    CAS  PubMed  Google Scholar 

  47. Jamaiyar, A. et al. Cardioprotection during ischemia by coronary collateral growth. Am. J. Physiol. Heart C. 316, H1–H9 (2019).

    CAS  Google Scholar 

  48. Heusch, G. & Yoshimoto, N. Effects of heart rate and perfusion pressure on segmental coronary resistances and collateral perfusion. Pflügers Arch. 397, 284–289 (1983).

    CAS  PubMed  Google Scholar 

  49. Baumgart, D., Ehring, T., Krajcar, M. & Heusch, G. A proischemic action of nisoldipine: relationship to a decrease in perfusion pressure and comparison to dipyridamole. Cardiovasc. Res. 27, 1254–1259 (1993).

    CAS  PubMed  Google Scholar 

  50. Prinzmetal, M., Kennamer, R., Merliss, R., Wada, T. & Bor, N. Angina pectoris. I. A variant form of angina pectoris; preliminary report. Am. J. Med. 27, 375–388 (1959).

    CAS  PubMed  Google Scholar 

  51. Ong, P. et al. High prevalence of a pathological response to acetylcholine testing in patients with stable angina pectoris and unobstructed coronary arteries. The ACOVA Study (Abnormal COronary VAsomotion in patients with stable angina and unobstructed coronary arteries). J. Am. Coll. Cardiol. 59, 655–662 (2012).

    CAS  PubMed  Google Scholar 

  52. Nakamura, M., Takeshita, A. & Nose, Y. Clinical characteristics associated with myocardial infarction, arrhythmias, and sudden death in patients with vasospastic angina. Circulation 75, 1110–1116 (1987).

    CAS  PubMed  Google Scholar 

  53. Morita, M. et al. Effects of oral l-citrulline supplementation on lipoprotein oxidation and endothelial dysfunction in humans with vasospastic angina. Immunol. Endocr. Metab. Agents Med. Chem. 13, 214–220 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Miyamoto, S. et al. Increased plasma levels of thioredoxin in patients with coronary spastic angina. Antioxid. Redox Signal. 6, 75–80 (2004).

    CAS  PubMed  Google Scholar 

  55. Hung, M. J., Cherng, W. J., Cheng, C. W. & Li, L. F. Comparison of serum levels of inflammatory markers in patients with coronary vasospasm without significant fixed coronary artery disease versus patients with stable angina pectoris and acute coronary syndromes with significant fixed coronary artery disease. Am. J. Cardiol. 97, 1429–1434 (2006).

    CAS  PubMed  Google Scholar 

  56. Yasue, H., Touyama, M., Shimamoto, M., Kato, H. & Tanaka, S. Role of autonomic nervous system in the pathogenesis of Prinzmetal’s variant form of angina. Circulation 50, 534–539 (1974).

    CAS  PubMed  Google Scholar 

  57. Kaski, J. C. et al. Local coronary supersensitivity to diverse vasoconstrictive stimuli in patients with variant angina. Circulation 74, 1255–1265 (1986).

    CAS  PubMed  Google Scholar 

  58. Yeung, A. C. et al. The effect of atherosclerosis on the vasomotor response of coronary arteries to mental stress. N. Engl. J. Med. 325, 1551–1556 (1991).

    CAS  PubMed  Google Scholar 

  59. Tsujita, K. et al. Coronary plaque component in patients with vasospastic angina: a virtual histology intravascular ultrasound study. Int. J. Cardiol. 168, 2411–2415 (2013).

    PubMed  Google Scholar 

  60. Ishii, M. et al. Acetylcholine-provoked coronary spasm at site of significant organic stenosis predicts poor prognosis in patients with coronary vasospastic angina. J. Am. Coll. Cardiol. 66, 1105–1115 (2015).

    CAS  PubMed  Google Scholar 

  61. Halcox, J. P. et al. Prognostic value of coronary vascular endothelial dysfunction. Circulation 106, 653–658 (2002).

    PubMed  Google Scholar 

  62. Danchin, N., Marzilli, M., Parkhomenko, A. & Ribeiro, J. P. Efficacy comparison of trimetazidine with therapeutic alternatives in stable angina pectoris: a network meta-analysis. Cardiology 120, 59–72 (2011).

    CAS  PubMed  Google Scholar 

  63. Jespersen, L. et al. Stable angina pectoris with no obstructive coronary artery disease is associated with increased risks of major adverse cardiovascular events. Eur. Heart J. 33, 734–744 (2012).

    PubMed  Google Scholar 

  64. Maddox, T. M. et al. Nonobstructive coronary artery disease and risk of myocardial infarction. JAMA 312, 1754–1763 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Brainin, P., Frestad, D. & Prescott, E. The prognostic value of coronary endothelial and microvascular dysfunction in subjects with normal or non-obstructive coronary artery disease: a systematic review and meta-analysis. Int. J. Cardiol. 254, 1–9 (2018).

    PubMed  Google Scholar 

  66. Herscovici, R. et al. Ischemia and no obstructive coronary artery disease (INOCA): what is the risk? J. Am. Heart Assoc. 7, e008868 (2018).

    PubMed  PubMed Central  Google Scholar 

  67. Camici, P. G. & Crea, F. Coronary microvascular dysfunction. N. Engl. J. Med. 356, 830–840 (2007).

    CAS  PubMed  Google Scholar 

  68. Camici, P. G. & Pagani, M. Cardiac nociception. Circulation 114, 2309–2312 (2006).

    PubMed  Google Scholar 

  69. Ohba, K. et al. Microvascular coronary artery spasm presents distinctive clinical features with endothelial dysfunction as nonobstructive coronary artery disease. J. Am. Heart Assoc. 1, e002485 (2012).

    PubMed  PubMed Central  Google Scholar 

  70. Kaski, J. C., Crea, F., Gersh, B. J. & Camici, P. G. Reappraisal of ischemic heart disease. Circulation 138, 1463–1480 (2018).

    PubMed  Google Scholar 

  71. Padro, T. et al. ESC working group on coronary pathophysiology and microcirculation position paper on ‘coronary microvascular dysfunction in cardiovascular disease’. Cardiovasc. Res. 116, 741–755 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Heusch, G. Myocardial ischemia: lack of coronary blood flow, myocardial oxygen supply-demand imbalance, or what? Am. J. Physiol. Heart Circ. Physiol. 316, H1439–H1446 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Heusch, G. α-Adrenergic mechanisms in myocardial ischemia. Circulation 81, 1–13 (1990).

    CAS  PubMed  Google Scholar 

  74. Baumgart, D. et al. Augmented α-adrenergic constriction of atherosclerotic human coronary arteries. Circulation 99, 2090–2097 (1999).

    CAS  PubMed  Google Scholar 

  75. Heusch, G. et al. α-Adrenergic coronary vasoconstriction and myocardial ischemia in humans. Circulation 101, 689–694 (2000).

    CAS  PubMed  Google Scholar 

  76. Heusch, G., Deussen, A. & Thämer, V. Cardiac sympathetic nerve activity and progressive vasoconstriction distal to coronary stenoses: feed-back aggravation of myocardial ischemia. J. Auton. Nerv. Syst. 13, 311–326 (1985).

    CAS  PubMed  Google Scholar 

  77. Gallagher, K. P., Matsuzaki, M., Osakada, G., Kemper, W. S. & Ross, J. Jr. Effect of exercise on the relationship between myocardial blood flow and systolic wall thickening in dogs with acute coronary stenosis. Circ. Res. 52, 716–729 (1983).

    CAS  PubMed  Google Scholar 

  78. Gallagher, K. P., Matsuzaki, M., Koziol, J. A., Kemper, W. S. & Ross, J. Jr. Regional myocardial perfusion and wall thickening during ischemia in conscious dogs. Am. J. Physiol. Heart Circ. Physiol. 247, H727–H738 (1984).

    CAS  Google Scholar 

  79. Ross, J. Jr. Myocardial perfusion-contraction matching. Circulation 83, 1076–1083 (1991).

    PubMed  Google Scholar 

  80. Maroko, P. R. et al. Factors influencing infarct size following experimental coronary artery occlusions. Circulation 43, 67–82 (1971).

    CAS  PubMed  Google Scholar 

  81. Braunwald, E. & Maroko, P. R. Limitation of infarct size. Curr. Probl. Cardiol. 3, 10–51 (1978).

    CAS  PubMed  Google Scholar 

  82. Hansson, N. & Daan, S. Politics and physiology: Hermann Rein and the Nobel Prize 1933–1953. J. Physiol. 592, 2911–2914 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Matsuzaki, M., Gallagher, K. P., Kemper, W. S., White, F. & Ross, J. Jr. Sustained regional dysfunction produced by prolonged coronary stenosis: gradual recovery after reperfusion. Circulation 68, 170–182 (1983).

    CAS  PubMed  Google Scholar 

  84. Heusch, G., Schulz, R. & Rahimtoola, S. H. Myocardial hibernation: a delicate balance. Am. J. Physiol. Heart Circ. Physiol. 288, H984–H999 (2005).

    CAS  PubMed  Google Scholar 

  85. Matsuzaki, M. et al. Effects of a calcium-entry blocker (diltiazem) on regional myocardial flow and function during exercise in conscious dogs. Circulation 69, 801–814 (1984).

    CAS  PubMed  Google Scholar 

  86. Matsuzaki, M. et al. Effects of beta-blockade on regional myocardial flow and function during exercise. Am. J. Physiol. 247, H52–H60 (1984).

    CAS  PubMed  Google Scholar 

  87. Matsuzaki, M., Guth, B. D., Tajimi, T., Kemper, W. S. & Ross, J. Jr. Effects of the combination of diltiazem and atenolol on exercise-induced regional myocardial ischemia in conscious dogs. Circulation 72, 233–243 (1985).

    CAS  PubMed  Google Scholar 

  88. Guth, B. D. et al. Experimental exercise-induced ischemia: drug therapy can eliminate regional dysfunction and oxygen supply–demand imbalance. J. Am. Coll. Cardiol. 7, 1036–1046 (1986).

    CAS  PubMed  Google Scholar 

  89. Guth, B. D., Heusch, G., Seitelberger, R. & Ross, J. Jr. Elimination of exercise-induced regional myocardial dysfunction by a bradycardic agent in dogs with chronic coronary stenosis. Circulation 75, 661–669 (1987).

    CAS  PubMed  Google Scholar 

  90. Guth, B. D., Heusch, G., Seitelberger, R. & Ross, J. Jr. Mechanism of beneficial effect of beta-adrenergic blockade on exercise-induced myocardial ischemia in conscious dogs. Circ. Res. 60, 738–746 (1987).

    CAS  PubMed  Google Scholar 

  91. Heusch, G. Myocardial stunning and hibernation revisited. Nat. Rev. Cardiol. https://doi.org/10.1038/s41569-021-00506-7 (2021).

    Article  PubMed  Google Scholar 

  92. Vanoverschelde, J. L. et al. Mechanisms of chronic regional postischemic dysfunction in humans. New insights from the study of noninfarcted collateral-dependent myocardium. Circulation 87, 1513–1523 (1993).

    CAS  PubMed  Google Scholar 

  93. Stanley, W. C., Recchia, F. A. & Lopaschuk, G. D. Myocardial substrate metabolism in the normal and failing heart. Physiol. Rev. 85, 1093–1129 (2005).

    CAS  PubMed  Google Scholar 

  94. Murashige, D. et al. Comprehensive quantification of fuel use by the failing and nonfailing human heart. Science 370, 364–368 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Lopaschuk, G. D., Ussher, J. R., Folmes, C. D., Jaswal, J. S. & Stanley, W. C. Myocardial fatty acid metabolism in health and disease. Physiol. Rev. 90, 207–258 (2010).

    CAS  PubMed  Google Scholar 

  96. Arima, Y. et al. Myocardial ischemia suppresses ketone body utilization. J. Am. Coll. Cardiol. 73, 246–247 (2019).

    PubMed  Google Scholar 

  97. Dennis, S. C., Gevers, W. & Opie, L. H. Protons in ischemia: where do they come from; where do they go to? J. Mol. Cell Cardiol. 23, 1077–1086 (1991).

    CAS  PubMed  Google Scholar 

  98. Orchard, C. H. & Cingolani, H. E. Acidosis and arrhythmias in cardiac muscle. Cardiovasc. Res. 28, 1312–1319 (1994).

    CAS  PubMed  Google Scholar 

  99. Arai, A. E., Grauer, S. E., Anselone, C. G., Pantely, G. A. & Bristow, J. D. Metabolic adaptation to a gradual reduction in myocardial blood flow. Circulation 92, 244–252 (1995).

    CAS  PubMed  Google Scholar 

  100. Liedtke, A. J., DeMaison, L., Eggleston, A. M., Cohen, L. M. & Nellis, S. H. Changes in substrate metabolism and effects of excess fatty acids in reperfused myocardium. Circ. Res. 62, 535–542 (1988).

    CAS  PubMed  Google Scholar 

  101. Lerch, R., Tamm, C., Papageorgiou, I. & Benzi, R. H. Myocardial fatty acid oxidation during ischemia and reperfusion. Mol. Cell Biochem. 116, 103–109 (1992).

    CAS  PubMed  Google Scholar 

  102. Opie, L. H. Metabolism of free fatty acids, glucose and catecholamines in acute myocardial infarction. Relation to myocardial ischemia and infarct size. Am. J. Cardiol. 36, 938–953 (1975).

    CAS  PubMed  Google Scholar 

  103. Kudo, N., Barr, A. J., Barr, R. L., Desai, S. & Lopaschuk, G. D. High rates of fatty acid oxidation during reperfusion of ischemic hearts are associated with a decrease in malonyl-CoA levels due to an increase in 5′-AMP-activated protein kinase inhibition of acetyl-CoA carboxylase. J. Biol. Chem. 270, 17513–17520 (1995).

    CAS  PubMed  Google Scholar 

  104. Liu, Q., Docherty, J. C., Rendell, J. C., Clanachan, A. S. & Lopaschuk, G. D. High levels of fatty acids delay the recovery of intracellular pH and cardiac efficiency in post-ischemic hearts by inhibiting glucose oxidation. J. Am. Coll. Cardiol. 39, 718–725 (2002).

    CAS  PubMed  Google Scholar 

  105. Crea, F. & Gaspardone, A. New look to an old symptom: angina pectoris. Circulation 96, 3766–3773 (1997).

    CAS  PubMed  Google Scholar 

  106. Korvald, C., Elvenes, O. P. & Myrmel, T. Myocardial substrate metabolism influences left ventricular energetics in vivo. Am. J. Physiol. Heart Circ. Physiol. 278, H1345–H1351 (2000).

    CAS  PubMed  Google Scholar 

  107. Murad, F., Mittal, C. K., Arnold, W. P., Katsuki, S. & Kimura, H. Guanylate cyclase: activation by azide, nitro compounds, nitric oxide, and hydroxyl radical and inhibition by hemoglobin and myoglobin. Adv. Cycl. Nucleotide Res. 9, 145–158 (1978).

    CAS  Google Scholar 

  108. Munzel, T., Daiber, A. & Mulsch, A. Explaining the phenomenon of nitrate tolerance. Circ. Res. 97, 618–628 (2005).

    PubMed  Google Scholar 

  109. Sellke, F. W., Myers, P. R., Bates, J. N. & Harrison, D. G. Influence of vessel size on the sensitivity of porcine coronary microvessels to nitroglycerin. Am. J. Physiol. 258, H515–H520 (1990).

    CAS  PubMed  Google Scholar 

  110. Daiber, A. & Munzel, T. Organic nitrate therapy, nitrate tolerance, and nitrate-induced endothelial dysfunction: emphasis on redox biology and oxidative stress. Antioxid. Redox Signal. 23, 899–942 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Jackson, J., Patterson, A. J., MacDonald-Wicks, L. & McEvoy, M. The role of inorganic nitrate and nitrite in CVD. Nutr. Res. Rev. 30, 247–264 (2017).

    CAS  PubMed  Google Scholar 

  112. Munzel, T., Daiber, A. & Gori, T. Nitrate therapy: new aspects concerning molecular action and tolerance. Circulation 123, 2132–2144 (2011).

    PubMed  Google Scholar 

  113. Munzel, T., Daiber, A. & Gori, T. More answers to the still unresolved question of nitrate tolerance. Eur. Heart J. 34, 2666–2673 (2013).

    PubMed  Google Scholar 

  114. Tarkin, J. M. & Kaski, J. C. Nicorandil and long-acting nitrates: vasodilator therapies for the management of chronic stable angina pectoris. Eur. Cardiol. 13, 23–28 (2018).

    PubMed  PubMed Central  Google Scholar 

  115. Wenzel, P. et al. Heme oxygenase-1: a novel key player in the development of tolerance in response to organic nitrates. Arterioscler. Thromb. Vasc. Biol. 27, 1729–1735 (2007).

    CAS  PubMed  Google Scholar 

  116. Gladwin, M. T. et al. Nitrite as a vascular endocrine nitric oxide reservoir that contributes to hypoxic signaling, cytoprotection, and vasodilation. Am. J. Physiol. Heart Circ. Physiol. 291, H2026–H2035 (2006).

    CAS  PubMed  Google Scholar 

  117. Munzel, T. & Daiber, A. Inorganic nitrite and nitrate in cardiovascular therapy: a better alternative to organic nitrates as nitric oxide donors? Vasc. Pharmacol. 102, 1–10 (2018).

    Google Scholar 

  118. Group, J. C. S. J. W. Guidelines for diagnosis and treatment of patients with vasospastic angina (coronary spastic angina) (JCS 2013). Circ. J. 78, 2779–2801 (2014).

    Google Scholar 

  119. Taylor, A. L. et al. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N. Engl. J. Med. 351, 2049–2057 (2004).

    CAS  PubMed  Google Scholar 

  120. Redfield, M. M. et al. Isosorbide mononitrate in heart failure with preserved ejection fraction. N. Engl. J. Med. 373, 2314–2324 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Borlaug, B. A. et al. Effect of inorganic nitrite vs placebo on exercise capacity among patients with heart failure with preserved ejection fraction: the INDIE-HFpEF randomized clinical trial. JAMA 320, 1764–1773 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Opie, L. H. Calcium channel antagonists in the treatment of coronary artery disease: fundamental pharmacological properties relevant to clinical use. Prog. Cardiovasc. Dis. 38, 273–290 (1996).

    CAS  PubMed  Google Scholar 

  123. Ong, P., Athanasiadis, A. & Sechtem, U. Pharmacotherapy for coronary microvascular dysfunction. Eur. Heart J. Cardiovasc. Pharmacother. 1, 65–71 (2015).

    CAS  PubMed  Google Scholar 

  124. Böhm, M., Schwinger, R. H. & Erdmann, E. Different cardiodepressant potency of various calcium antagonists in human myocardium. Am. J. Cardiol. 65, 1039–1041 (1990).

    PubMed  Google Scholar 

  125. Ponikowski, P. et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur. Heart J. 37, 2129–2200 (2016).

    PubMed  Google Scholar 

  126. Buck, J. D., Hardman, H. F., Warltier, D. C. & Gross, G. J. Changes in ischemic blood flow distribution and dynamic severity of a coronary stenosis induced by beta blockade in the canine heart. Circulation 64, 708–715 (1981).

    CAS  PubMed  Google Scholar 

  127. Seitelberger, R. et al. Intracoronary α2-adrenergic receptor blockade attenuates ischemia in conscious dogs during exercise. Circ. Res. 62, 436–442 (1988).

    CAS  PubMed  Google Scholar 

  128. Gottlieb, S. S., McCarter, R. J. & Vogel, R. A. Effect of beta-blockade on mortality among high-risk and low-risk patients after myocardial infarction. N. Engl. J. Med. 339, 489–497 (1998).

    CAS  PubMed  Google Scholar 

  129. Law, M. R., Morris, J. K. & Wald, N. J. Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies. BMJ 338, b1665 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Ettehad, D. et al. Blood pressure lowering for prevention of cardiovascular disease and death: a systematic review and meta-analysis. Lancet 387, 957–967 (2016).

    PubMed  Google Scholar 

  131. Dondo, T. B. et al. β-Blockers and mortality after acute myocardial infarction in patients without heart failure or ventricular dysfunction. J. Am. Coll. Cardiol. 69, 2710–2720 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Dargie, H. J. Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction: the CAPRICORN randomised trial. Lancet 357, 1385–1390 (2001).

    CAS  PubMed  Google Scholar 

  133. DiFrancesco, D., Ferroni, A., Mazzanti, M. & Tromba, C. Properties of the hyperpolarizing-activated current (if) in cells isolated from the rabbit sino-atrial node. J. Physiol. 377, 61–88 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Bucchi, A., Baruscotti, M. & DiFrancesco, D. Current-dependent block of rabbit sino-atrial node I(f) channels by ivabradine. J. Gen. Physiol. 120, 1–13 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Simon, L., Ghaleh, B., Puybasset, L., Giudicelli, J. F. & Berdeaux, A. Coronary and hemodynamic effects of S 16257, a new bradycardic agent, in resting and exercising conscious dogs. J. Pharmacol. Exp. Ther. 275, 659–666 (1995).

    CAS  PubMed  Google Scholar 

  136. Indolfi, C. et al. Mechanisms of improved ischemic regional dysfunction by bradycardia. Studies on UL-FS 49 in swine. Circulation 80, 983–993 (1989).

    CAS  PubMed  Google Scholar 

  137. Heusch, G. et al. Improvement of regional myocardial blood flow and function and reduction of infarct size with ivabradine: protection beyond heart rate reduction. Eur. Heart J. 29, 2265–2275 (2008).

    PubMed  Google Scholar 

  138. Swedberg, K. et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet 376, 875–885 (2010).

    CAS  PubMed  Google Scholar 

  139. Ohman, E. M. & Alexander, K. P. The challenges with chronic angina. N. Engl. J. Med. 371, 1152–1153 (2014).

    PubMed  Google Scholar 

  140. Ferrari, R. et al. Expert consensus document: a ‘diamond’ approach to personalized treatment of angina. Nat. Rev. Cardiol. 15, 120–132 (2018).

    PubMed  Google Scholar 

  141. Fox, K. et al. Relationship between ivabradine treatment and cardiovascular outcomes in patients with stable coronary artery disease and left ventricular systolic dysfunction with limiting angina: a subgroup analysis of the randomized, controlled BEAUTIFUL trial. Eur. Heart J. 30, 2337–2345 (2009).

    CAS  PubMed  Google Scholar 

  142. Werdan, K. et al. Effectiveness of ivabradine treatment in different subpopulations with stable angina in clinical practice: a pooled analysis of observational studies. Cardiology 135, 141–150 (2016).

    CAS  PubMed  Google Scholar 

  143. Bersin, R. M. & Stacpoole, P. W. Dichloroacetate as metabolic therapy for myocardial ischemia and failure. Am. Heart J. 134, 841–855 (1997).

    CAS  PubMed  Google Scholar 

  144. Newman, R. J. Comparison of the antilipolytic effect of metoprolol, acebutolol, and propranolol in man. Br. Med. J. 2, 601–603 (1977).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Wallhaus, T. R. et al. Myocardial free fatty acid and glucose use after carvedilol treatment in patients with congestive heart failure. Circulation 103, 2441–2446 (2001).

    CAS  PubMed  Google Scholar 

  146. Bergman, G., Atkinson, L., Metcalfe, J., Jackson, N. & Jewitt, D. E. Beneficial effect of enhanced myocardial carbohydrate utilisation after oxfenicine (l-hydroxyphenylglycine) in angina pectoris. Eur. Heart J. 1, 247–253 (1980).

    CAS  PubMed  Google Scholar 

  147. Cheng, J. F. et al. Discovery of potent and orally available malonyl-CoA decarboxylase inhibitors as cardioprotective agents. J. Med.Chem. 49, 4055–4058 (2006).

    CAS  PubMed  Google Scholar 

  148. Wang, W. et al. Malonyl CoA decarboxylase inhibition improves cardiac function post-myocardial infarction. JACC Basic Transl Sci. 4, 385–400 (2019).

    PubMed  PubMed Central  Google Scholar 

  149. Kantor, P. F., Lucien, A., Kozak, R. & Lopaschuk, G. D. The antianginal drug trimetazidine shifts cardiac energy metabolism from fatty acid oxidation to glucose oxidation by inhibiting mitochondrial long-chain 3-ketoacyl coenzyme A thiolase. Circ. Res. 86, 580–588 (2000).

    CAS  PubMed  Google Scholar 

  150. Tuunanen, H. et al. Trimetazidine, a metabolic modulator, has cardiac and extracardiac benefits in idiopathic dilated cardiomyopathy. Circulation 118, 1250–1258 (2008).

    CAS  PubMed  Google Scholar 

  151. McCarthy, C. P., Mullins, K. V. & Kerins, D. M. The role of trimetazidine in cardiovascular disease: beyond an anti-anginal agent. Eur. Heart J. Cardiovasc. Pharmacother. 2, 266–272 (2016).

    CAS  PubMed  Google Scholar 

  152. Szwed, H. et al. Combination treatment in stable effort angina using trimetazidine and metoprolol: results of a randomized, double-blind, multicentre study (TRIMPOL II). TRIMetazidine in POLand. Eur. Heart J. 22, 2267–2274 (2001).

    CAS  PubMed  Google Scholar 

  153. Peng, S. et al. The efficacy of trimetazidine on stable angina pectoris: a meta-analysis of randomized clinical trials. Int. J. Cardiol. 177, 780–785 (2014).

    PubMed  Google Scholar 

  154. Nalbantgil, S. et al. The effect of trimetazidine in the treatment of microvascular angina. Int. J. Angiol. 8, 40–43 (1999).

    CAS  PubMed  Google Scholar 

  155. McCormack, J. G., Barr, R. L., Wolff, A. A. & Lopaschuk, G. D. Ranolazine stimulates glucose oxidation in normoxic, ischemic, and reperfused ischemic rat hearts. Circulation 93, 135–142 (1996).

    CAS  PubMed  Google Scholar 

  156. Valdivia, C. R. et al. Increased late sodium current in myocytes from a canine heart failure model and from failing human heart. J. Mol. Cell Cardiol. 38, 475–483 (2005).

    CAS  PubMed  Google Scholar 

  157. Pieske, B. et al. Rate dependence of [Na+]i and contractility in nonfailing and failing human myocardium. Circulation 106, 447–453 (2002).

    CAS  PubMed  Google Scholar 

  158. Chaitman, B. R. et al. Effects of ranolazine with atenolol, amlodipine, or diltiazem on exercise tolerance and angina frequency in patients with severe chronic angina: a randomized controlled trial. JAMA 291, 309–316 (2004).

    CAS  PubMed  Google Scholar 

  159. Bairey Merz, C. N. et al. A randomized, placebo-controlled trial of late Na current inhibition (ranolazine) in coronary microvascular dysfunction (CMD): impact on angina and myocardial perfusion reserve. Eur. Heart J. 37, 1504–1513 (2016).

    PubMed  Google Scholar 

  160. Scirica, B. M. et al. Effect of ranolazine, an antianginal agent with novel electrophysiological properties, on the incidence of arrhythmias in patients with non ST-segment elevation acute coronary syndrome: results from the Metabolic Efficiency With Ranolazine for Less Ischemia in Non ST-Elevation Acute Coronary Syndrome Thrombolysis in Myocardial Infarction 36 (MERLIN-TIMI 36) randomized controlled trial. Circulation 116, 1647–1652 (2007).

    CAS  PubMed  Google Scholar 

  161. Morrow, D. A. et al. Evaluation of the glycometabolic effects of ranolazine in patients with and without diabetes mellitus in the MERLIN-TIMI 36 randomized controlled trial. Circulation 119, 2032–2039 (2009).

    CAS  PubMed  Google Scholar 

  162. Wilson, S. R. et al. Efficacy of ranolazine in patients with chronic angina observations from the randomized, double-blind, placebo-controlled MERLIN-TIMI (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST-Segment Elevation Acute Coronary Syndromes) 36 Trial. J. Am. Coll. Cardiol. 53, 1510–1516 (2009).

    CAS  PubMed  Google Scholar 

  163. Morrow, D. A. et al. B-type natriuretic peptide and the effect of ranolazine in patients with non-ST-segment elevation acute coronary syndromes: observations from the MERLIN-TIMI 36 (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST Elevation Acute Coronary-Thrombolysis In Myocardial Infarction 36) trial. J. Am. Coll. Cardiol. 55, 1189–1196 (2010).

    CAS  PubMed  Google Scholar 

  164. Ferrari, R. et al. Anti-anginal drugs — beliefs and evidence: systematic review covering 50 years of medical treatment. Eur. Heart J. 40, 190–194 (2019).

    CAS  PubMed  Google Scholar 

  165. Husted, S. E. & Ohman, E. M. Pharmacological and emerging therapies in the treatment of chronic angina. Lancet 386, 691–701 (2015).

    CAS  PubMed  Google Scholar 

  166. Montalescot, G. et al. 2013 ESC guidelines on the management of stable coronary artery disease: the task force on the management of stable coronary artery disease of the European society of cardiology. Eur. Heart J. 34, 2949–3003 (2013).

    PubMed  Google Scholar 

  167. Vidal-Petiot, E. et al. Cardiovascular event rates and mortality according to achieved systolic and diastolic blood pressure in patients with stable coronary artery disease: an international cohort study. Lancet 388, 2142–2152 (2016).

    PubMed  Google Scholar 

  168. Ambrosio, G., Tamargo, J. & Grant, P. J. Non-haemodynamic anti-anginal agents in the management of patients with stable coronary artery disease and diabetes: a review of the evidence. Diabetes Vasc. Dis. Res. 13, 98–112 (2016).

    CAS  Google Scholar 

  169. Bakris, G. L. et al. Metabolic effects of carvedilol vs metoprolol in patients with type 2 diabetes mellitus and hypertension: a randomized controlled trial. JAMA 292, 2227–2236 (2004).

    CAS  PubMed  Google Scholar 

  170. Wai, B. et al. Beta blocker use in subjects with type 2 diabetes mellitus and systolic heart failure does not worsen glycaemic control. Cardiovasc. Diabetol. 11, 14 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Kalra, P. R. et al. Impact of chronic kidney disease on use of evidence-based therapy in stable coronary artery disease: a prospective analysis of 22,272 patients. PLoS ONE 9, e102335 (2014).

    PubMed  PubMed Central  Google Scholar 

  172. Smilowitz, N. R., Gupta, N., Guo, Y., Mauricio, R. & Bangalore, S. Management and outcomes of acute myocardial infarction in patients with chronic kidney disease. Int. J. Cardiol. 227, 1–7 (2017).

    PubMed  Google Scholar 

  173. Juul-Möller, S. et al. Double-blind trial of aspirin in primary prevention of myocardial infarction in patients with stable chronic angina pectoris. The Swedish Angina Pectoris Aspirin Trial (SAPAT) group. Lancet 340, 1421–1425 (1992).

    PubMed  Google Scholar 

  174. Shepherd, J. et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N. Engl. J. Med. 333, 1301–1307 (1995).

    CAS  PubMed  Google Scholar 

  175. Fox, K. A. COURAGE to change practice? Revascularisation in patients with stable coronary artery disease. Heart 95, 689–692 (2009).

    PubMed  Google Scholar 

  176. Windecker, S. et al. Revascularisation versus medical treatment in patients with stable coronary artery disease: network meta-analysis. BMJ 348, g3859 (2014).

    PubMed  PubMed Central  Google Scholar 

  177. Velazquez, E. J. et al. Coronary-artery bypass surgery in patients with ischemic cardiomyopathy. N. Engl. J. Med. 374, 1511–1520 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  178. Neumann, F. J. et al. 2018 ESC/EACTS Guidelines on myocardial revascularization. Eur. Heart J. 40, 87–165 (2019).

    PubMed  Google Scholar 

  179. Murry, C. E., Jennings, R. B. & Reimer, K. A. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 74, 1124–1136 (1986).

    CAS  PubMed  Google Scholar 

  180. Hausenloy, D. J. et al. Ischaemic conditioning and targeting reperfusion injury: a 30 year voyage of discovery. Basic. Res. Cardiol. 111, 70 (2016).

    PubMed  PubMed Central  Google Scholar 

  181. Heusch, G. Myocardial ischaemia–reperfusion injury and cardioprotection in perspective. Nat. Rev. Cardiol. 17, 773–789 (2020).

    PubMed  Google Scholar 

  182. Heusch, G. Nitroglycerin and delayed preconditioning in humans: yet another new mechanism for an old drug? Circulation 103, 2876–2878 (2001).

    CAS  PubMed  Google Scholar 

  183. Maack, C., Dabew, E. R., Hohl, M., Schäfers, H. J. & Böhm, M. Endogenous activation of mitochondrial KATP channels protects human failing myocardium from hydroxyl radical-induced stunning. Circ. Res. 105, 811–817 (2009).

    CAS  PubMed  Google Scholar 

  184. Paggio, A. et al. Identification of an ATP-sensitive potassium channel in mitochondria. Nature 572, 609–613 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  185. O’Rourke, B. Evidence for mitochondrial K+ channels and their role in cardioprotection. Circ. Res. 94, 420–432 (2004).

    PubMed  PubMed Central  Google Scholar 

  186. Heusch, G. Molecular basis of cardioprotection: signal transduction in ischemic pre-, post-, and remote conditioning. Circ. Res. 116, 674–699 (2015).

    CAS  PubMed  Google Scholar 

  187. Cowie, M. R. et al. Adaptive servo-ventilation for central sleep apnea in systolic heart failure. N. Engl. J. Med. 373, 1095–1105 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  188. Stergiopoulos, K. et al. Percutaneous coronary intervention outcomes in patients with stable obstructive coronary artery disease and myocardial ischemia: a collaborative meta-analysis of contemporary randomized clinical trials. JAMA Intern. Med. 174, 232–240 (2014).

    PubMed  Google Scholar 

  189. Sara, J. D. et al. Prevalence of coronary microvascular dysfunction among patients with chest pain and nonobstructive coronary artery disease. JACC Cardiovasc. Interv. 8, 1445–1453 (2015).

    PubMed  Google Scholar 

  190. Cannon, R. O. 3rd. The sensitive heart. A syndrome of abnormal cardiac pain perception. JAMA 273, 883–887 (1995).

    PubMed  Google Scholar 

  191. Gallone, G. et al. Refractory angina: from pathophysiology to new therapeutic nonpharmacological technologies. JACC Cardiovasc. Interv. 13, 1–19 (2020).

    PubMed  Google Scholar 

  192. Hartikainen, J. et al. Adenoviral intramyocardial VEGF-DDeltaNDeltaC gene transfer increases myocardial perfusion reserve in refractory angina patients: a phase I/IIa study with 1-year follow-up. Eur. Heart J. 38, 2547–2555 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  193. Iwasaki, H. et al. Dose-dependent contribution of CD34-positive cell transplantation to concurrent vasculogenesis and cardiomyogenesis for functional regenerative recovery after myocardial infarction. Circulation 113, 1311–1325 (2006).

    CAS  PubMed  Google Scholar 

  194. Henry, T. D. et al. Autologous CD34+ cell therapy for refractory angina: 2-year outcomes from the ACT34-CMI study. Cell Transpl. 25, 1701–1711 (2016).

    Google Scholar 

  195. Povsic, T. J. et al. The RENEW trial: efficacy and safety of intramyocardial autologous CD34+ cell administration in patients with refractory angina. JACC Cardiovasc. Interv. 9, 1576–1585 (2016).

    PubMed  Google Scholar 

  196. Alunni, G. et al. The beneficial effect of extracorporeal shockwave myocardial revascularization in patients with refractory angina. Cardiovasc. Revasc Med. 16, 6–11 (2015).

    PubMed  Google Scholar 

  197. Kikuchi, Y. et al. Double-blind and placebo-controlled study of the effectiveness and safety of extracorporeal cardiac shock wave therapy for severe angina pectoris. Circ. J. 74, 589–591 (2010).

    PubMed  Google Scholar 

  198. Davies, A. et al. Management of refractory angina: an update. Eur. Heart J. 42, 269–283 (2021).

    CAS  PubMed  Google Scholar 

  199. Konigstein, M., Giannini, F. & Banai, S. The Reducer device in patients with angina pectoris: mechanisms, indications, and perspectives. Eur. Heart J. 39, 925–933 (2018).

    PubMed  Google Scholar 

  200. Verheye, S. et al. Efficacy of a device to narrow the coronary sinus in refractory angina. N. Engl. J. Med. 372, 519–527 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  201. Eisenberg, M. J., Brox, A. & Bestawros, A. N. Calcium channel blockers: an update. Am. J. Med. 116, 35–43 (2004).

    CAS  PubMed  Google Scholar 

  202. Lüscher, T. F. et al. A randomized placebo-controlled study on the effect of nifedipine on coronary endothelial function and plaque formation in patients with coronary artery disease: the ENCORE II study. Eur. Heart J. 30, 1590–1597 (2009).

    PubMed  PubMed Central  Google Scholar 

  203. Preston Mason, R. Pleiotropic effects of calcium channel blockers. Curr. Hypertens. Rep. 14, 293–303 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  204. Daiber, A., Wenzel, P., Oelze, M. & Munzel, T. New insights into bioactivation of organic nitrates, nitrate tolerance and cross-tolerance. Clin. Res. Cardiol. 97, 12–20 (2008).

    CAS  PubMed  Google Scholar 

  205. Effect of nicorandil on coronary events in patients with stable angina: the Impact Of Nicorandil in Angina (IONA) randomised trial. Lancet 359, 1269–1275 (2002).

  206. Bangalore, S., Messerli, F. H., Kostis, J. B. & Pepine, C. J. Cardiovascular protection using beta-blockers: a critical review of the evidence. J. Am. Coll. Cardiol. 50, 563–572 (2007).

    CAS  PubMed  Google Scholar 

  207. Koruth, J. S., Lala, A., Pinney, S., Reddy, V. Y. & Dukkipati, S. R. The clinical use of ivabradine. J. Am. Coll. Cardiol. 70, 1777–1784 (2017).

    PubMed  Google Scholar 

  208. Rayner-Hartley, E. & Sedlak, T. Ranolazine: a contemporary review. J. Am. Heart Assoc. 5, e003196 (2016).

    PubMed  PubMed Central  Google Scholar 

  209. Marzilli, M. et al. Trimetazidine in cardiovascular medicine. Int. J. Cardiol. 293, 39–44 (2019).

    PubMed  Google Scholar 

Download references

Acknowledgements

G.H. is supported by the Deutsche Forschungsgemeinschaft (DFG; SFB 1116 B8). T.M. is a principal investigator at the DZHK (German Center for Cardiovascular Research), Partner Site Rhine-Main, Mainz, Germany. C.M. is supported by the DFG (Ma 2528/7-1; SFB 894; TRR-219) and the Federal Ministry of Education and Research (BMBF; 01EO1504).

Author information

Authors and Affiliations

  1. Comprehensive Heart Failure Center (CHFC), University Clinic Würzburg, Würzburg, Germany

    Edoardo Bertero & Christoph Maack

  2. Institute for Pathophysiology, West German Heart and Vascular Center, University of Duisburg-Essen, Essen, Germany

    Gerd Heusch

  3. Department of Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany

    Thomas Münzel

  4. German Center for Cardiovascular Research (DZHK), Partner site Rhine-Main, Mainz, Germany

    Thomas Münzel

  5. Department of Internal Medicine 1, University Clinic Würzburg, Würzburg, Germany

    Christoph Maack

Authors
  1. Edoardo Bertero
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gerd Heusch
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Thomas Münzel
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Christoph Maack
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All the authors researched the data for the article, provided substantial contributions to discussions of its content, wrote the article and undertook review and/or editing of the manuscript before submission.

Corresponding authors

Correspondence to Thomas Münzel or Christoph Maack.

Ethics declarations

Competing interests

C.M. has received honoraria as a lecturer from AstraZeneca, Bayer, Berlin Chemie, Boehringer Ingelheim, Bristol-Myers Squibb, Novartis and Servier and has served as an adviser to Amgen, Boehringer Ingelheim, Novo Nordisk and Servier. The other authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Cardiology thanks R. Ferrari, J. López-Sendón, H. Ogawa and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Bertero, E., Heusch, G., Münzel, T. et al. A pathophysiological compass to personalize antianginal drug treatment. Nat Rev Cardiol 18, 838–852 (2021). https://doi.org/10.1038/s41569-021-00573-w

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41569-021-00573-w

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing