Author + information
- Antonio Delgado-Almeida, MD∗ ()
- ↵∗University of Carabobo Medical School, Clinical Research Unit and Ion Transport Research Laboratory, Instituto Docente de Nefrología y Urología, Piso 4, # 419, Urbanización La Viña, Valencia, Carabobo 2002, Venezuela
Recently β-blocker drugs have been accepted as the standard of care for angina and coronary heart disease, especially when patients have had myocardial infarction. However, the finding by Andersson et al. (1) on β-blocker effects only in recent myocardial infarcts opens an interesting question in cardiovascular pharmacology, in which 2 major points deserve consideration.
First, the references in Andersson et al. (1) demonstrated that treatment with β-blockers had no statistically significant impact on mortality compared to placebo or other active comparator in clinical trials for patients with stable angina (Ref. 7 in the Andersson et al. article), and were not associated with lower incidence of cardiovascular events in patients with previous history of myocardial infarction (MI), among patients with coronary heart disease (CHD) but no history of MI, or among patients with risk factors for atherosclerotic disease only (44,708 subjects) (Ref. 8 in the Andersson et al. article).
With further refinement, the AVANCE Register study (2,024 angina patients in stable condition, 419 cardiologists) (2) found that despite β-blockers (75% to 79%), statins (90% to 93%), antiplatelets (95% to 97%), nitrates (61% to 100%), and calcium antagonists (44%), a higher proportion of patients had angina (49.3%), including those with revascularization (66%) who had angina (59%). In addition, patients perceived their condition as being more serious than their physicians, independently of symptom intensity, suggesting that the optimal target for quality of life or angina has not been currently achieved. Unfortunately, no information is available on the number of patients who remain with ischemic electrocardiogram (ECG) with or without angina, in any specific groups of drug treatment, including coronary interventions.
As mentioned previously, a second point arises when coronary intervention or surgery is required to enhance coronary blood perfusion in CHD patients. However, the incontrovertible fact is that O2 supply is only possible at the capillary bed, involving the most critical role of erythrocyte K-dependent adenosine triphosphate (ATP) synthesis and releases for instantaneous H/K and O2/CO2 exchanges in myocardial capillary bed (Figure 1). In fact, because intracoronary administration of nitroglycerin fails to relieve angina induced by atrial pacing, which rapidly reversed by the intravenous or sublingual doses (3), it is reasonable to assume that the enhanced hemoglobin oxygen binding in the lung capillary bed could be a required step for the antianginal effects of nitrates or any other drug treatments.
This hypothesis is supported by the in vitro oxygen-K binding by human oxyhemoglobin discovery in our laboratory (4), along with the evidence that the increased erythrocyte-K content by Amiloride HCl dihydrate reverses angina and ST-T alteration of ischemia in CHD patients (5). Certainly, this K-dependent ATP function should be preserved in the presence of an inherited defect in red-blood-cell-potassium (RBC-K) uptake, or drugs affecting RBC-K transport including loop diuretic agents, propranolol or gastric H-K ions ATPase pump inhibitors.
Finally, although the ECG alterations of ischemia in resting ECG, or induced by pacing and treadmill tests are landmark evidence of CHD, the simple fact is that we have no definite information on drug treatment or coronary interventions that completely reverse ECG alterations and angina. Because extensive cardiovascular studies have documented that baseline ECG abnormalities or new and persistent ECG alterations are associated with increased cardiovascular events, it is clear that it is time to reassess the impact of drug treatment, coronary intervention, or coronary procedure in patients with CHD.
Electron microscopy view at the myocardial capillary net, in which diameters and blood flow is tightly controlled by a RBC-K dependent enzyme (pyruvate kinase activity) required for ATP synthesis and ATP release in the presence of low pH or PO2, is the most powerful regulator of capillary vasodilation and blood flow in healthy and ischemic tissues.
However, an anatomical aspect is well evident: the larger RBC diameter (7 ± 0.5 μm) versus most microvascular beds (3.5-5.0 μm). However, despite these narrower capillary diameters, the flow velocity of these cells in healthy subject is 300–400 μ/sec, critically dependent of RBC-K pyruvate kinase activity. Therefore, impaired vasodilation and longer transit time of RBC, instead of increased vascular resistances in conductive arteries, appears to be the major factor involved on the pathogenesis of hypertension and CHD, supporting a novel paradigm in the management and treatment of CHD and other cardiovascular diseases.
Please note: Philippe Gabriel Steg, MD, served as the Guest Editor for this Letter.
- American College of Cardiology Foundation
- Andersson C.,
- Shilane D.,
- Go A.S.,
- et al.
- Ganz W.,
- Marcus H.S.
- Delgado-Almeida A.