Amlodipine alters hemorheological parameters: Increased efficacy at the cost of edema?

BACKGROUND: Despite several decades of use of calcium channel blockers, the side effect of edema persists as a class effect, and its mechanism is unresolved. Amlodipine has effects on hemorheology (HR), and its hemodilutory property may partly contribute to its antihypertensive action. This aspect is not well studied, and the literature is sparse in this regard. OBJECTIVE: This experiment was planned to determine effect of a single-dose administration of amlodipine on HR parameters in normal human volunteers. METHODS AND RESULTS: Amlodipine (5 mg) or S (-) amlodipine (2.5 mg) was administered to 27 normal human volunteers. Whole-blood viscosity (WBV) at different shear rates, plasma viscosity (PV), red cell rigidity (RCR), red cell aggregation (RCA), hematocrit (Hct), plasma hemoglobin, along with plasma drug concentration were determined at time intervals, t = 0, 4, 8, 12, and 24 h. Statistically significant reductions were observed at tmax = 4 h in WBV at shear rates of 0.512 s-1 (p < 0.005), WBV at shear rates of 5.26 s-1 (p < 0.01), PV (p < 0.05), and Hct (p < 0.01). At t = 8 h, as drug concentration reduced, some of the changes persisted and later slowly decreased with the decreasing drug concentration till t = 24 h. Red blood cell-related parameters such as RCA and RCR remained unaltered. WBV values at all shear rates, when corrected for Hct = 0.45, did not show deviation from their original values at any time. CONCLUSIONS: Amlodipine causes a reduction in Hct and blood viscosity, along with hemodilution. These effects persist as long as the drug remains in plasma. Edema resulting from chronic dosing may be explained by the aforementioned effects. It is possible that antihypertensive action of the drug may be due to a combination of vasodilatation and an improvement in the HR properties.

Testosterone Therapy: An Assessment of the Clinical Consequences of Changes in Hematocrit and Blood Flow Characteristics.

INTRODUCTION: Clinical guidelines indicate that hematocrit should be monitored during testosterone replacement therapy (TTh), with action taken if a level of 0.54 is exceeded. AIM: To consider the extent of changes in hematocrit and putative effects on viscosity, blood flow, and mortality rates after TTh. METHODS: We focused on literature describing benefits and possible pitfalls of TTh, including increased hematocrit. We used data from the BLAST RCT to determine change in hematocrit after 30 weeks of TTh and describe a clinical case showing the need for monitoring. We consider the validity of the current hematocrit cutoff value at which TTh may be modified. Ways in which hematocrit alters blood flow in the micro- and macro-vasculature are also considered. MAIN OUTCOME MEASURES: The following measures were assessed: (i) change in hematocrit, (ii) corresponding actions taken in clinical practice, and (iii) possible blood flow changes following change in hematocrit. RESULTS: Analysis of data from the BLAST RCT showed a significant increase in mean hematocrit of 0.01, the increase greater in men with lower baseline values. Although 0 of 61 men given TTh breached the suggested cutoff of 0.54 after 30 weeks, a clinical case demonstrates the need to monitor hematocrit. An association between hematocrit and morbidity and mortality appears likely but not proven and may be evident only in patient subgroups. The consequences of an increased hematocrit may be mediated by alterations in blood viscosity, oxygen delivery, and flow. Their relative impact may vary in different vascular beds. CONCLUSIONS: TTh can effect an increased hematocrit via poorly understood mechanisms and may have harmful effects on blood flow that differ in patient subgroups. At present, there appears no scientific basis for using a hematocrit of 0.54 to modify TTh; other values may be more appropriate in particular patient groups. König CS, Balabani S, Hackett GI, et al. Testosterone Therapy: An Assessment of the Clinical Consequences of Changes in Hematocrit and Blood Flow Characteristics. Sex Med Rev 2019;7:650-660.

Cardiovascular risks of anemia correction with erythrocyte stimulating agents: should blood viscosity be monitored for risk assessment?

To date, all major clinical trials for anemia correction using erythrocyte stimulating agents (ESAs) failed to show improved outcomes for cardiovascular disease (CVD), stroke, and vascular thrombosis. Even moderate elevations in hemoglobin (e.g., to 13 g/dL) using erythropoietin have been associated with significantly increased risk of thrombotic cardiovascular events and heart failure. This review presents a biophysical rationale for increased risk of CVD among certain patients treated with ESAs and suggests a risk management approach based on blood viscosity. Whole blood viscosity is a key determinant of the work of the heart, and elevated blood viscosity appears to be both a strong predictor of cardiovascular disease and an important pathophysiological factor in the development of atherothrombosis. Blood donation has been shown to reduce viscosity. Reflecting these findings, studies in male blood donors and in women of premenopausal age with regular menstruation have shown reduced incidence of cardiovascular events such as myocardial infarction, angina, stroke, and the requirement for procedures such as percutaneous transluminal coronary angioplasty and coronary artery bypass graft compared with non-donors and postmenopausal women, respectively. We propose that blood viscosity monitoring should be considered as part of a cardiovascular risk assessment, whenever an increased cardiovascular risk is detected and particularly in the context of anemia correction.

Assessment by transient elastography of the viscoelastic properties of blood during clotting.

Blood clotting is a natural process that can be both beneficial and life-threatening for the human body. It allows the maintenance of hemostasis after vascular injury, but it can also cause deep vein thrombosis and heart stroke. This study aimed better to understand the clotting process from a biomechanical point of view by using an acoustic method. The long-term objective is the staging of the age of clots in deep veins for therapy planning. The transient elastography method using a shear elasticity probe served to evaluate the shear wave velocity (V(S)) and shear wave attenuation (alpha(S)) of porcine whole blood during in vitro clot formation. By solving an inverse problem, it was then possible to provide images of the elasticity (mu(B)) and of the viscosity (eta(B)) from clotting blood. The time-varying elasticity and viscosity were very similar to what has been observed for the sol-gel transition of polymers. The mechanical properties of blood clot, which were modified by varying the hematocrit and by adding heparin or fibrinogen, were clearly assessed by the transient elastography technique. It is concluded that the shear elasticity probe is an appropriate tool to quantify and follow the sol-gel transition of blood during clotting.

An assessment of the duration of cephapirin-induced coagulation abnormalities as measured by thromboelastography.

Cephalosporin antibiotics are used prophylactically in cardiothoracic surgery to prevent postoperative infection. In 30 patients undergoing primary elective coronary artery bypass grafting, the whole blood coagulation system was prospectively evaluated before, and 10 and 30 minutes after administration of 1 g of cephapirin (Cefadyl, Bristol Laboratory, Evansville, IN). All patients had normal preoperative coagulation studies and had not received anticoagulant or antiplatelet therapy within 7 days of surgery. At 10 minutes after cephapirin administration, 23 of 30 patients had a significant change in all phases of whole blood coagulation as monitored by thromboelastography (TEG). Thirty minutes after cephapirin administration there was no statistical difference compared with the baseline TEG. It is concluded that cephapirin can cause a significant but transient change in the viscoelastic properties of blood. Coagulation parameters of the TEG should be measured prior to cephapirin administration to prevent errors in establishing baseline values prior to cardiopulmonary bypass.

Clinical assessment of low molecular weight heparin effects in peripheral vascular disease.

This study was carried out, using the double-blind method vs placebo, on 36 patients suffering from stage II peripheral vascular disease (PVD) according to Leriche, to check the clinical and hemorrheologic effects of the administration of a new low molecular weight heparin (LMWH). After a one-month washout period, the patients were randomly assigned either to the group treated with the LMWH (15,000 aXaU/day sc) or to the group treated with indistinguishable placebo. At the start of the study and after three and six months of treatment, clinical, instrumental, and laboratory tests were performed to assess local and systemic efficacy and tolerance. The LMWH under study caused a statistically significant increase in claudication time, with a parallel increase in the absolute claudication distance and in the interval free of pain. The drug also led to a significant increase in activated partial thromboplastin time, the values of which, however, remained within the normal limits, and to a marked reduction in blood viscosity. No significant variation was observed in the tolerability parameters in the two treatment groups, and no local or systemic adverse reactions occurred.

Angiographic contrast agents: conventional and new media compared.

The contrast agents in current use are generally safe, but have certain undesirable side effects. These can be divided into four major areas: systemic reactions, cardiac effects, renal effects, and general vascular effects. For the most part, particularly in regard to cardiac and vascular manifestations, adverse effects are due to a combination of hypertonicity of the ionic contrast agent to blood, calcium binding, and direct chemical toxicity of the specific anion used. There have been many attempts to develop new agents, with a primary aim of lessening the adverse effects. Several of these compounds have undergone extensive experimental evaluation and are currently being used in clinical trials. All of these new agents have lower tonicity than conventional media at the same iodine content. They also appear to bind calcium less. Compared to conventional agents, these new compounds have less effect on the vessel wall and probably on blood coagulation, less effect on renal function, which is particularly important in patients with compromised renal function, and less effect on hemodynamic and electrocardiographic parameters. They also seem to cause much less discomfort during peripheral arteriography than current contrast media. These new agents may be commercially available by 1984 and probably will be significantly more expensive than conventional agents. It is not yet clear, because of higher cost, whether these agents will be used for all patients, or only for patients at particular risk of side effects from conventional contrast media.

[Assessment of potential blood substitute solutions with oxygen-carrying properties and their possible uses]. / Zur Beteiligung potentieller Blut-Ersatzlösungen mit Sauerstoffträgereigenschaften den deren Einsatzmöglichkeiten.

Beside the necessary volume effect (isoosmotic and isooncotic solution) and the physiological bicarbonate concentration (prevention of dilution acidosis) a possible blood substitute with O2 carrier characteristics should enable an optimal O2 transport: Viscosity as low as possible and shear rate independent (Newtonian behavior), O2 concentration at the given O2 partial pressure at least 6 ml/dl, and mean capillary O2 partial pressure as high as possible. For the judgement of such a blood substitute, the so-called O2 supply index is recommended, i.e., O2 concentration times mean capillary O2 partial pressure divided by viscosity.

Drug therapy in intermittent claudication: an objective assessment of the effects of three drugs on patients with intermittent claudication.

It has been suggested that, by reducing the viscosity of blood, flow through capillaries is increased with consequent improvement in the symptoms of patients with peripheral vascular disease. We examined the effects of treatment with drugs purported to reduce blood viscosity to test the validity of this claim. Measurements of viscosity and the rate of blood flow to the leg were made in a group of patients before and after treatment with three different drugs--tetranicotinoylfructose (Bradilan), oxypentifylline (Trental) and cinnarizine (Stugeron). All patients had intermittent claudication in one leg and the distribution of arteriosclerosis was similar in each patient. After treatment there was little or no change in blood viscosity and no change in the rate of flow recorded in the symptomatic legs. We did not find any objective evidence to support the use of these drugs in patients with intermittent claudication.