Hawthorn is the oldest known medicinal plant in European medicine; its actions on the heart were first described by Dioscorides in the first century. Hawthorn extracts have historically been derived from the flowers, leaves, and fruits of the plant. However, most of the data supporting the cardiac activity of hawthorn are based on evaluation of the dried flowering tops of the plants specifically from Crataegus monogyna or Crataegus laevigata.
There are fewer clinical studies on the extract of hawthorn berry alone. There is no evidence of a decrease in mortality. Based on a systematic review of 14 RCTs 14 and a meta-analysis of 13 RCTs 15 ; studies were short-term, and long-term data are lacking.
The leaves, flowers, and berries of hawthorn contain an abundance of oligomeric procyanidins and flavonoids, which are thought to be responsible for its pharmacologic effect. The most studied hawthorn extracts, WS and LI , are standardized to oligomeric procyanidins and flavonoids, respectively. The majority of the pharmacologic studies on hawthorn extract are in vitro and animal studies; however, several in vivo studies have also demonstrated its physiologic effects. Damage to the myocardium during ischemia may be related to free radical effects and the release of human neutrophil elastase from neutrophils.
Oligomeric procyanidins in the leaves and flowers of hawthorn inhibit human neutrophil elastase and act as a free-radical scavenger, which may attenuate damage to the myocardium caused by ischemia. Flavonoids activate endothelium-derived relaxing factor and inhibit phosphodiesterase, thereby increasing vasodilation. Hawthorn has traditionally been used to treat anxiety, asthma, hypertension, dyslipidemia, hypotension, angina, arrhythmias, heart failure, and indigestion.
The most substantial evidence for clinical benefits of hawthorn is its use in chronic congestive heart failure CHF. Limited evidence is available for other traditional uses; therefore, a more in-depth review of these conditions will not be included here. Results of two meta-analyses, including a Cochrane systematic review, found that when used as an adjunct to conventional treatment in patients with chronic CHF New York Heart Association [NYHA] classes I through III , hawthorn substantially increased maximal workload tolerance, increased exercise tolerance, decreased the pressure—heart rate product an index of cardiac oxygen consumption , and improved symptoms of fatigue and shortness of breath as compared with placebo.
Hawthorn extract WS is standardized to Hawthorn extract LI is standardized to 2. The authors concluded that the results suggest a marked benefit in symptom control and physiologic outcomes when hawthorn extract is used as an adjunctive treatment for chronic CHF. By the end of the trial, both groups had improved exercise capacity compared with baseline measurements, with no statistically significant differences between the two treatment arms. However, the investigators used a relatively low daily dosage of captopril The only absolute contraindication for the use of hawthorn is known hypersensitivity to Crataegus products.
Its use is not recommended during pregnancy because of potential uterine stimulation. One publication recommends against use in pregnancy based on results of animal studies and human case reports. It is therefore not currently recommended for children or breastfeeding mothers. The majority of studies indicate that oral hawthorn is well tolerated; vertigo and dizziness are the most common adverse effects. As many as one third of patients with heart failure are taking complementary and alternative medicine supplements, several of which may interact negatively with typical heart failure medications.
Hawthorn should be used with caution when combined with other herbs and supplements that have cardiovascular effects e. Hawthorn is usually standardized to its content of flavonoids 2. The daily dosage as reflected in the literature ranges from to 1, mg, but most physicians believe there is greater therapeutic effectiveness with higher dosages to 1, mg in two or three divided doses daily.
The German Commission E specifically recommends hawthorn leaf and flower as the parts of the plant to be used therapeutically. Despite the supported clinical benefits, any treatment for symptomatic heart failure with claims of inotropic activity should be studied for a long period to rule out any potential increase in mortality. This has been the case with several synthetic inotropic drugs.
In addition, because these products are not regulated by the U.
Food and Drug Administration, patients who insist on using hawthorn should be given a trial of at least four to eight weeks with a reputable supplement. Table 1 summarizes the key points about hawthorn. New York Heart Association classes I through III chronic congestive heart failure: effective for symptom control based on short-term studies, but no evidence of decrease in mortality.
Well tolerated overall; vertigo and dizziness are the most common adverse effects. May enhance the activity of digitalis; theoretic interactions with antiarrhythmics, antihypertensives, antihyperlipidemic agents. Known hypersensitivity to Crataegus products; insufficient reliable information for safety of use in children and in women who are pregnant or breastfeeding. Most effective dosage not currently known; recommended dosages range from to 1, mg per day in two or three divided doses.
Hawthorn should not be used in place of proven conventional therapies for heart failure; may be effective for symptom improvement when used as an adjunct to conventional therapies; use should be carefully considered and monitored. Product quality may vary. Already a member or subscriber? But what were the mechanisms within the membrane itself?
Clues came from study of the glomus type I cell of the carotid body, where hypoxia was found to close voltage-gated potassium channels in the cell membrane, thereby inhibiting potassium ion efflux, increasing the positivity within the cell, promoting membrane depolarization, and initiating neural discharge of the cell. Findings in the pulmonary arterial smooth muscle cell were that a similar mechanism caused membrane depolarization and contraction of the cell Figure 1 What still remains a mystery is precisely how the hypoxia is sensed.
The early idea that decreased intracellular ATP constitutes the hypoxic signal seems unlikely because intracellular energy stores are well maintained at P o 2 values far below those that depolarize the cells. Current research focus is on the diverse family of potassium channels, how they differ with age, location, and function, how they are controlled, and the intracellular consequences of their activation.
The effect of redox state on membrane potassium channel activity. Normoxia is associated with open channels, whereas hypoxia results in closing of the potassium channels, leading to membrane depolarization, opening of voltage-gated calcium channels, influx of calcium into the cytosol, and vasoconstriction. Oxidizing compounds mimic normoxia, while reducing agents mimic the effects of hypoxia. Modulation of hypoxic vasoconstriction. For the lung circulation during the last four decades, possibly the greatest amount of printer's ink has been spilled over the roles of chemical mediators in hypoxic pulmonary vasoconstriction.
As that ink dries, it has become clear that known chemical substances liberated by the lung, including, for example, the catecholamines, histamine, angiotension II, 5-hydroxytriptamine, prostaglandins, thromboxane, the leukotrienes, nitric oxide, and the endothelins are not THE responsible mechanism for hypoxic pulmonary vasoconstriction although at some time, each has been in the news 6 , What has been learned is that each of these chemical substances is to some extent metabolized by the lung circulation, and each has a role to play in circulatory control.
Thus, nitric oxide and prostacyclin support oxygenation and lung inflation in dilating the lung vasculature after birth 17 , The eicosanoids, prostacyclin, thromboxane, and leukotrienes are key determinants of pulmonary circulatory tone during various inflammatory stresses 6 , To a large extent these chemical mediators are responsible for the variable nature of hypoxic pulmonary vasoconstriction from person to person, and under varying conditions of age, gender, inflammation, altitude of residence, pregnancy, adrenergic tone, metabolic inhibition, redox state, ionic balance, temperature, alcohol intake, and exercise, just to name a few In addition, the various mediators not only modulate the effects of hypoxia on the lung circulation, but each is an important regulator of tone in its own right.
An increase in flow rate increases drag and appears to induce the endothelium to generate a signal that triggers relaxation of the subadjacent medial smooth muscle. In the conference proceedings of the Pulmonary Circulation , the word intima appeared several times, but the word endothelium did not appear.
Julius H. Comroe, Jr. He then considered the thinness of the barrier between the air and blood and its importance for oxygen transport. In a whole field of pulmonary endothelial science awaited discovery. That the discovery proceeded so slowly is remarkable, given the lung endothelial cell's strategic location—one of receiving the entire cardiac output, linking the pulmonary and systemic circulations, while also regulating smooth muscle tone by continuously signaling the vascular wall.
Lung endothelium linking pulmonary with systemic circulations.
Second report of the expert panel on detection, evaluation, and treatment of high blood cholesterol in adults. Am Heart J ; Med Decis Making ; 14 The NRI improved significantly. Themain carrier of cholesterol in plasma LDL-C is atherogenic. Ideally, it should be fast, inexpensive and offer high negative predictive power, such that it could reliably eliminate the large sub-group of patients with low to medium clinical suspicion of HF in whom the echocardiogram does not show any relevant disease. Price, 59,
Approximately one decade after the Chicago Pulmonary Circulation Conference, scientists began to realize that the lung endothelium metabolized circulating vasoactive substances. Those substances not particularly useful to the systemic circulation i. Endothelial receptors for these and other substances were then identified Subsequently, hordes of substances were found to be metabolized by the lung endothelium, including kinins, other peptides, catecholamines, purines, insulin, lipoproteins, clotting and complement components, and many others. Endothelium as a regulator of tone in the lung circulation.
Another decade later, in the late s, with the discovery and characterization of the vasodilator, prostacyclin, and the vasoconstrictor, thromboxane 16 , 20 , the concept arose that lung endothelium was more than a slave to the rest of the body, and that it had key roles to play in controlling the lung circulation itself. The endothelium was found to produce prostacyclin in response to vasoconstriction, as though to modulate shear stress within pulmonary vessels, and prostacyclin production appeared to be an important component for the crucial pulmonary vasodilation that normally occurs at birth Next, the key role of the endothelium in lung circulatory control was strongly reinforced with the discovery in the s of endothelial-derived relaxing factor EDRF 7 and the characterization of this factor as nitric oxide NO What is remarkable is that a compound as simple as NO has been so recently discovered, even though nitroglycerin and other oxides of nitrogen, which probably metabolize to NO in the body, have been known to be powerful dilators of blood vessels for more than a century.
In the decade since the identification of NO as the EDRF, and as our understanding has increased, so do we marvel at the beauty of its contribution to system design.
For example, among the fundamental design goals of vascular biology are the matching of lung vessel size to its blood flow and the restraining to within tolerable limits of shear stresses from the flowing blood. These design goals must be met: 1 continually; 2 for each vessel segment independently of other segments; and 3 during steady states as well as rapid change.
The goals would be facilitated if lung endothelial cells could sense shear stress and could modulate it by prompt local action, as foreseen by Rodbard Endothelial cells seem both to sense local shear and to initiate a response because of their inherent ability to synthesize NO from the ubiquitous amino acid, l -arginine, and molecular O 2 in response to increased shear Figure 2 , top panel. Because the NO molecule is small and soluble, it diffuses quickly from the endothelial cell to the neighboring smooth muscle cells, resulting in prompt vasodilation, which in turn reduces shear stress in that vascular segment.
And the effect is local, because NO has a brief half-life in tissue, and in blood it is bound to hemoglobin with an affinity even greater than that of carbon monoxide. Thus, in part through NO, the design goals for vascular regulation are met. Pathway of nitric oxide NO generation in the endothelial cell and mechanism of NO-induced relaxation in the smooth muscle cell top panel. Production of vasoconstrictors by the endothelium in response to a variety of stimuli contributes to the control of pulmonary vasomotor tone bottom panel.
As a result of its prompt local powerful actions, NO may be the lung's primary normal vasodilator with many key regulatory roles. It is considered to help maintain the normal low pulmonary vascular tone, to oppose increases in tone caused by acute or chronic hypoxia or other vasoconstrictors, to help regulate tone in fetal life, to be a major factor in the vasodilation that occurs at birth, and to mediate the reduced maternal pulmonary vascular tone associated with pregnancy. In diseases that damage lung endothelium, for example, primary pulmonary hypertension see below , loss of NO production contributes to high smooth muscle tone and further vascular damage.