Congestive Heart Failure

Heart diseases can be primarily grouped into three major disorders: cardiac failure, ischemia and cardiac arrhythmia.
Cardiac failure can be described as the inability of the heart to pump blood effectively at a rate that meets the needs of the metabolizing tissues. This occurs when the muscles that perform contraction and force the blood out of heart are performing weakly. Thus cardiac failures primarily arise from the reduced contractility of heart muscles, especially the ventricles. Reduced contraction of heart leads to reduced heart output but new blood keeps coming in resulting in the increase in heart blood volume. The heart feels congested. Hence the term congestive heart failure.
Congested heart leads to lowered blood pressure and poor renal blood flow. This results in the development of edema in the lower extremities and the lung (pulmonary edema) as well as renal failure.
The aglycone moiety: The steroid nucleus has a unique set of fused ring system that makes the aglycone moiety structurally distinct from the other more common steroid ring systems. Rings A/B and C/D are cis fused while rings B/C are trans fused. Such ring fusion give the aglycone nucleus of cardiac glycosides the characteristic 'U' shape as shown below. To view the 3-dimensional structure of the aglycone moiety click on the figure.

The steroid nucleus has hydroxyls at 3- and 14- positions of which the sugar attachment uses the 3-OH group. 14-OH is normally unsubstituted. Many genins have OH groups at 12- and 16- positions. These additional hydroxyl groups influence the partitioning of the cardiac glycosides into the aqueous media and greatly affect the duration of action.
The lactone moiety at C-17 position is an important structural feature. The size and degree of unsaturation varies with the source of the glycoside. Normally plant sources provide a 5-membered unsaturated lactone while animal sources give a 6-membered unsaturated lactone.
Sugar moiety : One to 4 sugars are found to be present in most cardiac glycosides attached to the 3-OH group. The sugars most commonly used include L-rhamnose, D-glucose, D-digitoxose, D-digitalose, D-digginose, D-sarmentose, L-vallarose, and D-fructose. These sugars predominantly exist in the cardiac glycosides in the -conformation. The presence of acetyl group on the sugar affects the lipophilic character and the kinetics of the entire glycoside. Because the order of sugars appears to have little to do with biological activity Nature has synthesized a repertoire of numerous cardiac glycosides with differing sugar skeleton but relatively few aglycone structures.

Structure - Activity Relationships
• The sugar moiety appears to be important only for the partitioning and kinetics of action. (see section on pharmacokinetics of cardiac glycosides) It possesses no biological activity. For example, elimination of the aglycone moiety eliminates the activity of alleviating symptoms associated with cardiac failure.
• The "backbone" U shape of the steroid nucleus appears to be very important. Structures with C/D trans fusion are inactive.
• Conversion to A/B trans system leads to a marked drop in activity. Thus although not mandatory A/B cis fusion is important.
• The 14-OH groups is now believed to be dispensible. A skeleton without 14-OH group but retaining the C/D cis ring fusion was found to retain activity.
• Lactones alone, when not attached to the steroid skeleton, are not active. Thus the activity rests in the steroid skeleton.
• The unsaturated 17-lactone plays an important role in receptor binding. Saturation of the lactone ring dramatically reduced the biological activity.
• The lactone ring is not absolutely required. For example, using ,-unsaturated nitrile (C=C-CN group) the lactone could be replaced with little or no loss in biological activity.

Pharmacokinetics of Cardiac Glycosides
The commercially available cardiac steroids differ markedly in their degree of absorption, half-life, and the time to maximal effect (see table below).
Agent GI absorption Onset (m) Peak (h) Half-life

Ouabain Unreliable 5-10 0.5-2 21 h
Deslanoside Unreliable 10-30 1-2 33 h
Digoxin 55-75% 15-30 1.5-5 36 h
Digitoxin 90-100% 25-120 4-12 4-6 days
Usually this is due to the polarity differences caused by the number of sugars at C-3 and the presence of additional hydroxyls on the cardenolide. Although two cardiac glycosides may differ by only one sugar residue their partition co-efficients may be significantly different resulting in different pharmacokinetics. For example, lanatoside C and digoxin differ only by a glucose residue and yet the partition co-efficient measured in CHCl3/16% aqueous MeOH are 16.2 and 81.5, respectively.
Glycoside Partition Coefficient

Lanatoside C (glucose-3-acetyldigitoxose-digitoxose2-digoxigenin) 16.2
Digoxin (digitoxose3-digoxigenin) 81.5
Digitoxin (digitoxose3-digitoxigenin) 96.5
Acetyldigoxin (3-acetyldigitoxose-digitoxose2-digoxigenin) 98.0
G-Strophanthin (rhamnose-ouabagein) very low
In general, cardiac glycosides with more lipophilic character are absorbed faster and exhibit longer duration of action as a result of slower urinary exretion rate. Lipophilicity is markely influenced by the number of sugar residues and the number of hydroxyl groups on the aglycone part of the glycoside. Comparison of digitoxin and digoxin structures reveals that they differ only by an extra OH group in digoxin at C-12, yet their partition coefficients differ by as much as 15 % points.

Biochemical Mechanism of Action
The mechanism whereby cardiac glycosides cause a positive inotropic effect and electrophysiologic changes is still not completely clear. Several mechanisms have been proposed, but the most widely accepted involves the ability of cardiac glycosides to inhibit the membrane bound Na+-K+-ATPase pump responsible for Na+-K+ exchange.
The process of muscle contraction can be pictured as shown below.

The process of membrane depolarization / repolarization is controlled by the movement of three cations, Na+, Ca+2, and K+, in and out of the cell. At the resting stage, the concentration of Na+ is high on the outside. On membrane depolarization sodium fluxes-in leading to an immediate elevation of the action potential. Elevated intracellular Na+ triggers the influx of free of Ca++ that occurs more slowly. The higher intracellular [Ca++] results in the efflux of K+. The reestablishment of the action potential occurs later by the reverse of the Na+-K+exchange.
The Na+ / K+ exchange requires energy which is provided by an enzyme Na+-K+-ATPase. Cardiac glycosides are proposed to inhibit this enzyme with a net result of reduced sodium exchange with potassium that leaves increased intracellular Na+. This results in increased intracellular [Ca++]. Elevated intracellular calcium concentration triggers a series of intracellular biochemical events that ultimately result in an increase in the force of the myocardial contraction or a positive inotropic effect.

COMMUNITY HEALTH: TIPS FOR HEALING SPIDER VEINS, CURING BAD BREATH

Make Spider Veins Disappear
LOVELY M. MIXON from New York City asked for ways to get rid of spider veins.
CHANCE DIEBOLD, N.D., a naturopath in Scottsdale, Ariz., responded via email: The only way to get rid of spider veins is by having them removed. Sclerotherapy, which involves injecting a substance into the veins that destroys them, is a less expensive and less invasive option than laser removal, and most licensed naturopathic physicians can perform it. Some conventional doctors also perform sclerotherapy, but I recommend the holistic approach that naturopaths take, Herbs like horse chestnut (Aesculus hippocastanum), horsetail (Equisetum arvense), and witch hazel (Hamamelis virginiana) can prevent spider veins if you use them regularly. Take 1 to 5 drops of horse chestnut tincture three times per day, 20 to 60 drops of horsetail tincture three to four times per day, and 10 to 60 drops of witch hazel tincture four times per day.
Freshen Stale Breath
GIGI wrote for suggestions to help her daughter,s chronic bad breath.
CHRISTI ANDRESS from Long Beach, Miss., responded via email: My daughter also suffered from chronic bad breath. Nothing helped until I took her to the doctor and we found she had acid reflux. Once the reflux was under control, her bad breath disappeared.
BETH HAHN from Arlington, Va., responded via email: My daughter had the same problem, We took her to an allergist Who found she was allergic to dust and cats. When we stripped the house of carpets and curtains, took all her stuffed animals out of her room, and put in an air cleaner, her bad breath and other symptoms disappeared right away.
K.V. responded via email: I also had stale breath when I was your daughter's age. My doctor said that my tonsils were larger than normal and that holes in my tonsils formed pockets that collected food. The doctor used an extra-long cotton swab to remove the built-up food. Gargling with salt water will help the smell and dislodge any trapped food.

JEANA G. responded via email: Supplementing with alfalfa tablets (Medicago sativa) and eating a diet rich in fruits and vegetables, with very few processed foods, helped clear up my bad breath.
VERA FANUZZI from Portland, Ore., responded via email: From my experience, a child's chronic badbreath can be the result of a milk intolerance. I've seen bad breath disappear when all forms of dairy were eliminated from the diet.
RON WING from Wichita, Kan., responded: According to Live Right For Your Type by Peter J. D'Adamo (Putnam, 2000), persistent bad breath sufferers may have polyamine levels that are too high. The best way to reduce your polyamine levels would be to follow the appropriate diet for your blood type.
Help for Eye Inflammation
VALERIE STARK wrote about the inflamed irises in her eyes and the vision problems that have resulted, including floaters,
JEANNE MELLETTE from Spartanburg, S.C., responded: For inflammation of the eye, rinse three to four times a day with eyebright tea (Euphrasia officinalis). To make the tea, pour 1 cup of boiling water over 2 teaspoons of the dried Cover and steep for 10 minutes. Strain through a paper coffee filter to remove all herb particles, and then cool to room temperature. Pour the tea into an eyecup (available at drugstores) and bathe each eye for at least five seconds, and up to one minute. Do a liver flush (drinking a mixture of teas, juices, or other ingredients that stimulate the elimination of stored toxic wastes) to alleviate floaters.
DIANE from New York City responded via email: Consider taking the following supplements, which may improve eye health: lutein (a carotenoid), glutathione (an antioxidant that helps make the enzyme glutathione peroxidase), and the herb bilberry (Vaccinium myrtillus). You should also try eye exercises found in vision therapy books, or see a vision therapist for instructions.

Eat Healthy While Traveling
AMANDA MARTIN from Plainfield, Ill., wrote for tips on how to eat a healthy diet with her hectic schedule as a flight attendant.
NANCY SCHNEIDER responded via email: Always eat breakfast. Pack cereal or a muffin so you don't have to depend on hotel or airport offerings. When I'm home and am able to cook healthy meals, I make a little extra, pack it in an oven- and microwave-safe Coming dish, and freeze it. When I go on a trip, I keep the dish cold with the ice on the plane or at the hotel, and heat it up when I'm ready to eat. In the United States, ethnic restaurants have the healthiest foods; try Ethiopian or Indian.
Where to Walk Safely
DENISE, a 13-year-old from Pennsylvania, asked for help finding safe places to walk for exercise.
CHRIS MALAKOWSKY from Longview, Wash., responded: You could take the bus to a safer location or try to find other people in your neighborhood who like to walk so you can walk together.