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VETERINARY CLINICAL CARDIOLOGY
CARDIOLOGY CONCEPTS
Heartworm Disease
General
1. What is canine Heartworm Disease?
Please refer to the most recent Canine and Feline Diagnosis, Treatment, and Prevention Guidelines set by the American Heartworm Society available at www.heartwormsociety.org

Heartworm is a parasitic pulmonary artery disease due to Dirofilaria immitis.

Review of the Parasitic Cycle:

  • Adult female heartworms release microfilaria into the circulation; these microfilariae can live up to 2 years in the circulation.
  • The mosquito is necessary to complete the life cycle of the D. immitis.
  • When the mosquito takes a blood meal from the dog, it ingests the microfilaria. After 2 weeks inside the mosquito, the D. immitis is now sufficiently mature to continue development within the dog when injected into the dog on the next mosquito bite (infective L3 stage).
  • 4 to 5 months after the D. immitis is injected into the dog, the larvae are present in the heart or pulmonary arteries.
  • 6 to 7 months after the D. immitis is injected into the dog, the adult parasite is ready to produce microfilaria.
2. Discuss the mechanisms of disease induced by heartworm infection.
The severity of disease is determined by the number of worms, duration of infection, and immune response to the infection.

Mechanism of Disease Production:

  1. Physical presence of adult worms in the pulmonary artery.

    The adult worms denude the endothelium of the small arteries. Platelets and WBC adhere to these areas and release platelet derived growth factor. Thrombosis and proliferation of the interna and medial smooth muscle cause arterial obstruction and increased vascular permeability with leakage of plasma into the interstitium and alveoli. The pulmonary arteries dilate, become tortuous, and lose their normal tapering and arborizing pattern. With pulmonary artery obstruction, pulmonary hypertension and cor pulmonale develop (right ventricular concentric hypertrophy).
  1. Obstruction of the right atrium and vena cava.

    An enormous worm burden develops acutely with massive numbers present in the right atrium and caudal vena cava. Intravascular hemolysis due to mechanical shearing results in anemia, hemoglobinemia, hemoglobinuria and jaundice. Signs of right heart failure occur secondary to obstruction and dysfunction of the tricuspid valve. Disseminated intravascular coagulation frequently develops. This complication occurs in endemic areas.
  1. Immune mediated microfilarial destruction.

    In some individuals, a high antibody level results in the destruction of microfilaria within the pulmonary capillaries as they are released from the adult, resulting in one form of occult heartworm disease. These cases usually are associated with the greatest degree of pulmonary pathology and most severe clinical signs. A hypersensitivity reaction with so-called allergic pneumonitis may result due to a marked increase in capillary permeability with mixed alveolar and interstitial disease. So-called pulmonary granulomatosis may occur. This is suggested by the radiographic finding of lung lobe consolidation.
  1. Dying adult worms with adulticide therapy.

    Adulticide therapy inevitably will cause destruction, fragmentation of adult worms, and pulmonary embolization. This will cause an acceleration of the vascular processes that create pulmonary disease. The massive bombardment of worm fragments results in:
    • Pulmonary arterial thrombosis.
    • Enhanced vascular permeability with interstitial and alveolar edema.
    • Disseminated intravascular coagulation.
    • Worsening of pulmonary hypertension.
  1. Renal disease.

    Glomerulonephritis appears to be a common histologic lesion in heartworm disease. However, azotemia, proteinuria, and hypoalbuminemia are rare. Amyloidosis is a very rare complication with heartworm disease
3. How does canine Heartworm Disease present?
  1. Signalment:

    - Dogs are at least 6 months of age; usually middle aged
    - Males and large breed dogs are more often infected than are females and small dogs
  1. History:
  1. Asymptomatic cases:
    - positive on yearly testing
  2. Symptomatic cases:
    - having frequented a heartworm endemic area (south eastern US)
    - weight loss, anorexia
    - chronic non-productive cough
    - labored respiration, exertional dyspnea
    - exercise intolerance, syncope
    - if heart failure present, may note abdominal distention
  1. Physical Examination:
    Most cases examined annually as a screen for heartworm infection show no clinical signs
    • Mild HWD:
      • cough on tracheal manipulation
    • Moderate HWD:
      • increased rate and depth of respiration
      • normal lung sounds or fine crackles on pulmonary auscultation
      • mild weight loss, partial anorexia
    • Severe HWD:
      • signs of right heart failure (elevated right atrial preload) - jugular distention or pulsation, ascites
      • increased rate and depth of respiration
      • fine crackles on pulmonary auscultation
      • split second heart sound on cardiac auscultation
      • emaciation, anorexia
      • distended abdomen
4. How is canine Heartworm Disease diagnosed?
Antigen testing is the most sensitive means of diagnosing heartworm infection. Complimentary tests include microfilaria detection techniques (to determine if this life stage is also present in an antigenemic dog), radiography, and echocardiography.
  1. Antigen tests:
    • Detect circulating adult female worm antigen
    • ELISA and immunochromatographic tests
    • These tests are the most sensitive method to screen an asymptomatic population or verify a suspected heartworm infection
    • Specificity is extremely high
    • The amount of antigen in the circulation is directly but imprecisely related to the number of mature female heartworms present.
      1. ELISA tests provide a graded response
      2. Immunochromatograhic tests do not provide a quantitative result
    • False positive results are very rare and usually due to a technical error. All positive results should be verified by a second antigen test.
    • False negative results are usually due to
      1. Light infection
      2. Female worms are still immature
      3. Only a male infection
      4. Technical error
    • The American Heartworm Society guidelines state that it is better to trust than to reject a test result unless it is contradicted by other strong clinical evidence
  1. Microfilarial detection:
    • Concentration techniques
      1. Modified Knott's technique- preferred method
      2. Filter test
    • Whole blood smear (wet mount) - insensitive, especially with low numbers of microfilariae
    • Microcapillary test - movement beneath the buffy coat in a microhematocrit tube may be visible microscopically, however this is also insensitive
    • Microfilaria testing should be performed in all antigen positive cases - validates the antigen test and identifies the dog as a reservoir of infection
    • Microfilariae negative cases (occult heartworm disease) may occur due to:
      1. prepatent infection (immature worms only)
      2. sterile worms
      3. unisex infection
      4. drug-induced sterility of adult worms
      5. immune-mediated reaction with antibody causing death of microfilariae and suppressing the production of microfilariae from female worms
    • D. immitis microfilariae must be differentiated from Acanthocheilonema reconditum (formerly Dipetalonema reconditum) )
    • Dirofilaria immitis Acanthocheilonema reconditum
      Head end tapered Head end parallel- sided
      Tail mostly straight Tail button hooked (not seen often)
      Body mostly straight Body mostly curved
      Length 270-325u Length 240-290u
      Width 6.7-7.3u Width 3.5-6.4u
  1. Radiology: May see:
    • Right ventricular enlargement
    • Main pulmonary artery enlargement
    • Dilation of peripheral pulmonary arteries
    • Tortuous pulmonary arteries
    • Pruned or truncated pulmonary arteries
    • The right caudal pulmonary artery is most affected; artery width > width of 9th rib where they cross
    • Evidence of pulmonary parenchymal disease
    • Radiographic changes occur early in the course of the heartworm disease
    • In severe cases see signs of right heart failure including pleural effusion, hepatomegaly, splenomegaly, or ascites
    • Pulmonary consolidation in severe cases
  1. Electrocardiography:
    • Signs of right ventricular enlargement only occur in the moderate to severe cases. These include:
      • S wave in leads I and II and III
      • MEA shifted to the right;
      • Deep S wave in V3 (S>0.7 mv or S>R)
  1. Blood work:
    • Hematology
      • Eosinophilia
      • Basophilia
    • Chemistry
      • Hyperproteinemia
      • Nephrotic syndrome (hypoalbuminemia, hypercholesterolemia, with proteinuria)
  1. Echocardiography:
    • Limited application for detection of worms. Worms may be visible in the main pulmonary artery or right branch, however most often worms are primarily in distal pulmonary arteries therefore not visible by ultrasound. Echo is useful, however, to detect secondary cardiac changes and pulmonary artery hypertension.
    • In severe disease, worms may be detected in the right ventricle or right atrium and caudal vena cava (caval syndrome).
5. How is canine Heartworm Disease treated?
Therapy may not always be 100% effective, however clinical signs and respiratory function can be markedly improved even though all worms may not be killed.

Goals of therapy:

  1. Manage heart failure if present
    1. Cautious use of diuretics
    2. Low Na diet
    3. Strict exercise restriction
    4. +/- arterial vasodilators
      • i. Sildenafil is a phosphodiesterase V inhibitor that may be particularly useful in treating pulmonary artery hypertension
      • ii. Amlodipine or hydralazine are alternative vasodilators
    5. +/- positive inotropes particularly pimobendan due to its inodilating properties
    6. After 7-14 days of exercise restriction and heart failure therapy, start adulticide therapy

  2. Adulticide therapy
    1. Melarsomine (Immiticide)
      1. The adulticide of choice
      2. Administered by deep IM injection in the lumbar muscles (L3-L5). Strict adherence must be paid to the manufacturer's instructions.
      3. The standard protocol can be administered for dogs at low risk of thromboembolic complications
        1. 2.5 mg/kg IM q 24 hr for 2 injections
        2. A second series of two injections 24 hours apart may be repeated in 4 months to address worms that were immature during the first series (and thus not susceptible to the adulticide).
      4. An alternate dosing protocol is recommended for dogs with more advanced disease, thus at greater risk of embolic disease
        1. A single injection of 2.5 mg/kg IM initially
        2. In 4-6 weeks follow with the two injection protocol given 24 hours apart
        3. The lower initial dose is expected to result in fewer worms killed to reduce the embolic load on the lungs
        4. This protocol is the treatment of choice by the American Heartworm Society, regardless of disease severity
      5. Diminishing anti-inflammatory doses of prednisone can be used to reduce the risk of pulmonary arteritis and embolization
      6. It is critical to enforce strict exercise restriction for a period of at least one month after each series of treatments
      7. Releasing (antigen test) should be performed 6 months post-adulticide treatment
      1. Ivermectin
        1. Continuous monthly administration of prophylactic doses of ivermectin is effective against young adult heartworms
        2. The adulticidal effect takes 1-2 years, however. Thus the infection persists and causes disease during this period of time. As such, ivermectin is not a substitute for conventional adulticide therapy and should only be considered for those who decline conventional adulticide therapy.
        3. Exercise restriction must be enforced for the duration (1-2 years) of this treatment.
        4. Periodic monitoring (Q 4-6 months) must be performed.

      1. Microfilaricide therapy
        1. Should be initiated as soon as a diagnosis of heartworm disease is made, thus this is often before adulticide therapy is initiated
        2. The macrocyclic lactones are the safest and most effective microfilaricidal agents
        1. Ivermectin, milbemycin oxime, moxidectin, selamectin
        2. Administer chemoprophylactic doses
        3. Complete elimination of microfilariae occurs within 6 months of uninterrupted treatment
        4. Milbemycin oxime is the most potent microfilaricide at the recommended dose and produces the most rapid clearance rate
          • Associated with the rapid death of a large number of microfilariae (especially in cases of large infection) some dogs may experience shock-like signs of tachycardia, weak pulses, pale mucus membranes and dyspnea (2% incidence). Volume expansion and administration of corticosteroids may be beneficial. Other reactions (4% incidence) include lethargy, anorexia, and vomiting. These reactions are mild, last <48 hours and usually require no treatment. Fatalities are rare.
        1. Prophylaxis:
          1. Heartworm is a preventable disease and chemoprophylaxis should be a priority for all dogs in endemic areas.
          2. Puppies as young as 8 weeks of age should be placed on prophylaxis
          3. Reduces the reservoir population
          4. For all dogs over 6 months of age heartworm status should be determined prior to starting chemoprophylaxis.
          5. Macrocyclic lactones are the drugs of choice (ivermectin, milbemycin oxime, moxidectin, selamectin)
            1. Kill microfilariae, 3rd and 4th stage larvae, and young adult heartworms in some cases
            2. Administered monthly
            3. Very safe
            4. Very effective
            5. Provide retroactive efficacy of at least 1 month
            6. Short term lapses in administration should not affect protection
            7. Begin prophylaxis within one month of the anticipated start of transmission and the last dose should be given within one month after transmission ceases
            8. Can begin medication in asymptomatic or mildly symptomatic infected dogs (see above)
            9. Dogs with moderate or severe infection may experience complications with the killing of many microfilariae simultaneously (see above), therefore initiation of treatment in hospital is recommended
            10. Collie dogs (autosomal recessive inheritance) and other p glycoprotein deficient dogs are unusually sensitive to high doses of ivermectin (doses in excess of 16 times the minimum effective prophylactic dose). Toxicosis has been reported with overdosage of other macrocyclic lactones.
          6. Diethylcarbamazine (DEC) is another chemoprophylactic choice however it requires daily dosing thus is rarely used (especially now in the face of availability of the monthly macrocyclic lactones)
            1. Efficacy is entirely dependent on daily use
            2. Therapy should begin 2 weeks before the onset of mosquito season and continue until 2 months after the end of mosquito season (first frost)
            3. Dogs must be shown to be amicrofilaremic before starting DEC as severe and potentially life-threatening reactions may occur when given to microfilaremic dogs
              • Reactions usually occur within 30-60 minutes and involve diarrhea, vomiting, depression, lethargy, incoordination, tachycardia, bradycardia, dyspnea, and peripheral circulatory shock

              Comments on Aspirin Therapy:

              While previously advocated either prior to adulticide therapy or concomitant with adulticide therapy to reduce the pulmonary artery endothelial and medial changes (so called pulmonary arteritis), aspirin is no longer recommended. It may even be contraindicated.
6. What is the prognosis with canine Heartworm Disease?
  1. Asymptomatic individuals
    1. response to therapy is excellent
  2. Individuals with mild to moderate disease
    1. response to therapy is usually excellent
    2. although all worms are rarely killed, the marked reduction in parasite burden results in a marked improvement of pulmonary function
  3. Individuals with severe right heart failure
    1. one can be cautiously optimistic about the response to therapy. With support for heart failure, and using a three injection protocol of melarsomine to promote a graded worm kill effect, most individuals usually respond
  4. Individuals with severe chronic interstitial disease
    1. may have persistent residual cough
7. How does feline heartworm disease differ from canine heartworm disease?
  1. General Remarks:
    • fewer adult worms are present (1 to 5)
    • clinical signs are usually more severe, usually due to heartworm death. The relative space occupied by the worms in the pulmonary arteries is larger as cats have smaller pulmonary arteries.
    • Occult Heartworm Disease (amicrofilaremia) is more common - 80% of infected cats. Occult infection occurs due to host immune-mediated clearance of microfilariae and suppression of microfilariae production.
    • where microfilaria are present they are usually of low numbers and of short life span. Mircofilaremia seldom persists beyond 228 days post infection (circulating microfilariae appear about 195 days post infection). Thus microfilaremia is short lived.
    • prepatent period is approx 7 months
    • the mechanisms of pulmonary pathology in the cat are similar and more severe than in dogs. Embolization of pulmonary arteries due to early heartworm death and host reactions are more intense than in the dog
    • aberrant migration is more common in cats
    • life span of adult worms is much shorter in the cat - 2-3 years.
    • pathology is related to:
      • Arrival of immature heartworms in the pulmonary arteries and their death
        1. Occurs about 3-4 months post infection
        2. Incites an inflammatory arteritis
        3. The clinical picture looks like allergic airway disease (asthma) - called Heartworm Associated Respiratory Disease (HARD)
      • Death of adult heartworms
        1. Live heartworms suppress the immune response
          • This permits many cats to tolerate their infection without ill effects
        2. Once mature worms begin to die - the degenerating worms incite pulmonary inflammation and thromboembolism
          • Single worm infections and their death can cause even cause severe reactions
      • Caval infections are rare in cats - due to small worm burden?
    • Whereas the antigen test to diagnose heartworm is the best test (gold standard) in dogs; because unisex infections consisting of only male worms or symptomatic immature infections are more common in cats, none of the available antigen tests can be relied upon to rule out heartworm disease in cats.
  2. Signalment:
    • cats of all ages usually 3-6 years; no breed predilection
    • 75% are males
  3. History:
    • many cats tolerate their infection without noticeable clinical signs
    • cats may die acutely, exhibit chronic signs or be asymptomatic
    • lethargy, anorexia, and weight loss
    • vomiting intermittently (50%)
    • coughing/dyspnea (50%)
    • sudden death
    • ascites, exercise intolerance, and signs of right heart failure are rare
  4. Physical Examination:
    • harsh lung sounds
    • fine crackles on auscultation of pulmonary field
    • CNS signs may occur due to aberrant filarial migration
  5. Radiology:
    • the best diagnostic tool
    • enlargement, tortuosity, and pruning of the pulmonary arteries especially the caudal pulmonary arteries
    • alveolar disease with patchy coalescent areas or consolidated lung lobes may be noted
    • pleural effusion (30%)
    • arterial changes are not as prominent in the cat as the dog
    • main pulmonary artery enlargement is not detected
    • pulmonary infiltrate with eosinophils (30%)
  6. Electrocardiography:
    • right heart enlargement (25%)
  7. Blood Work:
    • Hematology
      • eosinophilia - 33% incidence, usually resolves in 7 months
      • basophilia - not common, usually resolves
        hyperglobulinemia - usually present
    • Concentration techniques
      • most cats have no circulating microfilaria
      • same techniques as for dogs
    • Immunodiagnostics
      • IFA and ELISA are useful; sensitivity is about 50% with the ELISA tests
        • The antigen tests are highly effective at detecting even single adult female worm infections, however not good to detect unisex male or immature worm infections.
        • 50% - 70% of cats have at least one adult female worm
      • 30% of cats are IFA positive (rare for false positive)
        1. Antibody tests have the advantage of detecting both male and female worms, and larvae (antibody can be detected as early as 2 months post infection.
        2. Antibody tests do not indicate continued infection - only that exposure occurred.
        3. Different antibody tests vary in their sensitivity to each stage of larval development.
        4. Most cats that are antibody positive have only been transiently infected to the L4 larval stage.
      • Since both L5 larvae and adult worms are capable of causing clinical disease in the cat, both antigen and antibody tests are useful and should both be employed
  8. Goals of Therapy:
    1. Supportive therapy
      • severe exercise restriction
      • diuretics
      • corticosteroids: prednisone (1-2 mg/kg SID-TID) for cases of severe lung disease due to thromboembolism
    2. Adulticide therapy
      • a treatment of last resort for cats in stable condition but with clinical signs not controlled by corticosteroids
      • thiacetarsamide (0.22 ml/kg BID x 2 days)
      • melarsomine is toxic to cats at doses as low as 3.5 mg/kg
      • ivermectin at 24 ug/kg monthly administered for 2 years will reduce worm burden by 65%
      • to date there is no evidence that any adulticide therapy increases survival in cats
    3. Surgery
      • ideal to remove worms and not destroy/damage them in situ

    Comment: Massive thromboembolism occurs with killing adult worms; cats should be hospitalized and observed for 2 weeks post treatment.

    1. Microfilaricide therapy
      • usually not required
      • levamisole is effective
    2. Preventative
      • usually not required in Canada
      • monthly prophylaxis is safe and effective in areas where heartworm is endemic in dogs
        • oral (ivermectin or milbemycine oxime) or topical (moxidectin or selamectin)
        • these agents can be given even in cats that are antibody or antigen positive since miicrofilaremia is uncommon

  9. Prognosis:
    • most cats are successfully treated with restriction and corticosteroids
    • if right heart failure is present, they are difficult to manage
    • detectable antigenemia will disappear by 4-5 months of spontaneous or adulticide induce elimination
8. What is Occult Heartworm Disease?
Occult Heartworm Disease refers to the presence of D. immitis in the pulmonary arteries but with no circulating microfilaria (amicrofilaremic).

  1. Prevalence:
    • accounts for 15-25% of infected dogs
  1. Etiology :
    • prepatent infections
    • senile worms
    • unisexual infection
    • drug-induced sterility of adult worms
    • immune-mediated reaction with antibody causing death of microfilariae and suppressing the production of microfilariae from female worms
  1. Mechanism of disease:
    • In some individuals, a high antibody level results in the destruction of microfilaria within the pulmonary capillaries as they are released from the adult. This results in Occult Heartworm Disease. These cases usually are associated with the greatest degree of pulmonary pathology and most severe clinical signs. A hypersensitivity reaction with so-called allergic pneumonitis may result due to a marked increase in capillary permeability with mixed alveolar and interstitial disease. So-called pulmonary granulomatosis may occur. This is suggested by the radiographic finding of lung lobe consolidation.
9. How does Occult Heartworm Disease present?
  1. Signalment:
    • as for microfilaremic heartworm disease
  1. History:
    • owners complain of severe respiratory distress and coughing
    • historical signs of right heart failure will likely be present
  1. Physical Examination:
    • increased rate and depth of respiration
    • harsh lung sounds with crackles on respiration
    • signs of elevated right heart preload
      • jugular venous distention
      • positive hepato-jugular reflux
      • hepatomegaly
      • ascites
    • cardiac auscultation may be normal or a split S2 may be noted
10. How is Occult Heartworm Disease diagnosed?
  1. Definitive Diagnosis:
    • absence of circulating microfilariae
    • positive immunodiagnostic test
  2. Presumptive Diagnosis:
    • absence of circulating microfilariae
    • radiographs supportive of pulmonary artery and pulmonary parenchymal changes due to heartworm
  3. Radiography:
    • right ventricular enlargement
    • dilation of the main pulmonary artery
    • enlargement, tortuosity and/or pruning of the pulmonary arteries
    • pulmonary parenchymal changes of an alveolar pattern (coalescent fluffy [patchy] regions adjacent to pulmonary arteries)
    • may see consolidation of lung lobes (so-called pulmonary eosinophilic granulomatosis)
  4. Electrocardiography:
    • usually signs of right heart enlargement as described for microfilaremic heartworm disease
  5. Blood Work:
    • Hematology: eosinophilia - common; basophilia - common
    • Immunodiagnostics: IFA, ELISA, Agglutination Test
11. How is Occult Heartworm Disease treated?
  1. Supportive Therapy:
    • Aspirin: previously advocated either prior to adulticide therapy or concomitant with adulticide therapy to reduce the pulmonary artery endothelial and medial changes (so-called pulmonary arteritis) is no longer recommended. It may even be contraindicated.
    • Diuretic therapy: relieve pulmonary edema and fluid overload.
    • Marked restriction in exercise.
    • Corticosteroids: are recommended to reduce the pulmonary arteritis and risk/complications associated with pulmonary thromboembolism. There are as yet no studies to evaluate the effect of corticosteroids on the efficacy of melarsomine.
  2. Adulticide Therapy:
    • as for microfilaremic heartworm disease
  3. Microfilaricide Therapy:
    • not required; no microfilaria here
  4. Preventative Therapy:
    • as for microfilaremic heartworm disease
12. What is the prognosis with Occult Heartworm Disease?
With appropriate supportive therapy, the prognosis for complete recovery is relatively good.  These cases have both more severe heart disease as well as lung disease.

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