Lecture 16- : Heartworm infection and disease in dogs pt 1- Biology, Clinical Significance, & Prophylaxis

Where do adult Dirofilaria immitis worms primarily reside in infected hosts?

Pulmonary artery and vasculature of dogs, cats, and other mammals (e.g., pet ferrets).

What are the size differences between male and female Dirofilaria immitis worms?

Males: 12-20 cm, coiled tails

Females: 25-31 cm

What is the reproductive method of Dirofilaria immitis?

Viviparous reproduction (live birth of microfilariae).

What is the diagnostic stage of Dirofilaria immitis?

Microfilariae (vermiform embryonic stage) in circulation.

How do dogs become infected with Dirofilaria immitis?

Through bites from mosquitoes harboring infective-stage larvae.

Where do infective larvae migrate before reaching the pulmonary arteries?

Through subcutaneous tissue.

When do larvae reach the pulmonary artery and mature into adult worms?

Approximately 70 to 100 days post-infection.

How long is the pre-patent period before microfilariae begin circulating?

Around 6 months post-infection.

How does transmission to new hosts occur?

1. Female mosquitoes ingest microfilariae from infected hosts.

2. Microfilariae develop to the infective L3 stage in mosquitoes (~14 days at >57°F).

3. Mosquitoes transmit L3 larvae to new hosts during blood meals.

Where is Dirofilaria immitis enzootic?

Throughout the United States, including all lower 48 states and Hawaii.

What environmental factors influence heartworm transmission?

Temperature above 57°F (allows larval development in mosquitoes).

Sufficient precipitation (supports mosquito populations).

Seasonal and possibly year-round transmission in some regions.

What is required for the heartworm life cycle to continue?

The presence of infected animals to provide microfilariae for mosquito vectors.

Name some mosquito species in Tennessee that transmit Dirofilaria immitis

Culex species: Cx. pipiens, Cx. nigripalpus

Aedes species: Ae. trivittatus, Ae. albopictus, Ae. japonicus, Ae. vexans

Anopheles species: An. quadrimaculatus( = efficient vectors)

What mosquito genus feeds primarily at night?

Culex spp

What mosquito genus is most active at dusk and dawn?

Aedes spp.

Which mosquito species is an aggressive daytime feeder?

Aedes albopictus

What factors influence the efficiency of mosquito transmission of heartworm?

Vector efficiency (ratio of L3 larvae to microfilariae ingested).

Mosquito strain variability.

Mosquito feeding activity (time of day).

Microfilarial activity in the host.

Number and frequency of blood meals taken by mosquitoes.

Temperature variations (affects larval development rate in mosquitoes).

Why is microfilarial activity in the host important for transmission?

It must coincide with mosquito feeding activity for effective uptake.

How does temperature affect heartworm transmission?

The number of days where temperatures exceed 57°F determines larval development success in mosquitoes.

How does the prevalence of microfilaremic hosts impact transmission?

Higher numbers of infected hosts increase the likelihood of mosquitoes acquiring and spreading microfilariae.

Where do adult heartworms primarily reside in an infected dog?

Pulmonary arteries and the right side of the heart.

How do adult heartworms stimulate an immune response in the host?

Through immune stimulation of host tissues by adult worms and their secreted products.

What pathological changes occur in the pulmonary vasculature due to heartworm infection?

Obstructive fibrosis

Pulmonary endothelial damage

Narrowing of vascular bed with impaired blood flow

What cardiovascular effect does heartworm disease have on the host?

Reduced cardiac output due to vascular obstruction.

How does pulmonary hypertension affect the heart?

It induces compensatory hypertrophy, leading to right-sided heart enlargement.

What is a hallmark radiographic sign of severe heartworm disease?

Reverse D radiographic profile.

What are other key radiographic changes in heartworm disease?

Enlarged, thickened, and tortuous pulmonary arteries

Pulmonary infiltrates in caudal lung lobes

How can heartworm disease lead to kidney damage?

Through obstruction of the glomeruli.

What three factors contribute to kidney disease in heartworm-infected dogs?

1. Microfilariae

2. Antigen-antibody complexes

3. Wolbachia pipientis

What is Wolbachia pipientis?

An endosymbiotic gram-negative bacterium associated with heartworm disease.

How does Wolbachia contribute to heartworm pathogenesis?

It acts as an inciting factor in heartworm-associated inflammatory disease.

Where is Wolbachia found in the heartworm life cycle?

Present in arthropod vectors

Transmitted in utero from adult female worms to microfilariae

Why is Wolbachia essential for heartworm infection?

It is required for the survival of adult worms in the definitive host and the development of heartworms in mosquitoes.

What is Caval Syndrome?

A severe form of heartworm disease where large numbers of adult worms enter the right atrium and vena cava.

How does Caval Syndrome cause hemodynamic complications?

Obstructs blood flow

Interferes with the tricuspid valve function

Leads to hemolysis of passing blood

What are the clinical signs of Caval Syndrome?

Jaundice

Hemoglobinemia

Hemoglobinuria

What is the prognosis for Caval Syndrome if left untreated?

Fatal if not attended to promptly.

What does DIC stand for in the context of heartworm disease?

Disseminated Intravascular Coagulation ("Death is Coming").

What causes DIC in heartworm-infected dogs?

Massive activation and consumption of proteins involved in coagulation.

What is the primary consequence of DIC?

Uncontrolled hemorrhaging.

What secondary host response can be triggered by heartworm infection?

Heartworm-induced pulmonary thromboembolism.

Why is heartworm disease considered a major veterinary health issue?

It is one of the most significant diseases in companion animal medicine.

Despite effective preventatives, cases continue to appear in veterinary practices.

What factors contribute to the continued presence of heartworm disease?

Improved diagnostic methods detecting more cases

Highly effective preventive drugs not being consistently used

Increased client awareness, yet still persistent infections

In which geographic regions has heartworm disease spread?

Mississippi embayment and Gulf Coast

Hawaii

San Francisco area

What is unique about heartworm cases in Alaska?

All cases are linked to travel or relocation, with no evidence of local transmission.

How many cases of heartworm disease were reported by Tennessee veterinarians in 2022?

7,188 cases.

What was the state-wide prevalence of heartworm in Tennessee?

Approximately 1.75%

How does Tennessee compare to national heartworm prevalence?

Tennessee: 1.75%

U.S. average: 1.15%

Tennessee accounts for 3.4% of U.S. cases

Which U.S. states had the highest heartworm prevalence in 2022?

Texas: 22%

Louisiana: 6%

Alaska: 0.01%

What was the heartworm prevalence in Knox County, TN?

321 cases out of 40,803 tested (~0.79%)

Which Tennessee county had the highest heartworm prevalence in 2022?

Hardeman County with 11.38% (266 cases/2,338 tested)

What were the heartworm prevalence rates in Claiborne and Campbell Counties?

Claiborne County: 2.6% (16 cases/603 tested)

Campbell County: 4% (24 cases/571 tested)

How much does treating canine heartworm disease cost per case, on average?

Approximately $1,000 per case (AAHA estimate)

How much did heartworm treatment cost Tennessee pet owners in 2022?

An estimated $28,633,167 (28,633 cases x $1,000 per case).

Why is heartworm disease a financial burden on pet owners?

Unanticipated medical expenses

Potential cause/excuse for pet surrender

Emotional distress for families

How much would statewide heartworm prevention cost per year?

$5,153,940 ($180/year per pet)

How does the cost of heartworm prevention compare to treatment?

Prevention costs ~18% of treatment costs, making it a much more cost-effective option.

What percentage of heartworm cases are preventable?

100%

What discovery revolutionized heartworm prevention in 1983?

Ivermectin (IVM)

How does monthly ivermectin administration work?

It targets the infective L3/L4 larval stage before they develop into adult worms.

What was the heartworm prophylaxis before ivermectin?

Diethylcarbamazine (DEC)

Why was DEC less effective than modern preventatives?

Required daily administration

Extremely microfilaricidal

Contraindicated in heartworm-infected dogs due to severe reactions

What is the primary target of macrocyclic lactones (MLs) like ivermectin?

Glutamate-gated chloride channels (GluCls)

Why do macrocyclic lactones selectively affect parasites?

GluCls are unique to invertebrates and not found in mammals.

What happens when macrocyclic lactones bind to GluCls?

1. Slow and irreversible opening of chloride channels

2. Increased Cl⁻ permeability

3. Hyperpolarization of nerve & muscle cells

4. Flaccid paralysis of somatic muscles (prevents movement)

5. Paralysis of pharyngeal pump (prevents feeding)

6. Inhibition of female reproductive output

What is the ultimate effect of MLs on heartworms?

Inability to stay in place due to muscle paralysis

Inability to feed leads to death

Why do macrocyclic lactones (MLs) have a reduced adulticidal effect on filariid worms compared to GI nematodes?

Pharyngeal musculature is not well-developed in filarial worms (they don't rely on feeding like GI nematodes).

Different sensitivity of glutamate-gated chloride receptors among parasite phyla.

How do MLs affect the reproductive system of heartworms?

High affinity for GluCls binding sites in the uterine wall of adult females and male reproductive tract.

Leads to male sterility and disrupted embryogenesis.

How do MLs increase parasite susceptibility to the canine immune system?

Bind to Excretory-Secretory (ES) pore in juvenile larvae and microfilariae.

Inhibit secretion of Extracellular Vesicles (ESVs) that normally downregulate host immunity.

Increased exposure to host leukocytes, leading to immune destruction.

What is the ultimate result of ML treatment in heartworms?

Exposed parasites are dead parasites

What are the available formulations of heartworm preventatives?

1. Chewable

2. Topical

3. 6- or 12-month injectable

Do heartworm preventatives prevent heartworm infection?

No. They kill infective L3 and early L4 larvae acquired in the previous 30 days but do not prevent infection from occurring.

How do heartworm preventatives contribute to total parasite control?

Many products are combined with treatments for fleas, ticks, and GI worms for broader parasite protection.

How is the choice of heartworm preventative determined?

Based on client preference and additional indications (e.g., flea/tick control, GI parasite control, route of administration).

What genetic mutation is responsible for ivermectin sensitivity in some dogs?

MDR1 mutation (Multidrug Resistance 1)

What breeds are known to have ivermectin sensitivity?

First identified in Collie breeds, but now recognized in several other breeds.

Is ivermectin safe at heartworm preventive doses?

Yes, but at higher doses (~200 μg/kg), it can cause toxicity.

What are the signs of ivermectin toxicity?

Tremors

Ataxia

Blindness

Other neurological signs

Why is ivermectin toxicity more relevant in production animals?

Because of its broad-spectrum capability and higher dosages used in those contexts.

Are all macrocyclic lactone (ML) drugs safe at FDA-labeled doses?

Yes

What is a major concern with heartworm drug resistance?

Failure of monthly heartworm prophylaxis due to overexpression of P-glycoprotein (MDR1).

What is the function of P-glycoprotein (P-gp) in resistant heartworms?

Acts as an ATP-dependent drug efflux pump

Prevents macrocyclic lactones from accumulating in the parasite

Reduces drug efficacy

What was the first isolate where resistance was detected?

MP3 isolate of D. immitis.

Which heartworm preventatives were affected by resistance first?

HeartGard Plus (Ivermectin-based)

Interceptor (Milbemycin-based)

Why is Moxidectin still effective against resistant heartworms?

It does not efflux as readily through the P-gp pump.

Where is heartworm resistance primarily observed?

Mississippi Delta/Embayment region

What are contributing factors to heartworm resistance?

High rates of HW+ tests

Unprotected animals

Circumstantial association with Hurricane Katrina dogs

What heartworm prevention strategy has been incriminated in resistance development?

The "Slow Kill" method (using monthly preventatives instead of adulticide therapy).

Should dogs still receive monthly heartworm preventatives despite resistance concerns?

Yes! Prophylaxis is still the best strategy.

Why is annual heartworm testing important?

Early detection of preventative failure

Should include microfilaria testing for a complete picture

Where have genetically demonstrated resistant heartworm isolates been found?

Mississippi Delta/Embayment

High transmission areas with:

- Large microfilaremic host populations

- Suitable mosquito vectors

- High rates of transmission

What is the difference between Lack of Effectiveness (LOE) and Gaps in Owner Compliance?

LOE: True drug failure due to resistance (pharmaceutical liability).

Compliance Gaps: Missed doses, sharing between dogs, or incorrect administration.

What percentage of heartworm-positive dogs in a 301-case study had compliance gaps?

80.7% had gaps in purchase or administration.

What percentage of heartworm-positive dogs had unexplained resistance?

1.7% were not explained by owner compliance behaviors.

What are possible explanations for unexplained resistance cases?

Possible wild-type populations of resistant heartworms

Unclear geographic distribution