Feline pulmonary hypertension: are we overlooking an important comorbidity?

Abstract

Pulmonary hypertension (PH) is a potential complication in many disease states, yet it has been largely overlooked in feline medicine. Recently, increased awareness of potential underlying causes has led to a wider understanding of the disease process in humans, with a focus on tailoring therapy to include specific treatment of the underlying etiology. Most of these treatments are not yet available in veterinary medicine, but as they move from the human to the veterinary field, it would be beneficial to better understand the forms of PH encountered in different species. Recently, diagnosis and classification of PH in dogs has been the focus of an American College of Veterinary Internal Medicine consensus statement, yet this condition has received little attention in cats. It is therefore our intention to raise awareness of this condition in cats and to propose a classification system for the types of PH seen in feline patients. As new medications are developed for the treatment of PH, it is important to recognize which forms of PH are seen in feline patients and understand the etiology of the disease. There are many reports of PH (or suspected PH based on echocardiographic assessment) in cats. In this review, we highlight the large number of conditions, and different etiologies, that are associated with PH. Improving understanding of this condition will bring us closer to being able to investigate the benefits of potential new diagnostics and therapies as they become available.

Introduction

Pulmonary hypertension (PH), an abnormally increased pressure within the pulmonary vasculature, is a well-established syndrome in human medicine and is recognized in both dogs and cats.^1–3 In humans, diagnosis of PH requires assessment of the pulmonary arterial pressure (PAP) by catheterization of the right heart, with a mean PAP (mPAP) of ⩾25 mmHg at rest being diagnostic. ¹ Owing to the invasive nature of pulmonary pressure measurement, there have been difficulties in diagnosing and treating PH in small animals. Until recently, the veterinary literature has therefore contained relatively little discussion of this syndrome. However, with recent advances in diagnostic capabilities and newly available medications, interest in PH in veterinary patients has increased. Recently, the American College of Veterinary Internal Medicine published consensus statement guidelines for the diagnosis, classification, treatment and monitoring of PH in dogs. ² To date, no such guidelines exist for feline patients and much of our understanding of this syndrome in cats is extrapolated from either the human or canine literature.

PH is not characteristic of a specific clinical condition, but rather can be associated with numerous disorders.^2,3 Mechanisms of PH can be divided based on the absence or presence of abnormally high pulmonary vascular resistance (PVR). In cases with PH and increased PVR, the underlying cause may be pulmonary endothelial dysfunction (alteration in nitric oxide and prostacyclin pathways); pulmonary vascular remodeling and increased arterial wall stiffness; vascular luminal obstruction; increased blood viscosity or lung parenchymal destruction; or a combination of these factors. ² If there is no increase in PVR, PH can occur due to increased pulmonary venous pressure (ie, left-sided heart disease or compression of a large pulmonary vein [PV]) or increased pulmonary blood flow (ie, left-to-right shunting cardiac/vascular defects).

Experimental studies have been performed in anesthetized cats, suggesting the mPAP is 8–15 mmHg; ⁴ in a group of three conscious cats, mPAP was reported to be 24 ± 3 mmHg. ⁵ However, invasive measurement of the pressures within the right heart or pulmonary vasculature is not a routine clinical procedure in feline patients. Therefore, non-invasive estimates are often substituted for direct measurement. In many of the cases reported herein, echocardiographic parameters have been used to assess for PH. Echocardiography may be used to estimate pressure within the pulmonary arterial circulation. In the absence of right ventricular (RV) outflow tract obstruction, systolic PAP can be estimated from peak tricuspid regurgitation (TR) velocity using spectral Doppler then applying the simplified Bernoulli equation (pressure gradient = 4 × velocity) ² to derive the pressure difference between the right atrium and the right ventricle, ⁶ or by using a pulmonary regurgitant (PR) jet to estimate mPAP (again using the simplified Bernoulli equation). ⁷ In addition to TR and/or PR, clinically relevant PH is typically associated with a number of other echocardiographic findings, including RV hypertrophy (concentric, eccentric or both), flattening of the ventricular septum, RV systolic dysfunction, pulmonary artery (PA) dilation, reduced PA distensibility, rapid RV outflow acceleration times, notching of the RV outflow profile during deceleration and RA dilation. ⁶

The utility and feasibility of echocardiography for detecting PH in cats needs investigation. In dogs, there are a number limitations related to operator, patient and imaging technology that impact on the diagnostic accuracy; thus, echocardiography is best used as a tool to help assess the probability of PH, in conjunction with other clinical information, rather than a means of obtaining a definitive diagnosis. ² The limitations observed in dogs may or may not apply to cats. Further, the echocardiographic techniques and/or parameters required for PH assessment in cats may differ from the techniques and parameters routinely used in dogs, and research in this area is warranted. Until echocardiography or another practical test is confirmed as a reliable tool for assessing the probability of PH in cats, the prevalence of PH in various feline populations is likely to be underestimated.

Veterinarian-related factors may also impact on the estimates of PH prevalence in cats. The decision to recommend or pursue testing for PH ultimately lies in the hands of the clinician; thus, a feline patient is unlikely to be subjected to investigations for PH if the veterinarian’s index of suspicion for PH, based on prior education or training, is low. Additionally, screening for PH is not routinely performed in cats that may be at increased risk for developing PH, such as patients with chronic respiratory disease. Further, availability and/or cost of echocardiography or other diagnostic tests may be prohibitive in some cases, potentially resulting in an underdiagnosis of PH. Conversely, misinterpretation of diagnostic tests by veterinarians could lead to over-/incorrect diagnosis of PH in feline patients.

Another consideration in PH diagnosis is the possibility that cats do not develop PH as frequently or in response to the same conditions as dogs or other species. In dogs, PH is a common sequela to left-sided congestive heart failure (LCHF), whereas Doppler-derived PH was identified in only 17% of cats with LCHF in one study. ⁷ Another common cause of PH in dogs is untreated adult heartworm (Dirofilaria immitis) infection. In contrast, mature heartworm infection in cats experimentally infected with D immitis does not appear to result in overt PH, as assessed by echocardiography of the right heart in a study by Ray Dillon and colleagues. ⁸ The reported dissimilarities in prevalence of PH in cats and other species may be attributable to anatomic or physiologic differences in the pulmonary circulation and/or species differences in the right ventricle’s response to pressure overload.^9,10

Classification of PH

To enhance diagnostic evaluation, facilitate clinical studies and improve therapeutic management options, it has been suggested that pulmonary hypertensive disease should be grouped into categories.^2,11,12 Six categories have been proposed in dogs; pulmonary arterial hypertension (PAH); PH due to left-sided heart disease; PH due to respiratory disease or hypoxia; PH caused by a thrombotic or embolic disease; parasitic disease; and PH with unclear or multifactorial mechanisms. These are based on the presentation, underlying etiology and management options. ² A similar classification system has been published for the evaluation of PH in humans.11,12 As many of these diseases have been recognized in the cat, a similar classification system may be appropriate.

PAH

Group 1 PH or PAH is characterized by proliferation and occlusion of small pulmonary arterioles, leading to progressive elevation of PAP and PVR, and RV failure. This can occur for a variety of reasons:^2,11 idiopathic or heritable; drug or toxin induced; associated with PAH (APAH; congenital cardiac shunts, pulmonary vasculitis and pulmonary vascular amyloid deposition); and pulmonary veno-occlusive disease (PVOD) or pulmonary capillary hemangiomatosis (PCH).

Idiopathic or heritable PAH

In cats, there are no reports of idiopathic or heritable PH. This may be due to difficulties in diagnosing the condition and lack of recognition, or the syndrome might not affect cats. We feel that lack of recognition is most likely, having personally treated young cats where, after extensive investigations, no other underlying cause for PH could be identified (SM Cavanaugh, personal communication 2022).

Drug or toxin induced

In people, a list of therapeutic agents have been demonstrated to cause or are likely to lead to PAH, including toxic rapeseed oil, amphetamines, methamphetamines and amphetamine derivatives (which were marketed as weight-loss substances), L-tryptophan and possibly cocaine, phenylpropanolamine, St John’s wort, pergolide, selective serotonin reuptake inhibitors, leflunomide, interferon alpha and beta, phenylpropanolamine and some chemotherapeutic agents.^11,12 While some of these medications are used in feline medicine, there is currently little evidence of PAH occurring as a result of their administration. There is a single case report of reversible PH occurring in a cat after receiving a single dose of carboplatin, combined with radiotherapy. The authors attributed the PH to be likely secondary to pulmonary thromboembolism (PTE) in that case (group 4), although drug-induced PAH could not be ruled out. ¹³ In addition, cats have served as a model in the demonstration of raised PAP following acute overdoses with the tricyclic antidepressants amitriptyline, imipramine and iprindole. ¹⁴

APAH

In the canine classification, the APAH category has three subdivisions (congenital shunts, pulmonary vasculitis and pulmonary vascular amyloid deposition). ² In comparison, in humans, this category has further subdivisions for connective tissue disorders, porto-PH, HIV-associated PAH, schistosomiasis and chronic hemolytic anemia. ¹¹ While some of these may not exist in the cat, others certainly do, and therefore it is important to remain cognizant that cats with these disorders may have the potential to develop PH. However, there are no reports to date within the feline veterinary literature of PH occurring secondarily to these latter diseases. Therefore, the canine classification appears to be appropriate for cats. Congenital heart disease accounts for approximately 8% (n = 145/1817) of feline cardiac disease cases. ¹⁵ In that study, a total of 162 cats with congenital heart disease were identified; of these, it was reported that 50% of cases were due to ventricular septal defect (VSD), 10% to atrial septal defect (ASD) and 3% to patent ductus arteriosus (PDA), although other forms of congenital cardiac shunt are recognized. ¹⁵ One large case series assessing the echocardiographic findings in 50 cats with PDA documented PH in 45.7% of cases; 24.2% with left-to-right shunting PDA and all cats (n = 7) with right-to-left shunting PDA. ¹⁶ Likewise, a second series documenting PDA in 19 cats demonstrated PAH in 37%. ¹⁷ In contrast, in an earlier study reporting findings in 28 cats with PDA, PAH was only detected in 8% of cases. ¹⁸

The variations between reports may represent different diagnostic criteria, different stages of disease, and/or advancements in the ability to interrogate alterations on echocardiography. Previously, right-to-left shunting PDA with PAH has also been documented in single case reports.^19,20 In addition, a recent study assessing bidirectional and continuous right-to-left shunting PDAs in dogs and cats reported echocardiographic evidence of PAH in 2/3 cats with bidirectional PDAs. ²¹ In cats with left-to-right shunting PDA and PAH, surgical ligation is usually recommended. Alternatively, transcatheter occlusion of PDA may be suggested in some cats, but its use is somewhat limited by patient size.^22–24 In a study by Bascuñán et al, ¹⁶ seven cats with PDA and PAH underwent surgical ligation. One of the cats died intraoperatively and six survived to discharge. Long-term survival was documented in three of these cases, with a median follow-up of 7.4 years. Other case reports have also documented a positive outcome postoperatively in a cat with left-to-right PDA, PAH and right-sided congestive heart failure, ²⁵ and in a further two cats with PDA and PAH. ²⁶

Despite being the more prevalent defect, reports of PAH in cats with VSD are infrequent.^27,28 Other case reports document VSD alongside other abnormalities. In one such report, a cat with non-restrictive paramembranous VSD, secundum-type ASD and aortic dextropositioning was diagnosed with PH based on echocardiography. This case was followed from 10 weeks of age until death at 8 years, when a post-mortem examination demonstrated plexogenic lesions, a hallmark of severe, chronic PAH. ²⁹ Block and Glassman ³⁰ recently reported a case of partial atrioventricular septal defect with PH in a 9-month-old kitten. In another case report, a 7-month-old kitten was documented to have a right-to-left shunting VSD, right-heart failure, PAH and a caudal vena cava aneurysm. ³¹ Unfortunately, that cat only survived to 11 months of age, and no post-mortem examination was performed to determine the underlying pathology.

There are occasional reports of ASDs resulting in PAH in the cat.^32–34 In one study, 2/17 cats with ASD (one with a complete ASD and one with partial ASD with ventricular communication) were suspected of having PAH, based on echocardiography. ³³ In the case reported by Uechi et al, ³² an ostium secundum ASD with left-to-right shunting was identified and closed, leading to resolution of the clinical signs. In addition, cats with double-outlet right atrium (DORA) – a form of atrioventricular septal defect in which there is an extreme leftward deviation of the lower portion of the interatrial septum, resulting in insertion of the septum into the atrial wall left and posterior to the mitral valve (MV) orifice – have been reported to demonstrate PAH. ³⁵

Isolated partial anomalous pulmonary venous connection (PAPVC) is an uncommon congenital heart anomaly that is sporadically associated with PAH in people. ³⁶ The term PAPVC defines a group of congenital cardiovascular anomalies caused by the abnormal return of at least one, but not all, of the PVs directly to the right atrium or indirectly through a variety of venous connections from the anomalous PV. ³⁶ In many people with PAPVC there are concurrent cardiac abnormalities, particularly ASD, which was reported in 80% of people in one study. ³⁷ There are reports of this condition occurring in the cat.^38,39 One of these cases was reported to have left-sided and right-sided anomalous connections draining into the caudal vena cava, identified on CT. ³⁹ In that case no ASD was present, but there was echocardiographic evidence of PAH. In the second case the cat demonstrated right cranial, right caudal and left caudal PVs draining into the coronary sinus, along with an ASD and concurrent PAH. ³⁸

While cardiac shunts are not uncommon, there are only rare reports of either pulmonary vascular amyloid deposition ⁴⁰ or pulmonary vasculitis^41,42 in the cat. None of these studies has assessed PAP, although post-mortem changes in some suggest that PAH may have been present. ⁴¹

Schistosomiasis is reported as a cause of APAH in humans. ¹¹ As there are several parasitic diseases that can result in PH in small animals, the canine classification includes a separate category for PH secondary to parasitic disease. ² Other causes of APAH reported in humans (ie, connective tissue disease, porto-PH, HIV and chronic hemolytic anemia) have not been reported to cause APAH in cats. However, as PAH is rarely assessed, clinicians should be cognizant of the potential for these diseases to lead to PAH.

Type 1’

PVOD and PCH are individualized and classified as clinical group 1’ in the canine classification, ² and have recently been changed from 1’ to 1.6 in the human classification. ¹² The characteristic lesion in PVOD is the obliteration of small PVs by fibrous intimal thickening and irregular capillary proliferation. This leads to upstream congestion of the alveolar capillaries and pulmonary arterial remodeling, with a progressive increase in PVR, PAH and, ultimately, right-sided heart failure. ⁴³ In PCH, PH arises predominantly due to proliferation of alveolar capillaries, which may infiltrate into the pulmonary arteries, veins and bronchioles. ⁴⁴ These are uncommon diseases with similar pathological features and clinical presentation in people, which has led some to suggest that they are a single disease entity, termed simply as PVOD for ease.^45,46 It is important to differentiate PVOD from other forms of PH, as this disease carries a worse prognosis and treating with therapies appropriate for PAH can result in life-threatening pulmonary edema. ⁴⁶ Mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 (EIP2AK4) gene are responsible for many of the inherited forms of PVOD. However, other causes include exposure to chemotherapeutic agents (especially alkylating agents, mainly cyclophosphamide), tobacco smoke and organic solvents such as trichlorethylene (especially in combination with tobacco smoke). Finally, an immune-mediated form of the disease is seen, especially in association with sarcoidosis, granulomatosis of Langerhans, connective tissue disease, Hashimoto’s thyroiditis and, occasionally, HIV.^43,46 There are several reports of PVOD occurring in the dog,^47–50 and two reports of PCH in the cat.^51,52

PH due to left heart disease

Left-sided ventricular or valvular diseases can produce elevated left atrial (LA) pressures, which, in turn, can elevate pulmonary venous pressures and result in PCH and, ultimately, PH – so-called post-capillary PH. In people, left heart disease represents the most frequent cause of PH and this category is subdivided into PH due to heart failure with preserved left ventricular (LV) ejection fraction (LVEF), PH due to heart failure with reduced LVEF, valvular heart disease and congenital/acquired cardiovascular conditions leading to post-capillary PH.^11,12 In the canine classification it is suggested that this group is divided into LV dysfunction, with subcategories of dilated cardiomyopathy and myocarditis; valvular disease, with subcategories of myxomatous (degenerative) MV disease and valvular endocarditis; and congenital/acquired left heart inflow/outflow tract obstruction and congenital cardiomyopathies, with subcategories of MV dysplasia, MV stenosis and aortic stenosis. ² It has previously been suggested that, in cats, PH due to left heart disease should be divided into LV systolic dysfunction, LV diastolic dysfunction, valvular disease, congenital/acquired left heart inflow/outflow tract obstruction and congenital cardiomyopathies. ⁵¹ However, it is increasingly recognized that cats with infectious/inflammatory cardiac disease often present with a combination of endocarditis and myocarditis. Furthermore, there is frequently a combination of abnormalities in a single case, for example a cat with end-stage hypertrophic cardiomyopathy (HCM) could present with both systolic and diastolic dysfunction, and outflow tract obstruction. To simplify this, we consider the potential categories for type 2 PH to be: (1) acquired disease, including LV cardiomyopathy, degenerative mitral or aortic valve disease, LV myocarditis/endomyocarditis, mitral and/or aortic endocarditis, and LV and/or LA neoplasia; and (2) congenital, including mitral and/or aortic valve dysplasia/stenosis, and congenital inflow/outflow obstruction.

An experimental model of heart failure with preserved ejection fraction (HFpEF) has been developed in cats. In this model the development of PH in cats 4 months after aortic constriction was documented. The cats developed LV hypertrophy, LA enlargement, LV diastolic dysfunction and elevated LV end-diastolic pressures. ⁵³ In addition, a recent clinical report analyzed the prevalence of PH in cats with naturally occurring left-sided heart disease. These authors reported that 17% of cats with left-sided heart disease demonstrated echocardiographic evidence of PH. ⁷ Further analysis demonstrated that this was most common in cats with congenital heart disease (5/5 cases) but was present in 3/8 cats with restrictive cardiomyopathy (RCM), 2/6 with unclassified cardiomyopathy, 1/5 with dilated cardiomyopathy, 3/23 with end-stage HCM and 6/80 with HCM, suggesting that PH may be underdiagnosed in cats with cardiac disease. ⁷ In a second study assessing the underlying disease in cats with PH, 14/29 were found to have left-sided heart disease, with six cats with RCM and six with HCM demonstrating PH. ⁵⁴ In that study seven cats were documented as having congenital heart disease and PH, although the type of congenital heart disease was not discussed. ⁵⁴

There are reports of PH occurring in cats with congenital inflow/outflow tract obstruction. In a report of cats with supravalvular mitral stenosis, half of cases (7/14) were reported to have PH. ⁵⁵ However, of the seven affected cats, four had partial atrioventricular septal defects in association with a supravalvular mitral lesion, which has led some to suggest that these cats may, in fact, have had DORA. ³³ Furthermore, there are several reports of cats with cor triatriatum sinister and PH.^56–58 Cor triatriatum sinister is a rare congenital defect in which the LA is divided into two distinctive cavities (a proximal chamber into which the PVs drain and a distal chamber which communicates with the mitral apparatus). Cats with cor triatriatum sinister alone, or in combination with a persistent left cranial vena cava or incomplete atrioventricular septal defect, have been demonstrated to have concurrent PH.^56–58

There are currently no reports of PH in cats with endocarditis or myocarditis. However, the critical nature of many of these patients is often prohibitive for detailed echocardiographic assessment.

PH secondary to respiratory disease or hypoxia

Group 3 PH is composed of diseases which result in alveolar hypoxia and pulmonary artery vasoconstriction. The alveolar hypoxia may arise due to chronic lung disease, impaired control of respiration or increased PVR at high altitude. In people, the exact prevalence of PH in these conditions remains largely unknown. ¹¹ This is even more true with cats, where PH in pulmonary disease is a relatively new area of interest. However, experimental studies have demonstrated that the feline pulmonary vasculature is highly sensitive to the effects of hypoxia;^59,60 thus, it is likely that PH is a consequence of feline chronic respiratory disease.

Diseases that are potential causes of type 3 PH include (modified from the human and canine classifications):^2,11 chronic obstructive airway disease; primary pulmonary parenchymal disease (interstitial lung disease, infectious pneumonia and diffuse pulmonary neoplasia); other pulmonary diseases with mixed restrictive and obstructive pattern; obstructive sleep apnea/sleep-disordered breathing; chronic exposure to high altitude; developmental lung disease; and miscellaneous (bronchiolar disorders, bronchiectasis, emphysema, pneumonectomy).

Airway obstruction can involve either the upper or lower respiratory tract. In people, hypoxemia and hypercarbia from upper airway obstruction are recognized mediators of PH, and are particularly common in children. ⁶¹ In feline medicine, a single case of PH has been documented in a 1-year-old cat with chronic upper airway obstruction caused by an nasopharyngeal polyp. ⁶² Obstructive lower respiratory tract diseases, particularly feline asthma and chronic bronchitis, are common in cats, but, as yet, the incidence of PH in feline chronic bronchopulmonary diseases has not been investigated.

Primary pulmonary parenchymal diseases have been associated with PH in cats. Fibrotic interstitial lung disease (often termed pulmonary fibrosis) likely represents the end stage of progressive damage and reparation from a number of causes. Damage to, and destruction of, the pulmonary parenchyma leads to collagen deposition, with subsequent impaired respiratory function and hypoxemia.^63,64 As a result, cats with pulmonary fibrosis have been recognized to exhibit PH.^65,66 Interestingly, in one study, 6/23 cats with pulmonary fibrosis were found to have neoplasia (bronchoalveolar carcinoma in four, focal carcinoma with multifocal adenomas in one and histiocytic sarcoma in one). Unfortunately, in that study estimates of pulmonary pressure were not available and therefore the authors could not assess for PH. ⁶⁴ However, as most of these are solitary rather than diffuse neoplasms, the neoplastic process would unlikely be associated with PH. In the recent case series reported by Escalda et al, ⁵⁴ there was a case of PH that was reported to have ‘pulmonary neoplasia’, although there were no details provided regarding the form of neoplasia. There have also been recent reports of cats with infectious pneumonia demonstrating PH; one case was described in the presentation by Escalda et al, ⁵⁴ and another was described in a cat with left pulmonary artery coarctation and interstitial pneumonia. ⁶⁷

Toxin-induced acute lung injury and PH has been reported in the cat. There are numerous experimental studies in which cats are used as a model for PH. In one study designed to assess the role of microvascular pressure in the development of PH, ⁶⁸ oleic acid was used to induce acute lung injury in artificially perfused feline lungs. The authors demonstrated that in this model of acute lung injury an increase in microvascular resistance was followed by an increase in the arterial resistance and PAH. In other models of PAH, the Escherichia coli endotoxin was infused into cats, to induce PAH, and, with this, the modification of PAH in the presence of various vasoactive compounds.^69–72

Sleep apnea has been described in the cat; however, as yet, PH has not been described in association with sleep apnea in cats. ⁷³ Furthermore, no studies have assessed the effect of chronic exposure to high altitude on the feline pulmonary vasculature.

Congenital, isolated unilateral agenesis (or absences) of pulmonary arteries (UAPA) is a rare cardiovascular abnormality in which anomalous involution of the proximal sixth aortic arch occurs (leaving the connection between the intrapulmonary arteries and the distal sixth aortic arch). Although this is a cardiovascular anomaly, it results in pulmonary hypoplasia of the ipsilateral lung, enhanced blood flow to the contralateral lung and an increased risk of PH. ⁷⁴ There are several reports of UAPA in the feline veterinary literature, the most recent of which documented PH in this condition.^75–78

Various bronchiolar diseases are seen in feline patients. ⁴⁸ However, to date, PH has not been described in this group. There is a report of experimentally induced emphysema, in which cats developed PH, but this has not been reported in clinical cases. ⁷⁹

PH caused by thrombotic or embolic disease

It has been reported that PH may be present in 8.2% of people with acute pulmonary embolism. ⁸⁰ The likely mechanism for PH in thromboembolic disease is arteriopathy caused by endothelial dysfunction and/or pulmonary arterial vascular remodeling, luminal narrowing and increased PVR. ⁸⁰ It is likely that the following are both potential causes of PH in the cat: thromboembolism; and embolism or other pulmonary artery obstructions.

PTE is rarely diagnosed in the cat. ⁸¹ Many disease processes are known to predispose to PTE,^81,82 but diagnosis requires specialist facilities, and even when these are available, diagnosis can be challenging due to the unstable presentation of the patient. In the reported cases of PTE in cats, few have had echocardiography or PAP assessment. Several case reports have documented PH in cats with PTE, although some of these include patients with more than one disease process, which could have resulted in PH.^{13,67,83–85} In the case reported by Baron Toaldo et al, ¹³ the cat received a single dose of carboplatin prior to developing PTE and PH; in this case, it is not known if the PH developed as a result of the chemotherapeutic agent or the PTE. In the case reported by Valente et al, ⁶⁷ the cat presented with interstitial pneumonia, as well as coarctation of the pulmonary artery, with severe thrombosis and mid-intimal hypertrophy. Other cases reported include a 14-year-old male neutered, feline leukemia virus-positive cat with PH and cor pulmonale secondary to thromboembolism after repeated surgical debridement of an abscess, ⁸⁴ and a 10-year-old male Siamese with HCM. ⁸³ There is a single report of PH occurring secondarily to PTE, where no concurrent disease was identified. ⁸⁵

Parasitic disease

In the canine consensus guidelines, parasitic disease is added as a separate group, rather than being included with other forms of pneumonia. ² Parasitic diseases are classified separately as the development of PH is thought to be multifactorial. ² Conversely, in the human literature, schistosomiasis is the only parasitic disease included, classified as type 1 APAH. ¹² Since there are several known parasitic disorders reported to cause PH in cats, including the separate category – as in the canine literature – appears pertinent. Parasitic diseases associated with PH in the cat include D immitis, Aelurostrongylus abstrusus and Troglostrongylus brevior.

Feline heartworm disease (HWD) is caused by D immitis infection. Cats are less susceptible to infection than dogs (the natural reservoir), but infection can result in disease related to either immature worms (heartworm-associated respiratory disease) or, occasionally, adult worms. ⁸⁶ In HWD it has been suggested that PH may occur secondarily to endarteritis, pulmonary embolism and PTE, and/or inflammatory pulmonary parenchymal disease (with restrictive pulmonary fibrosis and stiffening of the bronchi being described).^8,87–90 PH has been documented in both experimental ⁸⁹ and clinical cases of HWD caused by adult heartworms in cats.^91,92

There are case reports of feline PH secondary to infection with A abstrusus.^93,94 In one study, ⁹³ there was clinical, radiographic and echocardiographic resolution of signs of bronchopneumonia and PH after therapy. Conversely, as described in a subsequent report, treatment of the PH and congestive heart failure was not successful. ⁹⁴ The prevalence of PH in cats with A abstrusus is unknown; in a study assessing the CT and echocardiographic features of naturally occurring disease, none of 14 cats demonstrated evidence of PH. ⁹⁵ However, infection with the lesser known parasite, T brevior, was associated with irreversible PH in a single case report. ⁹⁶

PH with unclear or multifactorial mechanisms

• Diseases with clear evidence of two or more underlying pathologies.

• Masses compressing the pulmonary arteries (neoplasia, fungal granuloma).

• Other disorders with unclear mechanisms.

Group 6 causes of PH have not been well described in the cat. However, several of the cases documented above do, in fact, have two or more potential pathologies and could therefore be classified as type 6 PH.^13,67,83 It is important to recognize that in some cases there can be multiple disease processes occurring, and that, where possible, the overall management plan should address all of the underlying disorders.

Diagnosis

There are no pathognomonic signs of PH. Indeed, in some published cases, owners reported no clinical signs, whereas others were presented for sudden death.^11,27,52 The manifestation of PH is not a disease in itself, but a hemodynamic and pathophysiological state brought about by a variety of underlying diseases. ² Therefore, it is important that clinicians are aware of the vast array of disorders which have been associated with PH, and that they remain vigilant in assessing cats with these disorders for PH. This is especially important in patients that have demonstrated a suboptimal response to standard therapy for their underlying disease. Any age or breed of cat can be affected, with young cats more likely to suffer underlying congenital or infectious causes, and older cats more likely to have underlying left-sided heart disease, chronic bronchopulmonary disease or thromboembolic disease. ³

Clinical signs may be related to the underlying disease process, but cats with PH are typically described as presenting with labored/difficulty breathing, lethargy, exercise intolerance, weight loss and, occasionally, cough, cyanosis or syncope.^{30,31,35,38,39,55,93,94,96} Physical examination findings are also non-specific and often related to the underlying disease process. Most reported are heart murmur (often noted as right-sided systolic), jugular distension or pulsation and auscultatory abnormalities such as crackles and/or wheezes tachypnea, or evidence of thromboembolism.^{30,31,35,38,93,94,96} There are few reports of laboratory findings in patients with PH. However, the authors would recommend a minimum database, including assessment for polycythemia, which could indicate right-to-left shunting or chronic hypoxia, heartworm antibody and antigen tests in endemic areas, fecal Baermann floatation for lungworm infections and, if possible, arterial blood gas analysis to assess for hypoxia (although obtaining this can be very difficult in a conscious cat, especially one with difficulty breathing – pulse oximetry might be considered as an alternative).

In people, PH has been associated with increased levels of cardiac troponin, atrial natriuretic peptide (ANP), cardiac brain natriuretic peptide and N-terminal pro-brain natriuretic peptide (NTpro-BNP).^97–99 While some studies have assessed cardiac biomarkers in dogs with PH,^100,101 to date, reports in cats with PH are sparse. ANP has been reported as being markedly increased (197 pg/ml; reference interval [RI] <45) in one cat with PH and ASD, ³² and NT-proBNP was elevated (170 pmol/l; RI 0–100) in a cat with PH and partial atrioventricular septal defect, ³⁰ and in the experimental model of HFpEF with PH. ⁵³ However, the significance of these elevations is unknown, as all cats in the aforementioned studies had PH associated with cardiac disease.

Electrocardiography may demonstrate signs of cardiac enlargement or dysrhythmias, but these are non-specific.^30,32,35 Radiographs can demonstrate a variety of abnormalities, including cardiomegaly, pulmonary infiltrates, blunting, tortuosity or enlargement of the pulmonary arteries, or of both the pulmonary arteries and veins, and hepatomegaly.^27,30,38

CT findings in people with PH include pulmonary artery enlargement with a ratio of the main pulmonary artery to thoracic aorta of >1. ¹¹ Thoracic CT is particularly useful in the diagnosis of PVOD. ¹⁰² In dogs and cats with PVOD or PCH, reported CT changes include perivascular nodular ground glass opacification, fissure lines and enlargement of the lobar pulmonary arteries.^51,102 In addition, CT can be especially useful in cases with suspected pulmonary fibrosis, in which a generalized reticular pattern with traction bronchiectasis and honeycombing, ground-glass attenuation or focal areas of soft-tissue consolidation with or without additional areas of soft-tissue attenuation have been reported.^65,66,103 CT with triphasic angiography can also be used in the detection of PTE, where obstruction of a vessel may be identified. ⁵¹

Echocardiography can be used as an early diagnostic test and has been used in cases with clinical findings or disease processes associated with PH. Findings suggestive of PH are detailed earlier in this review. Echocardiography is a non-invasive surrogate for right-heart catheterization in the clinical diagnosis of PH.

Treatment

Recommendations for the treatment of canine PH include strategies to decrease the risk of progression or complications associated with PH, treatment of the underlying disease and specific therapies for PH. ²

In people, strategies to decrease the risk of progression or complications from PH include restricted exercise, avoidance of high altitude and air travel, and avoidance of non-essential anesthesia. In addition, it is recommended that oestrogen-containing contraceptives, vasoconstrictors and beta blockers are avoided. ¹¹ Thereafter, treatment recommendations depend on the form of PH.

In cats, there is little published information on the treatment of PH. For group 1 disease, withdrawal of drugs, treatment of intoxication or closure of left-to-right shunts may be recommended. If there is right-to-left shunting and clinically significant polycythemia, treatment with phlebotomy or hydroxyurea may be beneficial. In humans, cases of PVOD have demonstrated sudden deterioration and death with phosphodiesterase (PDE) inhibitors. Within the feline veterinary literature, there are two cases of PCH, one of which was presented post mortem;52 the other demonstrated marked deterioration following treatment with sildenafil. The authors of that paper suggested that, as in humans, treatment of feline PCH with vasodilator therapy may lead to fatal pulmonary edema. ⁵¹ Cases with group 2 PH may improve with treatment of the underlying cardiac disease or, where indicated (and not detrimental to the underlying cardiac condition), the PDE V inhibitor sildenafil may be beneficial. In cases with group 3–6 PH, treatment of an underlying disorder, where possible, is advised. However, in some cases the underlying disease may not be treatable, or the PH may not resolve, despite treatment.

The majority of studies assessing specific treatment options for PH in small animals have focused on PDE V inhibition. In an early experimental study assessing the effect of a PDE V inhibitor (zaprinast) and a PDE III inhibitor (milrinone) on the pulmonary vascular tone of cats it was demonstrated that, with increased vascular tone, both medications had a vasodilator effect; however, this was greater with the PDE V inhibitor. ¹⁰⁴ Today, the most used PDE V inhibitor is sildenafil. It is recognized that sildenafil increases pulmonary vascular cyclic guanosine monophosphate, thereby increasing the activity of endogenous nitric oxide and decreasing vasoconstriction within the pulmonary vasculature. Studies have suggested that use of sildenafil benefits the patient by decreasing the clinical signs, increasing quality of life and, in some cases, decreasing echocardiographically derived estimates of PAP. Most of these studies have been performed on canine patients, although there are some reports of the use of sildenafil in cats with PH.^21,25,34 The authors have successfully used sildenafil in several cats with PH secondary to pulmonary fibrosis.

In humans, several other medications, including the prostanoids and the endothelial receptor antagonists, are used for the treatment of PH. ¹¹ The choice of medication is somewhat dependent on the type of PH diagnosed. Currently, these medications have received little attention in veterinary medicine and therefore recommendations regarding their use are unavailable.

Conclusions

PH can occur with many disease states and is likely to be underdiagnosed in the cat. By raising awareness of the broad spectrum of disorders that can be associated with PH and proposing the above classification system, it is hoped that more cases will be assessed for the presence of PH and potential treatment options explored.