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Patient Summary- Syncope and Pulmonary Hypertension

A Somali woman in her mid-30s with no significant past medical history presented with shortness of breath and exertional syncope. EKG revealed evidence of RV strain. CTA-PE protocol did not show PE. However, there was RV dilation and subsequent echocardiogram demonstrated normal LV, but moderately reduced RV function with evidence of RV pressure and volume overload. RVSP was estimated to be 188 mmHg!

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Case Media

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Episode Teaching

Pearls

1. Pulmonary hypertension (PH) can generally be categorized as pre-, post-, or combined pre- and post-capillary PH. Isolated pre-capillary pulmonary hypertension is characterized by: mean pulmonary artery pressure (mPAP) ≥ 20 mmHg, a pulmonary capillary wedge pressure (PCWP) ≤ 15 mmHg, and a pulmonary vascular resistance (PVR) ≥ 3 Woods units (WU). Pulmonary arterial hypertension (PAH) (WHO Group 1) falls under pre-capillary pulmonary hypertension.
   
2. Schistosomiasis is the most common cause of PAH (WHO Group I) worldwide. Approximately 7% of patient with hepatosplenic schistosomiasis have PAH. Some studies suggest that treatment of with praziquantel reverses vascular remodeling; however, there is point of no return, beyond which, anthelmintic therapies are ineffective to prevent progression.
   
3. Exertional syncope and pericardial effusion are both risk factors for higher mortality in PAH.
   
4. Women with severe PAH have extremely high risk of maternal morbidity and mortality. Endothelin receptor antagonists are contraindicated in pregnancy due to teratogenicity. Therefore, a pregnancy test must be obtained monthly while on this therapy.
   
5. Patients with a lower socioeconomic status, based on median household income, have more advanced PAH at the time of diagnosis.

Notes

1. How do you approach syncope?

Syncope is a sudden transient loss of consciousness associated with absence of postural tone followed by complete and usually rapid recovery. There should be not be clinical evidence of “non-syncope” conditions including seizures, hypoglycemia, drug or alcohol intoxication, concussion due to head trauma and so forth.

• One approach to determining the etiology of the syncope is to consider 4 major categories: orthostatic, reflex-mediated, cardiac-obstructive, or cardiac-electrical.
• Reflex-mediated (neurocardiogenic) syncope typically has a prodrome and encompasses vasovagal syncope, situational syncope, and carotid hypersensitivity.
• Orthostatic syncope is syncope occurring when rising from recumbency. It is generally associated with an orthostatic SBP drop by more than 20 mmHg or DBP drop by more than 10 mmHg with a compensatory rise in heart rate. We most commonly think of dehydration or hypovolemia causing orthostasis. Being post prandial can cause orthostasis as well. Neurogenic orthostatic hypotension (OH) involves excessive pooling of blood volume in the splanchnic and/or leg circulation. Upon standing, there is decreased venous return to the heart with a subsequent decrease in cardiac output and cerebral perfusion. The autonomic nervous system can typically increase vascular tone, inotropy and chronotropy; however, in neurogenic OH these mechanisms are inadequate. Conditions where neurogenic OH is relatively common include multiple system atrophy, Parkinson’s disease, Huntington’s disease, peripheral neuropathies (e.g., diabetes, amyloidosis), and spinal cord injury, amongst other etiologies. Finally, common medications associated with orthostatic syncope include diuretics, alpha blockers, and tricyclic antidepressants.
• Cardiac-obstructive syncope may occur from structural obstruction (i.e., aortic stenosis, HCM, mitral stenosis, pulmonary embolism) or other lesions which limit the stroke volume (i.e., pericardial tamponade, pulmonary hypertension.
• Cardiac-electrical syncope include both tachyarrhythmias and bradyarrhythmias, often without a prodrome.

2. What are the different types of pulmonary hypertension (PH)? What are the hemodynamic definitions of pulmonary hypertension?

• The WHO separates PH into 5 groups:
  • Group 1: Pulmonary arterial hypertension (e.g., idiopathic, heritable [BMPR2], anorexigen associated, drug or toxin-associated, HIV, connective tissue disease associated, schistosomiasis, portal hypertension, congenital heart disease, amongst other causes)
  • Group 2: Pulmonary hypertension due to left sided heart disease (e.g., HFrEF, HFpEF, left-side valvular heart disease)
  • Group 3: Pulmonary hypertension due to lung disease or hypoxia: (e.g.,COPD, ILD, OSA, hypoxia without lung disease such as high altitude, developmental lung disorders)
  • Group 4: PH due to pulmonary artery obstructions most commonly Chronic Thromboembolic Pulmonary Hypertension (CTEPH)
  • Group 5: Multifactorial causes such as hematologic disorders (chronic hemolytic anemia, as with myeloproliferative disorders), metabolic disorders (e.g., Gaucher disease, glycogen storage diseases, CKD), and systemic disorders (e.g., pulmonary Langerhans cell histiocytosis, neurofibromatosis, sarcoidosis)

When we consider the hemodynamics of pulmonary hypertension, we break down PH into isolated pre-capillary, isolated post-capillary, or combined pre-and post-capillary pulmonary hypertension.

	Mean Pulmonary Artery Pressure (mmHg)	Wedge Pressure (mmHg)	Pulmonary Vascular Resistance (Woods Units)	WHO Groups
Pre-capillary	> 20	≤ 15	≥ 3	1, 3, 4, 5
Post-capillary	> 20	> 15	< 3	2, 5
Combined pre- and post-capillary	> 20	> 15	≥ 3	2, 5, multifactorial

PAH falls under pre-capillary pulmonary hypertension, which is defined as mean pulmonary artery pressure (mPAP) ≥ 20 mmHg, a pulmonary capillary wedge pressure (PCWP) ≤ 15 mmHg, and a pulmonary vascular resistance (PVR) ≥ 3 Woods units (WU).

3. How do you work up suspected PAH?

• To start investigating for PAH, as always, we start with a thorough history and physical. The most common presenting symptom of pulmonary hypertension in general is exertional dyspnea/reduced exercise tolerance. Symptoms of PH can be nonspecific, especially early in its course, and thus there can be a delay in diagnosis. Remember, some patients have increased risk of developing PH and should be screened. These are patients with known risk factors for developing PAH, including relatives of patients with BMPR2 mutations, HIV, connective tissue disease (especially systemic sclerosis), portal hypertension, etc.
• Other accompanying symptoms may include chest pain, fatigue, and lightheadedness. Manifestations of more advanced disease include syncope, abdominal distension, and significant lower extremity edema attributable to right ventricular (RV) failure.
• Physical exam may reveal a loud P2, murmur of tricuspid regurgitation, an RV S3, jugular venous distension with or without Kussmaul’s sign, liver pulsatility, ascites, and/or peripheral edema.
• Review the CXR and EKG for findings consistent with pulmonary hypertension. Common EKG findings include right atrial enlargement, right axis deviation, RBBB, and an RV strain pattern in the right precordial leads. Findings on chest X-ray may include enlarged main and hilar pulmonary arteries (with loss of the peripheral blood vessels) and RV enlargement.
• Basic lab work should include a CBC with differential, biochemistry, TFTs, and HIV. The patient’s clinical presentation could lead you to screen for serologic evidence of connective tissue disorders or hepatitis. Cardiac biomarkers, including NT-proBNP, may have a role in prognosis and treatment response.
• Echocardiogram is essential in the evaluation of PH. In addition to estimating the pulmonary artery systolic pressure (PASP) by measuring the tricuspid regurgitant jet, we can characterize RV and RA size, RV function, and RV wall thickness, which may help both support the diagnosis and gauge prognosis for PH. Further, we can evaluate for left-sided heart disease contributing to PH. The presence of a pericardial effusion is a poor prognostic sign. 
• PFTs, overnight oximetry with blood gases, and CT chest can help delineate the relative contribution of pulmonary disease to the patient’s PH disease (WHO Group 3). VQ scan can rule out a diagnosis of CTEPH with high sensitivity (WHO Group 4).
• Right heart catheterization is necessary to confirm the diagnosis of PH. Furthermore, we can determine if a patient is “vasodilator responsive.” In the catheterization lab, a positive vasodilator response is defined as a decrease in mPAP ≥ 10 mmHg to an absolute value of ≤ 40 mmHg (without a decrease in cardiac output) with the use of inhaled nitric oxide or IV epoprostenol. If a patient has positive vasodilator test, calcium channel blockers can be initiated, however not all patients will be long term responders. We tend to do vasoreactivity testing in patients with PAH and not for other forms of PH (e.g., Pulmonary Veno-Occlusive Disease or Groups 2, 3, 4, or 5).

4. What are PAH specific pharmacologic treatments?

• Remember that PAH is fundamentally a disease of increased pulmonary vascular resistance (PVR) causing elevated pulmonary pressures. The consequence of increased PVR includes increased RV afterload and hypoxemia and the subsequent clinical manifestations of PAH. Normally, the pulmonary vascular bed has a balance between vasodilators and vasoconstrictors that can maintain a low-resistance, high-compliance state. This balance is disturbed in PAH and the goal of therapy is to “restore” balance between vasodilation and vasoconstriction.
• The management of PAH has 3 medication groups:
  • Nitric oxide pathway:
    • PDE5 inhibitors: Sildenafil and tadalafil. These medications prevent the breakdown of cGMP which mediates the potent vasodilator and inhibitor of platelet aggregation, nitric oxide. The most common side effect for these medications is headache. Remember these medications should not be taken with nitrates!
    • Soluble guanylate cyclase (sGC) stimulators: riociguat. These medications stimulate sGC and thus increase sensitivity to NO. Riociguat is primarily used in CTEPH, but can also be used in PAH (PATENT-1 and -2 Trials) including PAH associated with sickle cell disease
  • Endothelin-1 (ET-1) pathway:
    • Endothelin receptor antagonists (ERAs): macitentan, bosentan, ambrisentan. Endothelin-1 is produced by endothelial cells and acts on two receptors, endothelin receptor A (ET-A) and endothelin receptor B (ET-B). ET-A is expressed on vascular smooth muscle cells and ET-B on both smooth muscle cells and endothelial cells. Stimulation of both receptors tends to lead to vasoconstriction, while stimulation of ET-B leads to vasodilation. ERAs antagonize these receptors to shift the balance towards vasodilation (e.g., bosentan is a dual ET-A/ET-B antagonist and ambrisentan is a more selective ET-A antagonist). Common side effects are lower extremity edema and hepatotoxicity. NOTE: patient should not get pregnant on ERAs because of teratogenicity!
  • Prostacyclin Pathway
    • Prostacyclin analogs: epoprostenol, iloprost, treprostinil. Prostacyclin is a potent endogenous vasodilator and inhibits platelet aggregation. This class of medications have PO, SQ, IV, and inhaled formulations. Common side effects include headache, diarrhea, nausea, and jaw pain.
    • PCA-receptor agonist: selexipag (oral).

Also remember CCB in vasodilator responsive patients with PAH!

Other aspects of pharmacologic PAH treatment not discussed here include diuretics, digoxin, and oral anticoagulation, especially for patients with more advanced disease and on continuous parenteral prostacyclin therapy due to microthrombi in pulmonary arterioles.

5.How do we risk stratify PAH patients and response to treatment?

• The REVEAL 2.0 risk score helps determine 1 year mortality based on WHO group, renal function, functional class, age, heart rate, 6 minute walk test, BNP, presence of pericardial effusion of echocardiogram, PFTs, and RHC values.
• Patients should also undergo routine 6 minute walk test and/or cardiopulmonary exercise test to assess their functional status and response to medications. Biomarkers may be helpful to assess treatment response. Echocardiography and RHC may be used every 6 to 12 months in patients with unstable or deteriorating symptoms to guide therapy and then considered on a case-by-case basis in stable patients.

References

1. Badesch DB, Champion HC, Sanchez MA, et al. Diagnosis and assessment of pulmonary arterial hypertension. J Am Coll Cardiol. 2009; 54(suppl 1):S55-S66.
2. Barst RJ, Gibbs JS, Ghofrani HA, et al. Updated evidence-based treatment algorithm in pulmonary arterial hypertension. J Am Coll Cardiol. 2009; 54(suppl 1):S78-S84.
3. Benza RL, Gomberg-Maitland M, Miller DP, et al. The REVEAL Registry risk score calculator in patients newly diagnosed with pulmonary arterial hypertension. Chest. 2012; 141(2):354-362.
4. Delcroix M. and Naeije R.: “Optimising the management of pulmonary arterial hypertension patients: emergency treatments”. Eur Respir Rev. 2010; 19: 204.
5. Knafl D, Gerges D, King CH, Humbert M, Bustinduy AL. Schistosomiasis-associated pulmonary arterial hypertension: a systematic review. European Respiratory Review. 2020; 29 (155).
6. McLaughlin VV, Archer SL, Badesch DB, et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association: developed in collaboration with the American College of Chest Physicians, American Thoracic Society, Inc., and the Pulmonary Hypertension Association. Circulation. 2009; 119:2250-2294.
7. Nazzareno G, Corris PA, Frost A, et al. Updated treatment algorithm of pulmonary arterial hypertension. J Am Coll Cardiol. 2013; 62(sup 25):D60-D72.
8. Sherman, Stephanie (Host). (2019, January 31). Syncope (Episode 12) [Audio podcast episode]. In The Clinical Problem Solvers. https://clinicalproblemsolving.com/2019/01/31/episode-12-syncope-with-dr-stephanie-sherman/.
9. Simonneau G, Montani D, Celermajer DS, et al. Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur Respir J. 2019: 53(1).
10. Simonneau G, Robbins IM, Beghetti M, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2009; 54(suppl 1):S43-S54.
11. Sitbon O, Gaine S. Beyond a single pathway: combination therapy in pulmonary arterial hypertension. European Respiratory Review. 2016; 25 (142) 408-417.
12. Talwar A, Sahni S, Talwar A, Kohn N, Klinger JR. Socioeconomic status affects pulmonary hypertension disease severity at time of first evaluation. Pulm Circ. 2016; 6(2):191-195. doi:10.1086/686489.

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