Early Detection and Therapy of Asymptomatic Group 1 Pulmonary Hypertension Following Genetic Testing: A Case Involving Familial KCNK3 Variants

Pulmonary arterial hypertension (PAH) is defined by mean pulmonary artery pressure (mPAP) > 20 mm Hg and pulmonary vascular resistance (PVR) > 2 Wood Units (WU), without significant left heart, lung, or chronic thromboembolic disease. Diagnosis of symptomatic PAH is often delayed, which increases morbidity and mortality.¹ Genetic testing allows early identification of “at-risk” individuals, but raises questions about the timing of hemodynamic assessment and initiation of therapy. We report a family in which genetic testing revealed an autosomal dominant KCNK3 variant leading to identification of 2 asymptomatic relatives with mild PAH. This case highlights challenges in PAH management, now that early risk identification is possible.

The proband presented at age 5 months with symptomatic PAH and had a secundum atrial septal defect (subject III2 in Fig. 1). The defect was closed, and she was managed with sildenafil. Her PAH gene panel revealed what was previously considered a variant of uncertain significance (VUS) in an ion channel gene that is associated with PAH risk, KCNK3:c.289G>A, p.Gly97Arg. This variant is now considered to be likely pathogenic and was reported in a family with PAH. Functional studies have demonstrated that this variant results in a loss of KCNK3 channel function.² The proband’s paternal aunt (subject II3 in Fig. 1) died of malignant PAH at age 2 years but had not had genetic testing. Segregation studies found this KCNK3 variant was likely to have been inherited from her father (subject II1 in Fig. 1). This same variant was also identified in his brother (subject II2 in Fig. 1).

Figure 1.

Family pedigree showing phenotype and status for the familial KCNK3 c.289G>A variant. Circles indicate female sex; squares indicate male sex; the arrow indicates the proband. Individuals who underwent genetic screening and were found to be carriers are indicated by (+) . Individuals screened and found to not be carriers are indicated by (–). If genetic testing was not performed, or the genetic status could not be determined, this is indicated by (?). There is no contact with I-2; therefore, he has not been tested for the variant, and his clinical status is unknown. He is presumed to have the KCNK3 variant. II-3 died at age 2 years from malignant pulmonary arterial hypertension (PAH). No genetic testing was available at the time and her status is unknown, although we strongly suspect she had the familial variant.

Patient II1 presented at age 32 years and was asymptomatic, apart from occasional coughing paroxysms. Physical examination was significant for mild systemic hypertension and a loud P2 (Table 1). Laboratory testing revealed a normal electrocardiogram and mild hypokalemia. Transthoracic echocardiogram (TTE) demonstrated normal biventricular systolic function with mild right-chamber enlargements. Pulmonary artery systolic pressure could not be estimated due to inadequate tricuspid regurgitation (Fig. 1). Right heart catheterization (RHC) revealed an mPAP of 25 mm Hg (PVR 1.66 WU) with no response to inhaled nitric oxide. He was treated with sildenafil 20 mg orally, 3 times per day, which was added to diltiazem 240 mg daily, which he was taking for hypertension (after developing a rash on amlodipine).

Table 1.

Patient demographics and investigation results

		PATIENT II 1	PATIENT II 2
Demographics	Sex	M	M
	Age at clinic visit for suspected PH (years)	32	28
	Age now , Y	34	31
	Genetic variant	KCNK3 c.289G>A	KCNK3 c.289G>A
	Protein mutation	KCNK3 p. Gly97Arg	KCNK3 p. Gly97Arg
	Past medical history	None	None
	Symptom burden	Coughing fits that improved with exercise	Occasional wheeze secondary to smoking
	WHO functional class status	1	1
	Social history	Occasional marijuana use	Alcohol >10 drinks/wk Sedentary lifestyle Smoking: 1 pack/d for several years
Bedside investigations	Weight, kg	99.2	102.4
	Blood pressure, mm Hg	146/86	137/84
	Heart rate, bpm	46, regular rhythm	73, regular rhythm
	Physical examination findings	Loud P2	Inspiratory wheeze over R middle lobe Mildly loud P2
	BNP (≤ 150 ng/L) Potassium (3.7–5.3 mmol/L)	18 3.6	10 3.3∗
	ECG findings	Initial visit: normal ECG, no evidence of RVH 2-year follow-up: normal ECG	Initial visit: normal ECG, no evidence of RVH 2-year follow-up: normal ECG
Imaging	Transthoracic echocardiogram
	RV function- TAPSE (≥ 1.7 cm)	2.2	2.1
	RV basal diameter (< 4.1 cm)	4.1	3.8
	Right atrial longitudinal diameter (3.8–5.8 cm)	4.5	3.3
	Tricuspid regurgitation	None	Mild
	PASP (< 30 mm Hg)	Not available- lack of tricuspid regurgitation	28
	LVEF (> 50%)	62	61
	Pulmonary artery acceleration time (<130 ms)	160	100, with mid-systolic notching appreciated on tracing
Hemodynamics	Right heart catheterization
	Pre-vasodilator testing
	CO (4.0–8.0 L/min)	6.03	10.9
	CI (2.5–4.0 L/min/m2)	2.71	4.87
	Pulmonary artery saturation (60%–80 %)	79	Unknown
	PVR (< 2 WU)	1.66	0.92
	RAP (0–8 mm Hg)	11	4
	RVEDP (0–8 mm Hg)	15	10
	RVSP (15–25 mm Hg)	39	49
	mPAP (9–18 mm Hg)	25	25
	mPAWP (6–12 mm Hg)	15	15
	Post-vasodilator testing
	CO (4.0–8.0 L/min)	5.45	9.85
	CI (2.5–4.0 L/min/m2)	2.44	4.4
	Pulmonary artery saturation, %	74.3	Unknown
	PVR, WU	1.14	1.1
	RAP (0–8 mm Hg)	11	3
	RVEDP (0–8 mm Hg)	14	6
	RVSP, mm Hg	35	40
	mPAP, mm Hg	23	22
	mPAWP, mm Hg	16	10
Exercise tolerance	6- minute walk test
	Distance walked (400–700 m)	550	594
	SpO2 baseline, %	96	96
	SpO2 end of walk, %	96	96
	Leg fatigue pre	0	0
	Leg fatigue post	2	Unknown
	Interpretation	Preserved exertional SpO2. Low symptom burden	Absence of exertional hypoxemia on room air. 6-minute walk distance near lower limit of normal. Low symptom burden.

Units and references ranges (in brackets) have been listed, when appropriate. References ranges have been provided for post-vasodilator testing values for measures that were expected to remain unchanged despite administration of inhaled nitric oxide.

BNP, B-type natriuretic peptide; bpm, beats per minute; CI, cardiac index calculated via thermodilution equation; CO, cardiac output calculated via thermodilution equation; ECG, electrocardiogram; LVEF, left ventricular ejection fraction; LVH, left ventricular hypertrophy; M, male; mPAP, mean pulmonary artery pressure; with a drop in 10 mm Hg post–vasodilator testing indicating a positive response; mPAWP, mean post-arterial wedge pressure; NSR, normal sinus rhythm; PASP, pulmonary artery systolic pressure; p.Gly289Arg, glycine-to-arginine nucleotide substitution at position 289; PH, pulmonary hypertension; PVR, pulmonary vascular resistance; RAP, right atrial pressure; RV, right ventricular; RVEDP, right ventricular end diastolic pressure; RVH, right ventricular hypertrophy; RVSP, right ventricular systolic pressure; SpO2, oxygen saturation; TAPSE, tricuspid annular plane systolic excursion; WHO, World Health Organization.

^∗Aldosterone 360 pmol/L (Reference (ref) range: 83–979); renin 14.7 ng/L (ref range: 5–60.0), Aldosterone/renin ratio, 24 pmol/ng (ref range: < 50). Stated values refer to Patient II2. No corresponding data were made available for Patient II1.Given these limited values, no link was found between this KCNK3 variant and concomitant hyperaldosteronism.

Patient II2 was an asymptomatic 28-year-old male individual. His physical examination was unremarkable save for borderline systemic hypertension, a loud pulmonic component of his second heart sound (P2), and mild expiratory wheezing. Electrocardiogram and laboratory investigations were normal apart from mild hypokalemia. TTE was normal apart from borderline right ventricular enlargement and mild tricuspid regurgitation. Doppler-estimated pulmonary artery systolic pressure was 28 mm Hg, but pulmonary artery Doppler showed shortened acceleration time and mid-systolic notching (Table 1). The presence of a KCNK3 variant, loud P2, malignant family history, and borderline TTE findings (Fig. 1) prompted RHC, which revealed an mPAP of 25 mm Hg (PVR 0.92 WU), which was largely unchanged (to 22 mm Hg) after inhaled nitric oxide. Although conventional hemodynamic criteria for PAH-targeted therapy (mPAP > 20 mm Hg; PVR > 2 WU) were not met; the high-risk family history and presence of a KCNK3 variant supported an individualized approach, and he was started on amlodipine 10 mg daily (for systemic hypertension) and subsequently sildenafil 20 mg orally 3 times per day for early PAH. Both brothers remain asymptomatic 2 years later.

Discussion

PAH is associated with genetic variants in ∼10% of sporadic cases and 70% of familial cases.¹ Most variants are autosomal dominant with variable penetrance. Variants in BMPR2 account for 70% of all variants in PAH; however, KCNK3 variants have been implicated in familial and idiopathic PAH.³

KCNK3 encodes a pH-sensitive potassium channel that maintains a negative resting membrane potential in pulmonary artery smooth muscle cells, which inhibits voltage-gated calcium channels, thereby maintaining relaxed pulmonary arteries and low PVR.¹ Loss-of-function variants in KCNK3 channels cause membrane depolarization, raise intracellular calcium levels, and trigger pulmonary artery smooth muscle cell contraction, ultimately causing pulmonary hypertension.¹ Expressing the variant KCNK3 gene in transgenic rats induces PAH.⁴ The KCNK3 variant in this family is known to disrupt channel function ex vivo.⁴

Medications targeting PAH are largely vasodilators, including phosphodiesterase type-5 inhibitors, endothelin receptor antagonists, soluble guanylate cyclase stimulators, prostaglandins/prostaglandin agonists, and most recently, an activin trap, sotatercept.¹ Although our patients did not meet conventional criteria for therapy because PVR was < 2 WU, this gene variant has high penetrance in their family, and the family’s PAH phenotype was severe. Thus, with the goal of preventing disease progression, both brothers were started on PAH-targeted therapy.

The current diagnostic criteria for PAH require an mPAP > 20 mm Hg and PVR > 2 WU on RHC. Most patients diagnosed by conventional means have years of preceding exertional symptoms prior to RHC. Consequently, at presentation, hemodynamics typically show advanced PH, with an average mPAP of 50 mm Hg and PVR of 10.7 WU at diagnosis.⁵ Despite reductions in the diagnostic threshold of mPAP to identify pulmonary hypertension (from 25 to 20 mm Hg), these criteria still fail to identify genetically predisposed individuals who may be identified early, when asymptomatic, due to more proactive surveillance, and thus have only mildly abnormal hemodynamics.¹ Further complicating matters, genetic variants in PAH exhibit incomplete penetrance, such that a positive genetic test does not predict when or if an individual will develop PAH.² Montani et al. showed that amongst asymptomatic BMPR2 variant carriers in families with PAH, the annual incidence of developing PAH is only 0.99% in men and 3.5% in women, as discussed by Mocumbi et al.¹ The natural history of KCNK3 variants remains unknown.¹

Patients II1 and II2 were informed of the lack of guideline evidence supporting medical therapy, which was ultimately pursued, along with RHC, as a preventative approach in the absence of guidelines. Subsequent therapy was recommended on the presumption that early treatment might delay or prevent disease progression. Patient II2 had undergone a stress echocardiogram 15 months after starting sildenafil, with findings significant for an increase in pulmonary artery systolic pressure, from 29 to 52 mm Hg at stage 4 of the Bruce protocol, consistent with a pulmonary hypertensive response. Due to financial constraints, Patient II2 discontinued sildenafil use at 1 year following their stress test. Both patients remained asymptomatic when seen 2 years post-diagnosis; but further hemodynamic testing was not performed, reflecting the need for surveillance guidelines. Whether such patients merit annual TTE and a lower threshold for referral for RHC remains uncertain.

This report highlights the lack of clinical guidelines to inform the timing of RHC, medical treatment, and surveillance of asymptomatic individuals with a genetic predisposition to PAH who have hemodynamics below guideline thresholds. Therapy was previously only initiated in symptomatic patients with advanced hemodynamic derangements.¹ Yet we are now increasingly faced with the management of asymptomatic patients with early hemodynamic abnormalities, such as these brothers, who have pulmonary hypertension but technically do not qualify as PAH due to PVR < 2 WU. Advanced cases often have evidence of overt findings of right ventricular failure, but early in PAH, clinical findings may be subtle and easily missed. With greater access to genetic testing, physicians increasingly will encounter asymptomatic individuals who are at risk of PAH, raising the issue of when to perform RHC and initiate therapy. Extrapolating from preclinical models of PAH, preventative therapy is usually more effective than delayed therapies that attempt to regress established disease. However, this effectiveness comes with a price of procedural risk of RHC and the cost of longer courses of medication. Therapy of patients with mild PAH will require careful assessment as many carriers of this likely pathogenic variant may never develop PAH.

Conclusion

We present 2 asymptomatic siblings from a family with a history of malignant PAH carrying a likely pathogenic KCNK3 variant, both with near-normal physical examinations. These cases raise questions regarding the value of early RHC and therapy, which will likely become more common as genetic screening becomes more available. Prospective studies in asymptomatic familial variant carriers are needed to determine whether early, targeted PAH therapy has value in patients with hemodynamics that are milder than conventional treatment threshold values, although data will be limited by a scarcity of patients. This variant has now been reclassified by the laboratory as “likely pathogenic,” based on the American College of Medical Genetics criteria.

Novel Teaching Points.

• •Genetic screening serves as a pivotal tool in identifying individuals at risk for developing PAH.
• •Guidelines are needed that address surveillance and treatment strategies in asymptomatic carriers of PAH-associated genetic variants. Implementing preventative treatment in the absence of guidelines, for patients with elevated mPAP, may be considered on an individualized basis, informed by the patient's personal and familial risk factors.

Ethics Statement

Informed consent was obtained for patients included in this case report. Patient privacy has been protected through anonymization.

Patient Consent

The authors confirm that patient consent forms have been obtained for this article.

Funding Sources

This work was supported by a grant from the Canadian Institutes of Health Research.

Disclosures

The authors have no conflicts of interest to disclose.