Rapid Onset Idiopathic Pulmonary Hypertension: A Case Report with a Review of Echocardiographic Parameters

Abstract

Pulmonary hypertension (PHT) is an emerging issue. The prognosis in PHT is usually poor, independently from the etiology, with progressive right ventricle failure. Despite right Heart Catheterism is the gold standard for diagnosis of PHT, echocardiography provides important information about prognosis and is helpful in both follow-up and first evaluation of PHT patients, showing a good correlation with invasively measured parameters by right heart catheterization. However, it is important to understand the limits of this method, particularly in some settings, where transthoracic echocardiography has shown a lack of accuracy. In this case report we documented a case of rapid onset (3 months) idiopathic PHT and we provided a critical analysis of echocardiographic role in PHT.

INTRODUCTION

Pulmonary hypertension (PHT) is an emerging, yet still widely underdiagnosed, clinical condition defined by a mean pulmonary arterial pressure (mPAP) at rest ≥25 mmHg at right heart catheterization (RHC).[1,2]

Despite originally thought to be a rare condition, recent studies suggested a relatively high prevalence of PHT in general population (2.6%) and in particular among elderly (8.3% in subjects older than 85-year-old).[3] Irrespective of the leading cause, the natural history of PHT consists of progressive deterioration and a poor prognosis secondary to the right ventricle (RV) failure.[3]

However, distinguishing between different PHT etiology is crucial since it has important clinical, therapeutic, and prognostic implications.[4] Based on pulmonary artery wedge pressure (PAWP) and pulmonary vascular resistance (PVR), three PHT entities can be identified: precapillary PHT (with PAWP and PVR respectively ≤15 mmHg and >2 Wu), postcapillary PHT (PAWP >15 and PVR <2 Wu), and combined PHT PAWP >15 mmHg and PVR >3 Wu).[1,2] Pathophysiology may further classify PHT into five groups: (1) pulmonary arterial hypertension (PAH), (2) PHT secondary to left heart disease, (3) PHT due to lung disease or hypoxia, (4) chronic thromboembolic PHT, and (5) PHT of unclear or multifactorial origin.[5]

PAH is a precapillary PHT which usually affects younger subjects and more frequently women.[4] PAH incidence is estimated at around 2–5 cases per million and, despite many different causes have been described as potential determinants (e.g. heritable, drug-induced, secondary to connective tissue diseases, HIV or schistosomiasis related, pulmonary veno-occlusive disease, or pulmonary capillary hemangiomatosis), almost half of the cases are idiopathic PAH (IPAH).[2,4]

Despite the gold standard for PHT diagnosis is RHC, echocardiography plays a central and emerging role as both a screening tool for PHT and in providing prognostic information, and may be helpful in the initial distinction between precapillary and postcapillary PHT. Transthoracic echocardiography (TTE) is a widely available and safe technique, which, notably, showed a good correlation with hemodynamic parameters from RHC in terms of mPAP, PVR, and PAPs estimation.[6-9] Many echocardiographic scores and indexes have been proposed during the last 15 years, trying to distinguish precapillary from postcapillary PHT by noninvasive evaluation. Some of these methods showed a good concordance with RHC results.[6,8,9] However, although TTE allows fine analysis to enable proper diagnosis and prognostic stratification, even during follow-up, it is important to understand the limitations of TTE, particularly in some settings, where TTE has shown a lack of accuracy.

CASE REPORT

A 64-year-old woman was referred to our department for fatigue, mild dyspnea at rest, and pitting edema at lower limbs. She had a history of low pulmonary involvement cystic fibrosis diagnosed 36 years before for which she was routinely supervised with abdominal echography, pneumological evaluation with spirometry, and chest-computed tomography (CT). The last abdominal echography (performed in august 2021) was normal. Chest CT and spirometry showed respectively low pulmonary involvement (cylindrical bronchiectasis limited to superior and middle right lobe) and forced expiratory volume in 1 second (FEV1) 95% (July 2021). In November, an attempt to introduce ivacaftor/tezacaftor for cystic fibrosis therapy was made, but the drug was rapidly dismissed because of gastrointestinal intolerance.

Her cardiological history began the year before when continuous headaches led her to neurological evaluation and subsequent magnetic resonance imaging, enlightening parcellar ischemic lesions, and finally to pervium foramen ovale (PFO) diagnosis (positive bubble test at transesophageal echocardiogram). At that time, TTE and electrocardiogram were normal, showing normal biventricular function with normal estimated pulmonary pressures and sinus rhythm with rSr’ morphology in lead V1 without overt conduction abnormalities, respectively. In July 2021, she underwent percutaneous PFO closure. No residual shunt was enlightened at successive TTE evaluations in July and November 2021; pulmonary artery systolic pressure (PAsP) and RV function were still normal (respectively PAsP 30 mmHg and Tricuspid Annular Plane Systolic Excursion [TAPSE] 20 mm). In February 2022, due to increscent symptoms of dyspnea at rest and lower limb edema, she performed a new spirometry finding no variation compared to the previous exam (FEV1 95%). Blood chemistries were normal except for N-terminal pro-brain natriuretic peptide: 4524.

Electrocardiogram showed sinus rhythm at 90 bpm with “pulmonal P,” I degree A-V block (P-R 230 ms), and right bundle branch block; new onset S1Q3T3 pattern was also present.

She finally underwent TTE evaluation, which showed RV dysfunction (Tricuspid Annulus Systolic Excursion [TAPSE] 11 mm, Tricuspid annulus S’ wave [S’ tric] 7 cm/s, Fractional Area Change [FAC] 29%; RV Stroke Volume Indexed [RV SVi] 28 ml/mq; RV Strain-6.6%) with severely reduced TAPSE/PAsP ratio (0.13) Presence of both McConell sign and normal right atrium area (14 cmq) was suggestive of an acute failure. RV was also extremely dilated in comparison to the left ventricle (LV), which was D-shaped with flattening of the interventricular septum (LV Eccentricity index 1.74, and a RV/LV ratio of 1.5) [Figures 1 and 2].

Figure 1.

Apical four-chamber view. Right ventricular dilation seen at February’s evaluation

Figure 2.

Parasternal short axis view

Pulmonary pressure assessment showed high PAsP values (72 mmHg, tricuspid valve Vmax 3.8) and high mean pulmonary artery pressure value (assessed by both Chemla and Mahan methods, respectively >45 mmHg and >47 mmHg), pulmonary valve Acceleration Time was very short (65 ms) and mid-systolic notched [Figure 3]. “Flying W” sign was also appreciable in M-mode on the Pulmonary valve [Figure 3]. Right atrial pressure (RAP) was estimated >15 mmHg in light of inferior vena cava (IVC) diameter and collapsability (24 mm, noncollapsible), while left atrial pressure was observed to be normal (E wave 61 cm/s, mean E/e’ 9, normal left atrium dimensions). In line with these findings and her clinical history, we presumed precapillary PHT. To confirm our hypothesis, we decided to perform three scores employed in the echocardiographic differential diagnosis between pre and postcapillary PHT: echocardiographic pulmonary to left atrial ratio (ePLAR), Biventricular coupling index (BCI), and D’Alto score.

Figure 3.

Pulmonary valve acceleration time (a) and flying W sign (b)

ePLAR, was 0.46, suggestive of precapillary PHT; Biventricular coupling index and simplified D’alto score were respectively found 2.8 and 7, confirming that precapillary PHT was the most likely diagnosis.

She was immediately admitted to our intensive care unit and diuretic therapy started. A few days later chest CT and angioCT were performed showing no signs of pulmonary disease or embolism. Pulmonary scintigraphy ruled out chronic thromboembolism. The patient was successively sent to a referral center for PHT, where RHC confirmed severe precapillary PHT irresponsive to inhaled NO. Further causes of precapillary PHT were successively ruled out leading to IPAH diagnosis. In light of the extremely rapid onset and the severity of symptoms, upfront therapy with prostaglandins analog, endothelin receptor antagonist, and Cyclic guanosine monophosphate (cGMP) stimulator (Riociguat) was started.

DISCUSSION

Singularity of this case consists of the extremely rapid onset (about 3 months: from November to February) of IPAH and the consequent RV failure. Some echocardiographic features (McConnel sign, normal RV, and right atrium dimensions) suggest the rapid progression of high pulmonary pressures, which is confirmed by the patient history.

McConnel sign defines an akinetic RV mid-free wall with bouncing of the RV apex. The apical bounce results from a hyperdynamic LV exerting traction on the apical segment of a hypo/akinetic RV-free wall.[10]

McConnel sign has been first described in patients with acute pulmonary embolism (PE), the reason why it is usually considered to be a sign specific for PE.[10] However, some studies and case report reported the presence of McConnel to sign in patients with an acute rise in RV afterload independently from the presence of PE, thus it appears to be more specific for rapid RV afterload increase with consequent RV-PA uncoupling and acute severe RV dysfunction rather than PE per se.[10-12]

More important, this sign showed prognostic relevance in patients without PE, predicting a worse outcome.[12] It is well known how, differently from the LV, muscular fibers of the RV are predominantly longitudinally arranged; in the context of a pressure overload, this myocyte macrostructure is altered resulting in concentric hypertrophy. However, in the final stage of PHT progression, when concentric remodeling can no longer provide sufficient stroke volume, the RV begins to dilate.[13,14] Dilation allows, within limits, the RV to maintain stroke volume through Frank Starling’s law, and this adaptation happens either when concentric hypertrophy is no longer able to counterbalance the increase in afterload or when the increase in afterload is very severe and extremely rapid, as the adaptive response does not have time to establish.[13,14]

Pressure overload on RV affects indirectly also the LV, determining reduced LV preload due to both reduced RV stroke volume and reduced LV compliance, with altered LV relaxation. The latter, which determines the strongest impact on LV filling, is a consequence of ventricular interdependence. The right and LV are contained in the same non-distensible envelope, the pericardium. Increased pressure and volume of the right chamber result in compression and reduced distensibility of the left, RV/LV ratio >1, and D-shaped LV.[13] Hence, contraction pattern (McConnell sign), ventricular shape (including RV-free wall width), and chamber enlargement provide important information in regard to PHT onset time. In our case, McConnel sign and RV dilation without hypertrophy were suggestive of a quick increase in afterload.

In the context of a pressure overload, either acute or chronic end-stage, RV dilation expresses a severely uncoupled RV-PA. RV-PA coupling represents the interaction between rise in PVR, PA pressures, and RV adaptive mechanisms, which determine energetic consumption and stroke volume, namely RV efficiency. Thus, RV-PA coupling has an important prognostic implication.[13,15] According to the PV loop analysis, RV-PA coupling represents ventricular contractility to PA elastance ratio.[13] It has been proposed to noninvasively assess RV-PA coupling by the ratio between TAPSE and PAsP, as a surrogate of RV function and PA elastance, respectively. Several recent studies enlighten how a low TAPSE/PAsP is associated with a worse prognosis in patients with either pre or postcapillary PHT.[16-18] The most recent ESC Guidelines for PHT defined outcome at 1 year according to TAPSE/PAsP ratio: values below 0.19 are suggestive of >20% risk of death, while intermediate values (0.19–0.32) are suggestive of 5%–20% risk of mortality.[19]

Despite a high variability between studies in literature, there is substantial unanimity in defining a TAPSE/PAsP value below 0.35 as a predictor of bad outcome independently from the underlying disease.[16-20]

Our patient showed a dramatic TAPSE/PAsP ratio (0.13), suggesting a very poor prognosis. It appears clear how endotracheal tube (ETT) has a central role in PHT, as it provides prognostic information and allows routinary evaluation and Follow Up.

Moreover, as a first screening tool, ETT may precede RHC in characterizing PHT, helping in distinguishing pre- versus post-capillary PHT. In particular, three predictors of probability, ePLAR, BCI, and D’alto score, have been developed with the aim to distinguish precapillary from postcapillary and mixed PHT at a noninvasive evaluation.[6,8,9]

ePLAR expresses the ratio between maximal tricuspid regurgitation velocity and the mean E/e’ ratio as a surrogate of PCWP. A cutoff of 0.4 m/s was found able to distinguish precapillary PHT from postcapillary and combined PHT with high discriminating power (area under curve [AUC] =0.76).[8] BCI demonstrated an even higher diagnostic accuracy (AUC 0.82, sensitivity 73%, specificity 78%) in defining precapillary PHT according to a 1.9 cutoff value.[9] BCI is obtained by the following formula , where eRVSWi is the product of RV Svi, Tr maximum PG and a correction factor of 0.0136. Similarly to ePLAR, mean E/e’ is considered as the PCWP index.[9]

BCI and ePLAR substantially have been elaborated from similar physiological concepts: They both compare right chambers afterload with LV filling pressures (indirect expression of PCWP). ePLAR appears easier to calculate, as it is needed only for mean E/e’ and maximal Tricuspid Velocity, while BCI requires more parameters, RV outflow tract velocity time integral to RV Svi estimation, in a change of a more accurate result. Clearly, these two indicators are strongly bounded to right heart function and pressures and the nature of tricuspid regurgitation. In the context of a severely misfunctioning RV and/or very high RAP, gradient across TV may be reduced, as RV is incapable to generate the high pressures, and pressure gradient between the right atrium and the RV is reduced. In such cases, right chambers become more similar to a “conduit” rather than a “pump” and real pulmonary pressures may be underestimated by echocardiography. Thus, false-negative results or underestimated values may be obtained with both indicators. Similarly, a severe or massive TV insufficiency may lead to under-sampling of the regurgitant maximal velocity and (consequently) PG across the TV. This is not a secondary aspect as most cases of PTH lead to a progressive RH failure and dilation and it appears even more relevant if considered that, frequently, patients undergo echocardiographic evaluation only when RH failure symptoms are overt and RV is severely dilated, with dilated TV annulus which worsens TV insufficiency.

In our case, the onset of precapillary PHT was very aggressive with the development of very high pulmonary pressures, probably partially underestimated because of RV acute failure. However, TV regurgitant velocity was still very high, thus indicators were not substantially influenced by RH failure.

Differently from ePLAR and BCI, D’Alto score is based on a “qualitative” assessment rather than a “quantitative” estimation.[6,8,9] The presence or absence of five typical features (right heart chamber larger than the left, LV eccentricity index >1.2, dilated IVC without inspiratory collapse, E/e’ ratio < =10, and RV forming the heart apex) defines the likelihood of having precapillary PHT.[6] Each item has a specific weight in points, for a maximum overall score of 34 points.[6] D’Alto score >5 is suggestive of precapillary PHT (positive predictive value of 67.9% and a negative predictive value of 77.5%).[6] E/e’ <10 (16 points) and dilated IVC without inspiratory collapse (10 points) are the most important predictor, as the presence of just one of them may suggest precapillary PHT.[6] Notably, the mean E/e’ ratio has a central role in all of these predictors, as it is assumed as a surrogate of LA pressure and consequently of PCWP. Thus, it is important to underline that mean E/e’ showed to not accurately represent LA pressure for many reasons.[21,22] First, normal e’ showed high normal range variability (5–18 cm/s).[22] Moreover, in cases of septal desynchrony (such as RV pacing or left bundle branch block), nonoptimal beam alignment due to wall dyssynchrony makes septal and lateral e’ underestimated.[21] Similarly, when high RV pressures lead to paradoxical septal motion, or in the context of D-shaped LV, e’ could be underestimated, resulting in a possible source of bias using ePLAR, D’Alto Score, or BCI. Finally, it is well known how e’ is strongly influenced by several confounders, such as inotropic infusion therapy, mitral valve disease, and LV structure.[23] However, except for borderline cases, E/e’ showed to be extremely useful in identifying augmented LA pressures.[24]

Nevertheless, it should be remembered that echographic parameters should be integrated by clinical evaluation, interpreting data and measurements in light of patient’s-specific clinical-anamnestic context. All the aforementioned parameters are summarized in Table 1

Table 1.

Echocardiographic items in pulmonary hypertension

Parameter	Evaluation	Definition	Assessment	Cutoff	Advantages	Limitations
PAsP[25]	Quantitative	Stim of PAsP	4v2 tric+RAP	PHT: >30 mmhg	Correlates well with hemodynamic invasive parameters by RHC	Underestimates PAsP in: RV dysfunction, massive TV regurgitation, and very high RAP Not valid if: PV stenosis or RVOT obstruction
PAmP[25]	Quantitative	Stim of PA mean pressure Key parameter to define PHT	4v2 pulm (0.61×RVSP) + 2* 79− (0.45×PV-AT)**	PHT: >20 mmHg	Correlates well with hemodynamic invasive parameters by RHC	Time-consuming: Accurate mPAP measurements require multiple evaluation (possibly with different methods)
PV-AT[25]	Quantitative and qulitative	Stim of PA impedance (pressures and PVR)	Time from PV opening to peak systolic velocity (by PWD)	PHT and high PVR: <105 ms Mid-systolic “notch” pattern	Easy to measure Almost always feasible	Lack of precise quantitative definition of PA pressures and PVR
TAPSE/PAsP[16]	Quantitative	Noninvasively stim RV-PA coupling		RV-PA uncoupling: <0.35	Important prognostic implication Easy to measure	TAPSE not valid after CS PAsP limits Lack of a universal cutoff (not unanimous consensus between studies)
E/e’[21,25]	Quantitative	LAP and PCWP surrogate	Transmitral PWD (E wave) PW-TDI (e’)	High LAP: >15	Well-identifies rise in LAP Easy to measure	Septal e’ not valid when: Desynchrony, paradoxical septal motion and D-shape of LV Strongly influenced by several confounders: Inotropic infusion therapy, mitral valve disease, and LV structure
ePLAR[8]	Quantitative	Distinguish pre- from post-capillary PHT		Precapillary: >0.5 Postcapillary: <0.2	Easy to measure Distinguish pre- versus post-capillary and mixed PHT	False negative/underestimated values in: RV dysfunction, Massive TV regurgitation Limits of E/e’ Not accurately distinguish postcapillary from mixed PHT
BCI[9]	Quantitative	Distinguish pre- from post-capillary PHT		Precapillary: >1.9	More accurate then ePLAR	Many parameters required False-negative results/underestimates values in: RV dysfunction, massive TV regurgitation Limits of E/e’
D’Alto et al. score[6]	Qualitative	Asses the probability of precapillary PHT	Presence of five typical items: RV>LV=3 points Lvei>1.2=4 points Dilated IVC, no inspiratory collapse=10 points E/e’ ratio≤10=16 points RV forming the heart apex=1 point		Always feasible	Qualitative assessment Limits of E/e’ False positive when IVC is dilated for other reason
McConnell’s Sign[10]	Qualitative	Suggest acute PHT onset	RV apical «bounce» with hypocontractile mid and basal segments	-	Easy to identify Always feasible	Aspecific
Flying W Sign[25]	Qualitative	Suggest high PA impedance (pressures and PVR)	«W» sign at M-mode doppler on PV	-	Easy to obtain	Replaced by PV-AT

*Chemla method, **Mahan method. RVSWi=Right ventrcle stroke work index, °RVSWi=RVSWI×tricuspid valve systolic peak PG, PA=Pulmonary artery, PV=Pulmonary valve, PAsP=PA systlic pressure, mPAP=Mean PA systlic, PV-AT=PV acceleration time, BCI=Biventricular coupling index, PHT=Pulmonary hypertension, RAP=Right atrial pressure, RV=Right ventricle, RVSP=RV systolic pressure, PVR=Pulmonary vascular resistances, LAP=Left atrial pressure, PCWP=Pulmonary capillary wedge pressure, PWD=Pulsed wave doppler, LV=Left ventricle, IVC=Inferior vena cava, RHC=Right heart cathetherism, RVOT=RV outflow tract, TV=Tricuspide valve, PG=Pressure gradient, TAPSE=Tricuspid annular plane systolic excursion, ePLAR=Echocardiographic pulmonary to left atrial ratio, PAmP= mean Pulmonary Artery pressure; PW-TDI=Pulsed Wave-Tissue Doppler Imaging, CS=Cardiac Surgery, E/e’=Ratio between E wave by pulsed-wave Doppler of mitral flow and mean e’ wave obtained by PW-TDI in the basal segment of septal and lateral LV wall

CONCLUSION

In this case, we have documented that IPAH can develop in a relatively short time frame (3 months). TTE can provide extremely important information on the timing of PHT onset, prognosis, VA-PA coupling, and even the pre-or postcapillary nature of PHT. However, the limitations and weaknesses of a method must always be kept in mind, especially when performing extremely fine assessments. Therefore, an integrated approach, taking into account clinical and echocardiographic features, is always the wisest choice.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.