Non-invasive imaging techniques for early diagnosis of bilateral cardiac dysfunction in pulmonary hypertension: current crests, future peaks

Pulmonary arterial hypertension (PAH) is a chronic and progressive disease that eventually leads to heart failure (HF) and subsequent fatality if left untreated. Right ventricular (RV) function has proven prognostic values in patients with a variety of heart diseases including PAH. PAH is predominantly a right heart disease; however, given the nature of the continuous circulatory system and the presence of shared septum and pericardial constraints, the interdependence of the right and left ventricles is a factor that requires consideration. Accurate and timely assessment of ventricular function is very important in the management of patients with PAH for disease outcomes and prognosis. Non-invasive modalities such as cardiac magnetic resonance (CMR) and echocardiography (two-dimensional and three-dimensional), and nuclear medicine, positron emission tomography (PET) play a crucial role in the assessment of ventricular function and disease prognosis. Each modality has its own strengths and limitations, hence this review article sheds light on (i) ventricular dysfunction in patients with PAH and RV–LV interdependence in such patients, (ii) the strengths and limitations of all available modalities and parameters for the early assessment of ventricular function, as well as their prognostic value, and (iii) lastly, the challenges faced and the potential future advancement in these modalities for accurate and early diagnosis of ventricular function in PAH.


Introduction
Pulmonary arterial hypertension (PAH) stands as a chronic and progressive ailment culminating in right heart failure (HF) and eventual fatality within a relatively brief timeframe if left unattended.A distinct manifestation of severe precapillary pulmonary hypertension (PH), an advancing pulmonary vascular disorder culminating in right HF and demise, is chronic thromboembolic pulmonary hypertension (CTEPH), acknowledged as a complication arising from pulmonary embolism (PE).These two variations of precapillary PH may exhibit analogous pathological alterations within the distal pulmonary vasculature, encompassing intimal thickening and remodeling of pulmonary resistance vessels, eccentric intimal fibrosis, intimal fibromuscular proliferation, and the development of plexiform lesions (1).PH is one of the most common diseases, often associated with other underlying conditions (i.e., Group 2 and 3 PH).Conversely, pulmonary vascular resistance (PVR) is not forcibly increased in Group 2 PH, considering that the isolated postcapillary form is, by definition, characterized by PVR < 2 units (2).PH precipitates a multifaceted cascade of pathological events within the right ventricle (RV), leading to hypertrophy, dilatation, fibrosis, and metabolic perturbations.This intricate process is instigated by the heightened afterload imposed on the RV, ultimately culminating in the manifestation of right heart failure and consequential mortality (3).Prior investigations have substantiated the pivotal role of RV function as a significant prognostic determinant in patients afflicted by PH, irrespective of the diverse etiological factors underlying the condition (4).Given the continuous nature of the circulatory system and the holistic nature of the left and right ventricles, which are determined by the presence of a shared septum and pericardial constraints, the interdependence of the RV and left ventricles (LV) is a factor that requires consideration (5).Although the overwhelming majority of studies have emphasized RV dysfunction in individuals with PAH, a recent study indicated that LV dysfunction may also be present in this population (6).Hence, accurate and early diagnosis of PAH, as well as cardiac function, plays a crucial role in the treatment of such patients.
Right heart catheterization (RHC) is known to be a gold standard modality for the diagnosis and treatment strategies of PAH (7).According to the guidelines issued by the Sixth World Symposium on Pulmonary Hypertension (WSPH) in 2018, hemodynamic diagnosis via RHC, with a mean pulmonary artery pressure (mPAP) above 20 mmHg indicating PAH updated from the previous 25 mmHg, delineates PAH into five distinct groups (1).The WSPH classifications of PH are presented in Table 1.Hemodynamic changes in the RV, including parameters like mPAP, PVR, and a diminished RV cardiac index (CI), exhibit significant associations with unfavorable clinical outcomes in PAH as identified through RHC (8).The non-invasive approach toward early diagnosis of ventricular dysfunction in daily practice has its own strengths and limitations.The aim of this literature review is to briefly illuminate the current status of PH and elucidate the following: (i) the intricacies of ventricular dysfunction and ventricular interdependence observed in patients with PAH, (ii) the strengths and limitations of non-invasive imaging modalities utilized for the early detection of ventricular dysfunction in these individuals, and (iii) subsequently the challenges faced and possible potential future directions in these modalities for the management of such patients.

Ventricular dysfunction in patients with PAH RV dysfunction in patients with PAH
Although changes in the pulmonary vasculature are the primary cause of PAH severity of symptoms, and survival is strongly associated with right ventricular function, right heart failure is the main cause of mortality in patients with PAH (10).The pathophysiological mechanisms underlying PAH, although not fully elucidated, encompass a myriad of intricate processes including vasoconstriction, inflammatory responses, thrombotic events, and abnormal endovascular remodeling.Although our understanding remains incomplete, these multifaceted pathways contribute to the complex nature of PAH (11).The eventual outcome manifests as a gradual constriction of the pulmonary arteries, accompanied by elevated PAP and resistance.In response to the pressure overload, the right heart initially adapts through concentric hypertrophy; however, over time the RV experiences significant dilation leading to complications such as tricuspid regurgitation as well as volume and pressure overload.This progressive RV dilation causes a decline in RV contractility.Concurrently, the leftward bowing of the septum hampers left ventricular filling, resulting in decreased LV stroke volume (SV) and cardiac output.The diminished cardiac output, coupled with heightened RV intramural pressure, compromises systolic RV coronary perfusion, which normally occurs throughout the entire cardiac cycle encompassing both the systole and diastole.Consequently, a detrimental cycle ensues characterized by RV dysfunction and low cardiac output, ultimately culminating in progressive RV failure and eventual mortality (10,12).Regardless of etiology, RV adaptation to increased pressure load is the main determinant of outcome (13,14); however, mortality because of RV failure is significantly higher in systemic sclerosis-related PAH (SSc-PAH) than idiopathic PAH (IPAH) (15), and the studies also suggest that patients with SSc-PAH have depressed RV contractility compared with associated PAH (APAH) at similar afterloads may be because of intrinsic systolic function rather than enhanced pulmonary vascular resistive and pulsatile loading (16).

LV dysfunction in patients with PAH
Although PAH is predominantly a right heart disease and RV dysfunction has been the focus of research on people with PAH, a recent study suggested that LV dysfunction may also exist in such a population (6,17).The deleterious consequences arising from RV dysfunction, dilatation, and hypertrophy on left ventricular function commonly referred to as interventricular interaction, have been observed in patients with pulmonary hypertension (PH) (18).Manifestations such as septal flattening and leftward deviation, characteristic of a "D-shaped" left ventricle, ensue due to heightened RV pressure, and these geometric alterations may exert an adverse impact on LV function (19).Furthermore, the compromised RV stroke volume, resulting in an under filled left ventricle, has the potential to detrimentally influence longitudinal LV function.Interestingly, pulmonary acceleration time (PAcT) and TR Doppler velocities (reflecting RV systolic pressures) correlated with early diastolic (E) velocities at the septal and mitral valve levels.These findings suggest that PH had a greater impact on the diastolic compared with the systolic cycle of the LV (20).Echocardiography reveals classic RV alterations in severe secondary pulmonary arterial hypertension (sPAH), including RV dilatation, decreased contractility, and paradoxical motion of the interventricular septum (IVS) with concomitant right heart failure.
However, a notable scarcity of data exists regarding the impacts of RV failure on the left heart chambers, specifically in light of the potential geometric changes in the RV due to pressure overload in PAH, which may adversely affect the LV (21).It has been shown that LV dysfunction is associated with a worse prognosis and more severe disease and may develop as a subsequent result of primary PH (22).Left ventricular global longitudinal strain (LVGLS) was found to be independently linked with mortality in a recent study involving individuals with severe PAH (19).In a study, 114 patients with severe pulmonary hypertension with normal LV ejection fraction were compared with 70 normal controls of similar age and gender distribution.The authors found that the LVGLSs were found reduced in patients with severe PH.LVGLS [HR = 1.11 (CI, 1.01-1.22);P = .04]was found to be independently associated with mortality (19).Similarly, another concept proposed is that RV pressure overload eventually leads to LV diastolic dysfunction in PH (23).Pathophysiologically, LV diastolic dysfunction is due to a distortion of IVS toward the LV in the presence of RV pressure overload (24).

RV-LV interdependence in PAH
Although PAH is defined by normal LV filling pressures, LV performance may be compromised.Theoretically, patients with PAH should have normal left cardiac structure and function.Nevertheless, because they share an IVS and pericardial sac, the RV and LV do not operate independently (25).Since the IVS is shared by both ventricles within the same pericardial sac, increasing RV pressure load causes the septum to bow toward the left ventricle, which alters LV geometry and reduces LV filling (26).The majority of patients with PAH have right-sided disease, while in later stages of the condition reduced left-sided function may also become apparent (6).The interdependence of the RV and LV is an issue that needs to be taken into consideration because of the continuous structure of the circulatory system and the holistic character of the left and right ventricles, which is defined by the presence of a shared septum and pericardial limitations (5).From the perspective of the cardiac systolic-diastolic phase, prior research has shown that increased RV afterload, particularly in people with PAH, causes an elongated systolic phase, which in turn shortens diastole and influences the LV diastolic function (27).A study by Gan et al. (26) aimed to investigate the contribution of direct right-to-left ventricular interaction to LV filling and SV in 46 patients with PAH by using cardiac magnetic resonance (CMR).When comparing patients with PAH to control subjects, there was a decrease in SV, left ventricular end-diastolic volume (LVEDV), and LV peak filling rate (26).Their findings indicate that, in patients with PAH, ventricular interaction mediated by IVS compromises LV filling.As a result, aberrant RV loading reduces the RV cardiac output by influencing the ventricle's function through both direct and indirect interactions.We may examine some of the results more closely if we keep this idea of ventricular interdependence in mind.First, it is intriguing to note that patients with PAH have lower LV septal circumferential strain (CS) than controls.In a typical situation, the LV pressure is higher than the RV.Like the rest of the LV, the IVS is circumferentially tensioned to endure this pressure gradient (28).It is interesting to note that LV CS did not decrease in patients with concurrent pulmonary hypertension and aortic stenosis (29).The main factor for lower LV septal CS in PAH appears to be RV pressure load in conjunction with septal displacement (29).Takamura et al. (30) also reported an intriguing finding: improvements in LV global, septal, and non-septal CS were linked to improvements in hemodynamic measures.Increased LV CS was more closely linked to this improvement than increased RV free wall longitudinal strain (FWLS) (30).In a similar contest, another concept might be found in interventricular desynchrony.During normal cardiac function, contraction and relaxation of both ventricles occurs somehow simultaneously.Ventricular distortion however varies among the patients with PAH, while the RV free wall continues to shorten even after the pulmonary valve closes and the LV free wall begins to relax as soon as the aortic valve closes (31).In summary, aberrant loading of one ventricle impacts the structure and functionality of the other due to the ventricles' series coupling within the pericardium.This ventricular dependency in PAH can be shown by monitoring the distortion of the LV and RV.

Radiological approach in early diagnosis of ventricular dysfunction in PAH Transthoracic echocardiography
According to the diagnostic algorithm, transthoracic echocardiography (TTE) is the next suggested diagnostic test for individuals with a history and signs or symptoms indicative of PH (32).Based on current guidelines, the pulmonary arterial systolic pressure (PASP) is determined by combining the peak tricuspid regurgitant (TR) velocity with additional two-dimensional (2D) and Doppler findings to assess the likelihood of PAH and determine whether additional evaluation is necessary (7).In addition to the more traditional and well-established assessments of RV function, more recent years have seen the introduction of some highly intriguing non-conventional approaches.Most often, the tricuspid annular plane systolic excursion (TAPSE) is used as a stand-in for the RV function (33).TAPSE (Figure 1A) is a powerful 2DE tool for measuring RV function as well as a significant parameter for disease prognosis (34)(35)(36).The significance of RV TAPSE in RV function in patients with PH was first carried out by Forfia in 2006 (34).A cutoff value below 18 mm was associated with RV dysfunction and worse survival.In a study by Vitarilli et al. (37), for a cutoff value of 16 mm, the sensitivity and specificity of RV failure were found to be 76% and 64%, respectively.In the case of TAPSE  as well as for right ventricular functional area change (RVFAC), at a cutoff value of 38% the sensitivity and specificity for RV failure were found to be 72% and 60%, respectively.Similarly, in 146 patients with PAH, a study for the prognostic value of echocardiography by Mercurio et al. (38) found that TAPSE and degree of tricuspid regurgitation were highly associated with survival (p < 0.01, p = 0.04, respectively).Nevertheless, it was unable to predict mortality in later research, particularly in the New York Heart Association (NYHA) Classes III-IV and RV dilatation (39).
In addition, it predominantly mirrors the longitudinal RV function and is dependent on volume (39).It has been demonstrated that RVFAC (Figure 1B) and right ventricular size, measured at the end diastole, are predictive of survival (39).RVFAC is a recognized prognostic indicator of heart failure and sudden cardiac death in the course of PAH (40).
RV-myocardial performance index (RVMPI) or Tei-index (Figure 2A) is another non-conventional method as a combined indicator of both systolic and diastolic functions.RVMPI for the assessment of RV was first described by Tei in 1996 (41).In their model, the index was increased by 0.93 in PH vs.0.28 in the control group.A higher RVMPI of 0.88 or 0.688 indicated a higher chance of survival (39,42).A study by Vorhies et al. (43) demonstrated that LV and RVMPI markers of global ventricular function were significantly increased in patients with PH compared with in the normal control.However, RVMPI is a load-dependent parameter that increased afterload and reduced preload increase the index (44).Hence the index could not be used to assess change in ventricular contractile function.

2D speckle tracking echocardiography
2D speckle tracking echocardiography (STE) has shown itself to be a dependable, accurate, feasible, and angle-independent quantitative method for assessing RV function in recent years (36,45).The advantage of this method is that it provides a very precise analysis of individual myocardial segments' functions (46).Myocardial strain (ϵ) refers to the alteration in cardiac tissue caused by an external force, calculated using the formula ϵ = (Lsystole-Ldiastole)/Ldiastole, where L represents length, and the result is multiplied by 100 to express myocardial deformation as a percentage throughout the cardiac cycle.A positive value signifies lengthening, while a negative value indicates shortening.Utilizing strain imaging presents a viable non-invasive method for evaluating cardiac mechanics, offering the potential to detect subclinical ventricular dysfunction (45).Strain derived from STE can be delineated across various regions of the RV free wall or presented as an average encompassing visualized segment, recognized as the GLS.The results are expressed as a percentage, where a more negative numerical value denotes greater shortening of the myocardial segment during systole.Deterioration in strain is indicated by a less negative number or lower absolute value than anticipated, indicating reduced deformation along the longitudinal axis.GLS conventionally encompasses the basal, midventricular, and apical RV free segments, but may also extend to encompass the basal, midventricular, and apical segments of the IVS (45).The most common measurement of strain in the RV is GLS; however, individual longitudinal segmental strain is also being investigated in PH (47).
STE permits the early diagnosis of subclinical RV impairment (48).Speckle-tracking echocardiography, employed for ventricular strain and torsion analysis, has augmented the understanding of alterations in systolic function among adult patients with PH.Sachdev et al. (49) demonstrated that LR longitudinal peak systolic strain (−15 ± 5%) and strain rate (−0.80 ± 0.29 s) are predominantly decreased in patients with PAH.Notably, discernible reductions in systolic torsion, as well as longitudinal   (50).In a cohort of 55 patients with PAH (32 SSc-PAH and 23 IPAH), the authors found significant regional differences in RV function between SSc-PAH and IPAH at similar afterloads.Notably, although while patients with SSc-PAH had shorter durations of PAH illness, they still had anomalies in RV contractile as identified by RVLSS.However, results point to differential RV myocardial illness that separates non-invasively detectable PAH subtypes that may be linked to SSc-specific microvascular disease and/or myocardial fibrosis (50).
As already stated, due to the continuous circulatory system and shared septum, the RV-LV interdependence is a great matter of concern.Researchers have claimed that through ventricular dependence there is LV dysfunction in PH (26).A study by Burkett et al. (54) found that LVGLS was found significantly reduced in patients with PH in comparison with matched controls.The authors also stated that the strain and strain rate were predominantly found reduced within the septum in relationship with invasive hemodynamics and functional PH measures (54).

Tissue Doppler imaging
RV function can also be evaluated by measuring the longitudinal peak velocity at the basal segment of the free wall using tissue Doppler imaging (TDI), and tissue velocities change during the isovolumic phase (55).There is an entire review article based on Doppler measurements of RV function (56).In PH and associated right ventricular remodeling due to increased afterload, functional tricuspid regurgitation takes place (57).Tricuspid regurgitant velocity (TRV) is still a classic measurement for screening purposes of patients with suspected PH (57).The tricuspid regurgitant pressure gradient (TRPG) can be calculated from TRV using Bernoulli equation, (P = 4 V 2 ).A study by Fisher at al. validated the accuracy of TRV against catheter, and inaccuracy was found greater than 48 mmHg in 48% cases (58).In the absence of pulmonary valve stenosis, the resultant pressure is equivalent to pulmonary arterial systolic pressure.While, this aids in the assessment of pulmonary pressure, it does not reflect RV function (58).In conclusion, TRV is angle dependent and depends on the right heart function.Right HF may result in less TRV because of reduced contraction and greater annular dilatation.
Tricuspid annular systolic (S′) velocity (Figure 2B) and S′ velocity time integral (VTI) are other tissue Doppler measurements.S′ and VTI measurements were found significantly decreased in pulmonary hypertensive patients in comparison with control and were found consistent with RV systolic dysfunction (43).For the assessment of RV function, a value of less than 10 cm/s is now recommended as a measure of RV impairment in echocardiographic guidelines (59).TDI also allows assessment of LV diastolic function by direct measurements of myocardial velocities independently of cardiac preload (24).

3D echocardiography
Owing to the complex geometry, crescent shape, and complex mode of contractility of the RV, 2D echocardiography (2DE) is unable to locate the RV inlet and outlet in the same image.Consequently, three-dimensional echocardiography (3DE) is a more precise and feasible tool than 2DE for the assessment of RV volumes and function (60).RV function measured with 3DE (Figure 3) was found to be more closely correlated with gold standards CMR and cardiac catheterization (36,(61)(62)(63).Despite this, the accessibility of 3D echo is greater than CMR, which makes this an attractive alternative.In addition, strain imaging has been combined with 3DE to accurately predict RV ejection fraction (EF) (64).A prior investigation by Vitarelli et al. (37) revealed a moderate association (Pearson correlation coefficient ranging from −0.51 to −0.64) between 3DE-RVEF and 3D-RVEF exhibited the highest area under the curve (0.89, P < 0.05) when compared with other 3DE parameters for hemodynamic indices found by RHC in identifying hemodynamic indicators of RV failure (a composite of Ci < 2 L/min/m 2 and RA P > 15 mmHg).By receiver operating curve (ROC) analysis, 3DE-RVEF (0.89) has the highest area under the curve (AUC) (95% CI; 0.68-0.99,P < 0.05) with the cutoff value of EF 39% and 90% and 83% sensitivity and specificity, respectively.The most recent study by Liu et al. (63) demonstrated that 3DE-derived RVEF had the potential to predict the intermediate-high risk stratification (AUC 0.82, 95% CI 0.73-0.91,P < 0.001), which showed the best predictive capacity.To be specific, EF < 26.39% had an 81.6% sensibility and 73.8% specificity to predict intermediatehigh risk stratification.3D-RVEF (OR 0.82, 95% CI 0.75-0.90,P < 0.001) was identified as an independent predictor of intermediate-high risk stratification in patients with PAH.The authors concluded that 3DE-derived EF and free wall strain (FWS) had the potential to independently predict intermediatehigh risk stratification in patients with PAH, and the predictive capacity was retained after adjustment for demographic data.Similar findings were found by Murata et al. (65), whose study's ROC analysis showed that 3DE-RVEF was more accurate in predicting cardiac events, such as hospitalization, intervention, and mortality than other hemodynamic measurements, such as mPAP, with an AUC of 0.78.3DE-derived speckle tracking has proved itself a reliable method for RV systolic function evaluation and survival prediction (61,64).Smith et al. (64) aimed to assess the RV strain with 97 consecutive patients with established pulmonary hypertension disease in comparison with 60 controls, with the help of 3DE-derived strain.In comparison with normal controls, the strain analyses (area strain, redial strain, circumferential strain, and longitudinal strain) were all found reduced.RV global area strain (RVGAS) was found to be a significant determinant of all-cause mortality [HR: 3.49; 1.21-7.07with 95% confidence interval (CI); P = 0.017].Hence, 3DE-derived strain analysis is a reliable tool for the assessment of disease outcome in such patients.

Cardiac magnetic resonance imaging
A non-invasive method for obtaining detailed, threedimensional pictures of the heart is cardiac magnetic resonance imaging (CMRI).It offers details on the anatomy, physiology, and structure of the right heart that are not easily accessible by other techniques like echocardiography and RHC.The most reliable method for measuring RV volume and ejection fraction (RVEF) is CMR, especially when steady-state free precession (SSFP) cine imaging is employed (66).A study by van de Veerdonk et al. (67) suggested that RVEF measured by CMRI was a better predictor of mortality than PVR (area under the ROC curve: 0.749 vs. 0.628).A sample of patients with IPAH was researched by Holverda et al. (68) to determine how their stroke volume responded to exercise.MRI was used to evaluate cardiac function both at rest and during submaximal activity.They discovered that patients with IPAH had a decrease in RVEF during exercise, indicating a symptom of RV failure.
T1 mapping, a newly developed CMRI technique, measures native RV T1 based on pre-and postcontrast T1 timings to detect widespread myocardial anomalies (69).T1 mapping may be a useful tool for identifying fibrosis, which has recently been linked to both maladaptive responses that lead to increased diastolic stiffness and adaptive responses that prevent cardiomyocyte overstretch and preserve RV shape for optimal function (70).Similarly, in a case control study Ostenfeld et al. (17) demonstrated that despite a preserved global LV function, the LV function is affected in patients with PH.They found that LV atrioventricular plane displacement (AVPD) and corresponding longitudinal contribution to LV SV was lower in patients compared with controls.Interestingly, the decreased longitudinal contribution to LVSV was not seen in the RV, contrary to previous findings in RV volume overload (17) (Figure 4).

CMR tissue-tracking technology
Tissue-tracking (TT) technology (strain analysis) has been used in recent years to get myocardial strain parameters by showed that global radial strain (GRS), global circumferential strain (GCS), and global longitudinal strain (GLS) were significantly found lower in patients with PAH in comparison with the healthy controls (73).The authors concluded that CMR-TT is a non-radioactive and non-invasive powerful tool for evaluating RV and LV dysfunction in PAH with preferable feasibility and repeatability (73).

Nuclear medicine
The first-pass radionuclide angiography (FP-RNA) method is regarded as a gold standard method for RVEF measurement.Imaging is obtained dynamically after the first quick transit of administered radiolabeled red blood cell (RBC) over a brief period (5-10 cardiac cycles) via the right atrium, right ventricle, pulmonary artery, lungs, and left heart.Because overlapping activity from overlaid structures is eliminated, FP-RNA can reliably quantify RVEF as the radioactive bolus moves through the heart chambers and major arteries (74).However, because of its technological complexity, this approach depends on a highquality tracer bolus injection, quick imaging capture, and the right postimaging data processing and reconstruction.An alternative method for calculating RVEF is the Gated Blood Pool SPECT (GBPS) instead of FP-RNA.GBPS involves a tomographic acquisition of the heart, allowing for the separation of the RV from the right atrium and LV.This characteristic makes GBPS particularly well-suited for precise RVEF measurements.Furthermore, the imaging acquisition process for GBPS is simpler and boasts a higher success rate compared with FP-RNA (74).RVEF calculations in patients with chronic thromboembolic pulmonary hypertension were performed using both GBPS and FP-RNA.The results indicated a strong correlation between the two methods (r = 0.68, P < 0.0001), but the RVEF calculated using GBPS was also overestimated (51% + 14% calculated from GBPS vs. 37% + 12% from FP-RNA, P < 0.01) (75).In conclusion, RVEF should be measured using FP-RNA if methodology is not an issue.Otherwise, because of its greater procedural success rate and relatively simple imaging capture, GBPS is advised.RVEF is computed using correlations from GBPS.This tool is not used routinely for RVEF measurements because it does not provide other parameters such as RV volume as it is purely counting base calculation.
Sympathetic nervous system (SNS) hyperactivity has a wellrecognized role in the pathophysiology of HF with reduced LVEF.Changes in the sympathetic nervous system have been linked to the PAH pathogenesis.The cardiac SNS activity in 12 consecutive patients with PAH was investigated to find a potential relationships with disease severity indicators using 123 I-metaiodobenzylguanidine ( 123 I-MIBG) nuclear imaging, (76).When measured as the early and late heart-to-mediastinum ratio (H/M), cardiac 123 I-MIBG uptake in PAH was considerably lower than in controls.The study showed significant impairment in cardiac SNS in PAH.This impairment correlated with indices of PAH severity (76).Cardiac sympathetic dysfunction may be a contributing factor to the development of right heart failure in PAH.

PET scanning
PAH is typified by perivascular inflammation, smooth muscle layer hypertrophy, lung vascular intimal lesions, and concurrent RV remodeling.These factors may eventually result in a reduction in RV function such as RV failure.RV failure development is largely determined by the RV metabolic state, which is defined by the degree of ischemia and glycolysis.These factors combine to form a vicious cycle that includes hypoxia, increased RV systolic pressure (RVSP), decreased RV output, and additional myocardial ischemia.In this contest, 2-deoxy-2-[( 18)F]fluoro-D-glucose (FDG) positron emission tomography (PET) has been used for the measurement of glucose uptake (GU) as an indicator of glucose metabolism in the right heart and pulmonary vasculature (77).Currently, non-invasive imaging of the size and function of the RV is used in the clinical evaluation of patients with PAH, and the 6-min walk test and cardiopulmonary exercise testing (CPET) are used to measure exercise capacity.Invasive hemodynamic evaluation is also performed on these patients.Nonetheless, patients with PAH exhibit a great deal of diversity in their clinical course.Studies suggest that increased pulmonary arterial pressures are associated with higher 18F-fluorodeoxyglucose (FDG) uptake in the right ventricle using PET imaging (78).There is proof that pressure overload causes a "metabolic shift" in cardiomyocytes, and FDG uptake is correlated with the advancement of PAH and unfavorable outcomes (79).A study by Bukhari et al. (80) compared the two ventricles to determine the RV and LV indices determined by PET scanning to correlate with the severity of IPAH as determined by hemodynamic and CPET; the study assessed myocardial blood flow (MBF) and substrate metabolism for the RV and LV in IPAH.The findings of this investigation shed light on how increases in RV afterload affect RV blood flow and substrate metabolism.They also showed that RV blood flow and metabolism in patients with IPAH can be measured using dynamic PET scanning.They concluded that in patients with IPAH, PET scanning using 13N-NH3 and 18 F-FDG seems to be a practical method for measuring RV blood flow and RV metabolism.
Another concept in PET scanning is the integrated hybrid design, which is hybrid PET/MRI scans in patients diagnosed with PAH.With benefits for imaging dynamic processes visible on either PET or MRI, the integrated hybrid design offers genuinely simultaneous PET and MRI (81,82).This new noninvasive diagnostic tool is the simultaneous PET/MRI system.PET is a cutting-edge technique that employs short-acting radiopharmaceuticals to enable molecular imaging and provide information on the intracellular metabolic processes occurring within cells.MRI, the second part of this hybrid system, produces very high-quality anatomical images (83).To sum up, elevated glucose metabolism in the RV as shown by FDG PET is linked to progressive alterations in the pulmonary vascular bed and reduced RV function.When PET and MRI are combined, it may be possible to provide important information about RV function and identify clinical worsening early in patients with PAH (83).

Challenges and future directions
Non-invasive imaging modalities play a crucial role in the early diagnosis of right and left ventricular functions in PH.Echocardiography is often the initial choice, offering a real-time assessment of pulmonary pressures, RV size, and function, and the presence of tricuspid regurgitation.However, echo has limitations in fully characterizing RV function and may not capture subtle changes.CMR emerges as a powerful tool, providing detailed anatomical and functional information, including accurate RV volumes, function, mass, and myocardial strain.CMR is particularly adept at identifying early structural changes in both ventricles, contributing valuable insights into PH progression.PET scans, with their ability to assess metabolic and cellular activity, offer additional perspectives on myocardial function in PH, aiding in early detection.Challenges in these modalities include limited availability, cost considerations, and the need for specialized expertise as well as some sort of radiation exposure.Future directions involve the refinement of quantitative parameters for early PH detection, the integration of artificial intelligence to enhance accuracy, and the development of standardized protocols to facilitate multicenter research.Combining the strengths of echo, CMR, and PET holds promise in advancing our understanding of PH pathophysiology, facilitating early diagnosis, and tailoring targeted interventions for improved patient outcomes.Techniques such as advanced strain imaging, fourdimensional (4D) flow MRI, and parametric mapping in cardiac MRI may provide more sensitive indicators of early ventricular dysfunction in PH.Artificial intelligence (AI) and machine learning algorithms (MLA) have the potential to revolutionize the interpretation of imaging data.These technologies can aid in the automated analysis of complex datasets, enabling quicker and more accurate identification of subtle changes in ventricular function associated with PH.
Similarly, integrating imaging findings with circulating biomarkers associated with early ventricular dysfunction may provide a more comprehensive diagnostic approach.Combining imaging and biomarker data could enhance the sensitivity and specificity of early PH detection.While these advancements hold great promise, their successful integration into clinical practice will require rigorous validation, standardization, and collaboration among researchers, clinicians, and industry stakeholders.(34,35).
Maximum systolic excursion of the lateral tricuspid annulus (M-mode) between end-diastole and peak systole (<16 mm).

TDI
The longitudinal velocity of the tricuspid annular plane (S′ value <0.095 m/s) • Reproducible • Validated against radionuclide EF. • Good correlation with normal control • Angle dependent.
• Requires a high frame rate.
• Reflect the function of a small subsection of the RV, (Basal) section.
• Cannot apply to regional wall motion abnormalities.
Tissue Doppler of the RV free lateral wall (S′) Global longitudinal strain (GLS), % systolic shortening of the RV free wall.
• Regional and global function.

Discussion
This article highlights various non-invasive imaging modalities used for the early detection and assessment of left and right ventricular dysfunction in PH and the prognostic utility of each approach (Tables 2, 3).Each modality has its own strengths and limitations, which are discussed in Table 4 in detail.Conventional 2D TTE, speckle-tracking strain imaging, and 3D echocardiography are more specialized techniques that are increasingly becoming part of the standard of care in monitoring right heart structure and function.The 2D traditional parameters such as tricuspid regurgitant velocity and TAPSE for RV function assessment play a crucial role.However, the limitations of TAPSE in predicting mortality and its dependence on volume are noted.Advanced techniques such as 2D STE provide more comprehensive insights into RV function, with the RVGLS demonstrating significant prognostic significance in PH patients.TDI and 3DE offer additional perspectives, particularly in evaluating longitudinal peak velocity and RV volumes, respectively.
CMR emerges as a powerful tool, offering precise measurements of RV volumes and ejection fraction.T1 mapping in CMR enables the identification of fibrosis, providing insights into myocardial anomalies associated with PH.CMR tissuetracking technology, based on strain analysis, proves effective in evaluating RV dysfunction non-invasively.PET scanning, specifically 2-deoxy-2-[( 18)F]fluoro-D-glucose (FDG) PET, sheds light on the metabolic state of the right heart and pulmonary vasculature in PAH.The integration of PET/MRI offers a novel hybrid imaging approach, combining molecular and anatomical information for a more comprehensive assessment of RV function.
In synthesis, according to significant discoveries in the recent literature, although PH is predominantly a right heart disease, due to the factor of shared septum and pericardial sac, LV function is also a matter of concern in such patients.Each noninvasive modality mentioned previously offers distinctive contributions to the prompt diagnosis of ventricular dysfunction, thereby facilitating improved timely management in affected individuals.Among these modalities, CMR stands out as a gold standard test for early identification of ventricular function, also serving as a crucial prognostic indicator in such cases.However, it is important to note that CMR does present notable contraindications, including but not limited to claustrophobia, presence of implanted magnetic devices such as left ventricular assist devices, and its high cost.These limitations warrant consideration in routine clinical practice.Recent advancements in echocardiography especially the fully automated 3DE quantification also has an emerging role in patients with PH.Overall, these imaging modalities contribute valuable diagnostic and prognostic information in the context of PH, with ongoing research focusing on refining and expanding these techniques.The exploration of novel biomarkers, artificial intelligence integration, and advancements in imaging technology are anticipated to further enhance the early detection and monitoring of ventricular dysfunction in pulmonary hypertension.

Conclusion
Non-invasive modalities such as echocardiography, nuclear imaging, and CMR are all useful for screening, classifying, prognosticating, and monitoring the effectiveness of therapy in  PH.The standardized algorithm using echocardiographic parameters such as TAPSE, FAC, TDI, and strain analysis in the early diagnosis of dysfunction can also be supplemented with CMR methods.CMR is already considered the gold standard for assessment of the function.Each modality can complement the other in the early diagnosis of ventricular dysfunction in PAH.A thoughtfully crafted clinical strategy should consider the availability of expertise, necessary imaging equipment, and analytic software within a value-based framework.Innovative imaging methodologies like strain imaging, 3D echocardiography, FDG-PET, and dual PET/MRI scan can assess the function of PAH.These techniques can be employed alongside conventional imaging modalities to track disease progression and evaluate the response to therapeutic interventions.
a for patients with idiopathic, hereditable, or drug-induced PAH (reduction of mPAP ⩾ 10 mmHg to reach an absolute value of mPAP ⩽ 40 mmHg increased or unchanged cardiac output).1.5.2Long-term response to CCBs [NYHA Functional Class I/II With sustained hemodynamic improvement (same or better than achieved in the acute test) after at least 1 year on CCBs only].

TABLE 2
Modalities hazardous analysis for mortality in patients with PAH using different approaches.

TABLE 3
Comparative evaluation of parametric approaches in PAH for accurate hemodynamic risk stratification.3DE, three-dimensional echocardiography; AUC, area under the curve; CI, confidence interval; RVAS, right ventricular area strain; RVEF, right ventricular ejection fraction; RVGAS, right ventricular global area strain; RVGLS, right ventricular global longitudinal strain; RVEF, right ventricular ejection fraction; RVFAC, right ventricular fractional area change; TAPSE, tricuspid annular plane systolic excursion; NA, not available; n, number of patients.

TABLE 4
Summary of imaging techniques for RV functional assessment in PAH.