Worldwide Epidemiology of Pulmonary Hypertension Associated With Left Heart Disease

Authors: Suela Vani, Filippo Novarese, Matteo Toma, Italo Porto, Pietro Ameri

Abstract

Globally, around 1 in 2 patients with left heart disease (LHD) has pulmonary hypertension (PH). The prevalence of PH associated with heart failure, mitral regurgitation, aortic valve disease, hypertrophic cardiomyopathy, and cardiac amyloidosis has mainly been investigated in high-income countries, especially the United States and Europe, by transthoracic echocardiography without right heart catheterization confirmation. It is estimated that around 80% of patients with hypertrophic cardiomyopathy or cardiac amyloidosis, around 65% of patients with heart failure or mitral regurgitation, and around 40% of patients with aortic valve disease have PH. In contrast, data about PH associated with mitral stenosis and rheumatic heart disease are primarily from low-income countries. The prevalence is around 80% in mitral stenosis—as determined by right heart catheterization in candidates for surgery or balloon valvuloplasty—and around 45% in rheumatic heart disease based on transthoracic echocardiography screening. PH associated with LHD (PH-LHD) clinical trials have focused on PH secondary to heart failure and have most often been performed in the United States and Europe (sites from these countries in 53.3% and 43.3% of the trials, respectively). The heterogeneous epidemiology of PH-LHD may reflect actual differences in the frequency of the underlying types of LHD, but it may also be the consequence of detection and reporting biases. Regional health authority choices, diagnostic capacity, and socio-economic factors likely influence the selection of the sites of PH-LHD trials. Efforts are needed to better characterize the worldwide burden of PH-LHD and to conduct truly global clinical trials.

1. Introduction

Pulmonary hypertension (PH) is a common complication of left heart disease (LHD), ensuing from the backward transmission of elevated left-heart filling pressures to the pulmonary circulation.^[1]^ A subset of patients develops functional and structural alterations of pulmonary arterioles and venules, which heighten pulmonary vascular resistance (PVR) and compound PH associated with LHD (PH-LHD) [Figure 1].^[2]^ The pathogenesis of pulmonary vascular remodeling in PH-LHD includes defective nitric oxide signaling and enhanced endothelin-1 expression and activity, but it is only partially understood.^[3,4]^

The hemodynamic diagnosis of PH-LHD requires that the mean pulmonary arterial pressure (mPAP) is > 20 mmHg and pulmonary artery wedge pressure is > 15 mmHg, as measured by right heart catheterization (RHC) at rest.^[5]^ The mPAP threshold was recently lowered from the previous one of 25 mmHg, since the current cut-off coincides with the upper limit of the mPAP range in healthy individuals.^[6]^ Moreover, it is in agreement with the evidence that a mPAP > 20 mmHg increases the risk of mortality.^[7,8]^

PH-LHD is further categorized into 2 hemodynamic (1) isolated post-capillary PH (Ipc-PH) when PVR is ≤ 2 Wood units (WU) and (2) combined post- and pre-capillary PH (Cpc-PH) in the presence of PVR > 2 WU.^[5]^ Ipc-PH corresponds to stages of disease in which retrograde propagation of high left atrial pressure mostly accounts for the increase in pulmonary arterial pressure (PAP), whereas Cpc-PH reflects the occurrence of pulmonary vascular remodeling.^[9]^ The PVR threshold for the subclassification of PH-LHD in Ipc-PH and Cpc-PH was also recently reduced from 3 to 2 WU because large retrospective analysis highlighted that prognosis worsens starting from PVR beyond 2 WU.^[8,10]^

The transpulmonary gradient (TPG; calculated mPAP − PAWP) and the diastolic pressure gradient (DPG; calculated  diastolic PAP − PAWP) are other RHC-derived measures that have been proposed to distinguish between Ipc-PH and Cpc-PH. TPG > 12 mmHg and DPG > 7 mmHg are considered proxies of pulmonary vascular remodeling.^[11]^ However, TPG is influenced by stroke volume and PAWP. DPG is not affected by stroke volume, and studies based on both histology and RHC suggest that it is more accurate than TPG to detect the remodeling of pulmonary arterioles.^[12]^ Nonetheless, the prognostic value of DPG has been questioned.^[13,14]^

Irrespective of the hemodynamic definition, patients with Cpc-PH have more pronounced ventilatory responses to exercise, lower pulmonary arterial compliance, impaired right ventricular function, and shorter life expectancy than those with Ipc-PH.^[15]^ The worse survival is mainly due to the development of right ventricular failure.^[16]^

In this article, we review the literature about worldwide epidemiology of PH-LHD. Unlike the global burden of chronic respiratory diseases, this topic has not systematically been addressed in recent years.^[17]^ We also cover the prognostic impact of PH-LHD since it is commonly assessed together with PH-LHD prevalence.

2. Methods

The PubMed database was searched by entering the following “pulmonary hypertension” “group 2 pulmonary hypertension” “left heart disease” “heart failure” “mitral regurgitation” “mitral stenosis” “aortic regurgitation” “aortic stenosis” “rheumatic heart disease” “hypertrophic cardiomyopathy”, and “cardiac amyloidosis”. The relevant abbreviations (eg, PH) were also used.

Since the underlying etiology is not normally specified in studies on PH associated with heart failure (PH-HF), we considered this entity separately from PH associated with specific types of LHD (ie, valvular heart disease (VHD), hypertrophic cardiomyopathy (HCM), and cardiac amyloidosis). To provide aggregate measures for multiple studies, we calculated the average of the mean, median, or percent values in each study. Information about PH-LHD clinical trials was retrieved in the ClinicalTrials.gov and EudraCT databases.

3. PH-HF

Most studies on the prevalence of PH-HF have followed the classification of HF into HF with reduced ejection fraction (HFrEF), HF with mid-range or mildly reduced ejection fraction (HFmrEF), and HF with preserved ejection fraction (HFpEF). The main findings are shown in Figure 2.^[16181920212223242526272829]^

3.1. HFrEF and HFmrEF

Left ventricular systolic dysfunction is the hallmark of HFrEF and is also found in HFmrEF. HFmrEF has other similarities with HFrEF, particularly the predominance of ischemic heart disease as etiology and the response to neurohormonal inhibitors and angiotensin receptor-neprilysin inhibitors.^[30]^ Thus, we discuss these 2 HF phenotypes together.

Key studies of the prevalence of PH in HFrEF and HFmrEF were conducted in high-income countries and are listed in Table 1.^[16181920212223242526272829]^ The mean age of the included patients was 63.5 years, and the majority of patients were male (58.9%). Overall, the proportion of subjects with PH was similar when determined by transthoracic echocardiography (TTE) or RHC (60.4% vs. 60.6% respectively). Except in 1 case, the investigators adopted the previous mPAP threshold of 25 mmHg for the diagnosis of PH, with potential exclusion of subjects with mPAP between 20 and 24 mmHg. There was a direct correlation between elevated PAP and all-cause mortality [Figure 2].^[16181920212223242526272829]^

3.2. HFpEF

HFpEF is characterized by left ventricular ejection fraction (LVEF) ≥50% and predominant left ventricular diastolic dysfunction. This condition may be secondary to distinct forms of LHD (sometimes referred to as HFpEF mimickers)—for example, aortic stenosis—or may be self-standing, most frequently in obese individuals or elderly women with cardiovascular and non-cardiovascular comorbidities, such as arterial hypertension, atrial fibrillation (AF), and diabetes mellitus.^[1]^ It is anticipated that the number of patients with HFpEF will almost double by 2030, mainly because of increasing incidence of self-standing HFpEF.^[31]^

In the main studies of PH in HFpEF, patients had or were assumed to have HFpEF without any underlying specific LHD, although it cannot be excluded that some instead had HFpEF mimickers. The included subjects were from Europe and the United States, but also from Japan and international cohorts [Table 1].^[16181920212223242526272829]^ The mean age was 63.6 years, and the mean body mass index was 29.1 kg/m^2^. The female to male ratio was around 1. Like in patients with HFrEF/HFmrEF, it is possible that PH was underdiagnosed when RHC was employed since the mPAP cut-off was 25 mmHg. The mean patient age (62.6 years vs. 72.6 years) and the proportion of female patients (43.6% vs. 51%) were lower in high-income vs. low- or middle-income countries. In half of the investigations in high-income countries, PH was assessed by RHC. Combining TTE and RHC data, the prevalence was 47.5% [Figure 3]. Conversely, the prevalence of PH in cohorts from low- or middle-income countries was only determined by TTE and was 33.5%. Hospitalization and mortality were more likely in patients with higher systolic PAP (sPAP) and tricuspid regurgitation velocity.^[25]^ Furthermore, the presence of Cpc-PH, as defined by PVR >3 WU, portended an increased risk of mortality.^[24]^

4. PH associated with VHD

4.1. Mitral stenosis

Mitral stenosis represents a model of PH-LHD pathophysiology. The reduction in the mitral valvular area directly causes a rise of left atrial pressure and, thereby, pulmonary pressure. In addition, fibrosis of the chronically stretched wall reduces the compliance of the left atrium and magnifies the increase in filling pressure, which propagates to the pulmonary circulation. AF develops over time, further impairing left atrial function. As a result, virtually any patient presents with PH during the course of mitral stenosis.^[32]^

There were 6 studies that determined the prevalence of PH associated with mitral stenosis in cohorts from India, the Middle East, and the United States, always by means of RHC [Table 2].^[333435363738394041424344454647]^ The age of subjects from low- or moderate-income countries was younger than from high-income countries (39.8 years vs. 56.7 years). Of the patient group, 24.7% were male. LVEF was reported only in 1 investigation and was 52%.^[35]^ The main cause of mitral stenosis was rheumatic heart disease (RHD). Overall, more than 70% of patients with mitral stenosis had PH, with the caveat that they were symptomatic in most investigations and, thus, had the highest likelihood to have advanced VHD with PH. Patients in the United States had PH more often than patients from other countries (81.5% vs. 51.5%), suggesting an even stricter selection [Figure 4A].^[333435363738]^ Even modest increases in PAP were associated with adverse surgical outcomes, although the degree of PH making surgery prohibitive is debated.^[48]^

In patients in the United States with mitral stenosis and sPAP 35–44 mmHg, cardiac surgery halted PH progression and improved long-term survival at the cost of acceptable 30-day mortality.^[36]^ In a small sample study from India, mortality rose from 5.5% to 28.5% when PAP was supra-systemic. Mubeen et al^[49]^ concluded that surgery for mitral stenosis is feasible as long as PAP is lower than systemic pressure. Interestingly, histological analysis of lung biopsy specimens did not reveal specific changes in pulmonary arterioles in the group with supra-systemic PAP.

The outcomes of patients with PH associated with mitral stenosis undergoing percutaneous balloon mitral commissurotomy were different depending on the study location. In the United States, the procedure was shown to be safe and effective to treat patients with mitral stenosis and severe PH, with immediate pulmonary hemodynamic improvement and sustained benefit up to 3 years after the procedure.^[37]^ Conversely, PVR remained elevated after percutaneous balloon mitral commissurotomy or valvuloplasty in patients from Saudi Arabia, possibly because the presence of Cpc-PH that was not modified by intervention.^[34]^

4.2. Mitral regurgitation

Like mitral stenosis, mitral regurgitation increases left atrial pressure directly and indirectly, via left atrial dilation and stiffening [Figure 1]. The high left atrial pressure is transmitted to the pulmonary circulation in a retrograde manner, with a peak during the systolic backflow through the regurgitant mitral valve, which causes the appearance of large V-waves in the PAWP waveform at RHC.^[50]^

Figure 4B^[394041424344454647]^ and Table 2^[333435363738394041424344454647]^ present key studies evaluating PH resulting from primary and secondary mitral regurgitation. All were from high-income countries in Europe, North America, and Australia, mainly because the focus was the effect of transcatheter mitral valve repair (TMVR).

The included patients had a mean age of 74.7 years, and 47.6% were male. Mean LVEF, as calculated based on the information in 7 investigations, was 56.7%. The prevalence of PH was highly variable due to differences in assessment methods, PH definition, and mitral regurgitation severity. It varied from 23% in degenerative mitral regurgitation with leaflet flail, when the cut-off of sPAP was 50 mmHg,^[46]^ to 69.9% in German patients with sPAP >37 mmHg enrolled in the Transcatheter Mitral Valve Interventions (TRAMI) registry.^[44]^ In the largest TTE-based investigation, 59.6% of 9,638 patients affected by moderate to severe mitral regurgitation had PH, and 30% had sPAP 30–39.9 mmHg.^[39]^

Both TTE-estimated sPAP and RHC-measured PAP were reported to decrease early after TMVR or cardiac surgery, and a prompt reduction in PAP was a strong independent predictor of favorable long-term clinical outcomes.^[515253]^ It is noteworthy that TMVR reduced sPAP to a greater extent than guideline-directed medical therapy alone.^[45]^ Even mild PH was an independent predictor of perioperative mortality in patients undergoing surgery for mitral regurgitation.^[42]^ Conversely, the presence of PH did not increase the risk of in-hospital mortality in patients undergoing TMVR, nor did it affect the rate of procedural success and in-hospital major adverse cardiovascular events.^[43]^ Higher sPAP correlated with higher post-discharge short- and long-term mortality after both mitral regurgitation surgery and TMVR.^[42,44]^

4.3. Aortic stenosis

The main studies of the prevalence of PH in aortic stenosis included patients undergoing transcatheter aortic valve replacement (AVR) or surgical AVR in high-income countries in Europe, North America, and Australia. The mean age was 77.9 years, and 45.2% of subjects were male [Table 3].^[54555657585960616263646566]^ LVEF was always reported, and the mean value was 55.6%. PH was found in 6% of asymptomatic patients with aortic stenosis^[67]^ and in 47%–75% of those treated by surgical AVR or transcatheter AVR [Figure 5].^[5455565758596061]^ Around 10% of subjects scheduled for transcatheter AVR and evaluated by RHC had Cpc-PH.^[57]^

PH was associated with worse prognosis in patients with aortic stenosis, with the risk of all-cause death rising from sPAP values > 35 mmHg.^[54]^ The severity of PH did not influence the risk of transcatheter AVR-related complications or 30-day mortality. However, sPAP > 60 mmHg was an independent predictor of 1-year mortality.^[55]^ RHC data indicated that 1-year mortality is higher in subjects undergoing transcatheter AVR who have Cpc-PH but not in those who have Ipc-PH, as compared to patients without PH. Moreover, improvement of sPAP and right ventricular function at 1-year follow-up is less common in the former than in the latter.^[57,60]^

PH before surgical AVR was associated with prolonged ventilation, longer stay, and higher in-hospital mortality. Long-term survival was also negatively influenced by pre-operative PH, with 5-year survival being 62%–68% in patients with no or mild PH at the time of surgical AVR and 52%–57% in those with moderate or severe PH.^[56]^ Post-procedural, residual PH was associated with worse prognosis than pre-procedural PH.^[56]^

4.4. Aortic regurgitation

We found a small number of studies on the prevalence of PH in patients with aortic regurgitation [Table 3]^[54555657585960616263646566]^ [Figure 3]^[6263646566]^. All were conducted in high-income countries. The mean age was 70 years, and females outnumbered males (55% vs. 45%). LVEF was reported in 2 studies, and the mean was 58.5%. In the largest investigation, based on TTE, PH was found in almost 45% of 8,392 patients with isolated aortic regurgitation and preserved LVEF.^[62]^ In another study relying on RHC, PH was demonstrated in 36.7% of 805 subjects with aortic regurgitation.^[64]^ The prevalence of PH dropped to between 16% and 24% when only severe PH was considered.^[65,66]^

Patients with aortic regurgitation with PH had greater left ventricular end-diastolic and end-systolic dimensions, lower LVEF, and higher grades of mitral regurgitation than those without PH.^[65]^ Moreover, they faced higher all-cause mortality.^[62]^ AVR was shown to lower sPAP from 66 mmHg to 31 mmHg in a small surgical sample and operative mortality was acceptable (3%) even in patients with severe PH, supporting the choice to perform AVR also in this challenging subgroup.^[63]^

4.5. RHD

RHD is still highly prevalent in Africa, the southeast and middle-east regions of Asia, the Caribbean islands, and some Latin American countries because the likelihood of the disease is increased by factors relating to overcrowding, poor hygienic conditions, low education, and limited access to care.^[68]^ RHD typically affects the left cardiac valves, especially the mitral one. Annulus dilatation, chordal elongation, and leaflet prolapse cause mitral regurgitation, and commissural fusion leads to mitral stenosis. Isolated involvement of the aortic valve is rare, whereas bi-valvular disease is common.^[69]^

PH is an expected complication of RHD, along with HF and AF, and it has been estimated that 3.75 million individuals in the world suffer from RHD-related PH, with this etiology being the cause of 10% of PH cases in Africa and 6% of PH cases in Asia.^[70]^ Real-world data suggest that RHD accounts for even higher proportions of patients with PH-LHD.^[717273]^ Furthermore, RHD is the most common cause of PH in African children, together with unoperated congenital heart disease.^[74]^ Table 4^[757677787980818283]^ lists the 9 studies reporting the prevalence of PH in subjects with RHD, without details of the affected valves. The investigations were mainly carried out in Africa and South Asia,^[757677787980818283]^ and no investigations were done in high-income countries. The mean age was 31.6 years, and 34% of the patient population was male. The mean LVEF was 58.4% (based on 3 studies).

On average, 44% of patients had PH, but with great variability [Figure 3]. In the Global Rheumatic Heart Disease Registry (REMEDY) study, up to 28% of patients presented with elevated PAP.^[75]^ In patients admitted to hospitals in Africa, India, and Yemen and enrolled in the Registry of Rheumatic Heart Disease in Western and Central Africa (VALVAFRIC) or REMEDY, the frequency of PH was almost 30%.^[75,76]^ The prevalence of PH was higher in studies with smaller samples, peaking at 87% in children referred for cardiac surgery.^[81]^ In a pooled sample of 3,750 patients with RHD from 2 studies, the prevalence of PH was 12.9%.^[84]^ The variability of these metrics may be explained by differences in patient populations and RHD phenotypes.^[85]^

5. PH associated with HCM

We found 10 studies that evaluated the prevalence of PH in HCM [Table 5].^[86878889909192939495]^ All were performed in high-income areas—the United States, Europe, China, and Japan—and were mostly in tertiary centers.

One study relied on RHC performed before septal myectomy^[94]^ and the other ones on TTE^[868788899091929395]^. The mean age of the included patients was between 50 and 60 years, 44.8% were female, and mean LVEF was 67.5% (based on 8 studies).

PH was reported in 12%–62% of patients, depending on the definition [Figure 3]. The highest rates were found in HCM with an obstructive phenotype^[96]^ and in apical variants.^[95]^ Older age (especially in women), AF, HF symptoms, moderate-severe mitral regurgitation, and higher obstruction gradients were correlates of more severe PH in obstructive HCM.^[92,93,96]^ More than two-thirds of patients with end-stage HCM had PH, contributing to the poor prognosis of the disease at this stage.^[90]^

PH portended an increased risk of morbidity and mortality^[86]^ and was associated with higher peri-operative risk in subjects undergoing cardiac surgery.^[97]^ However, it did not negatively influence the outcomes of septal alcohol ablation and surgical myectomy.^[94]^ In fact, patients with moderate-severe PH had maximum benefit from the elimination of the left ventricular tract outflow obstruction.^[92]^ The reduction in PAP may be progressive over time and long-lasting after treatment of left ventricular outflow tract obstruction.^[92]^

6. PH associated with cardiac amyloidosis

The 5 studies investigating the prevalence of PH in patients affected by cardiac amyloidosis were performed in the United States or Europe [Table 6].^[9899100101102]^ All were based on RHC, taking advantage of the need of endomyocardial biopsy for the diagnosis of cardiac amyloidosis. The mean age was 70 years, men and women were equally represented, and LVEF was overall mildly reduced. All studies included subjects with light chain cardiac amyloidosis; 3 also included subjects with transthyretin cardiac amyloidosis.

The prevalence of PH was > 75% in all studies, even when the cut-off of mPAP was 25 mmHg instead of 20 mmHg [Figure 3].^[9899100101102]^ Ipc-PH was the predominant PH-LHD subtype, followed by Cpc-PH. Strikingly, purely pre-capillary PH was also described, possibly because of amyloid deposition in pulmonary capillaries and arterioles.^[103,104]^ No difference in PH prevalence was found between transthyretin cardiac amyloidosis and light chain cardiac amyloidosis, although pulmonary hemodynamics affected the prognosis of transthyretin cardiac amyloidosis more than the prognosis of light chain cardiac amyloidosis.^[100]^ Higher mPAP and PVR were predictors of increased mortality.^[99]^

7. Clinical trials

We identified 59 clinical trials for patients with PH-LHD in the ClinicalTrials.gov and EudraCT databases [Table 7].^[105106107108109110111112113114115116117118119120121122123124125126127128129130131132133134135136137138139140141]^ The vast majority focused on PH-HF. It is possible that a few subjects with PH associated with VHD, PH associated with HCM, or PH with cardiac amyloidosis were unintentionally enrolled in these trials, but these types of LHD were exclusion criteria.

The most represented nations were the United States and those in Europe, accounting for 26 trials (43.3%) and 32 trials (53.3%), respectively. Within Europe, the trials in Germany, Italy, Austria, the United Kingdom, and Spain outnumbered those in other countries. Regions other than North America and Europe were much less frequently involved. There were 16 studies (26.7%) that recruited Asian patients, mainly from Israel and China (10% for each nation); only 1 to 3 trials included subjects from the Russian Federation, India, Korea, Singapore, or Japan. Only 1 or 2 trials enrolled Brazilian, Argentinian, Australian, or Egyptian patients.

The tested interventions were drugs, except for 2 investigations of pulmonary artery denervation, which were conducted in China.^[126]^ One trial in Japan focused on children with PH requiring surgery for congenital heart disease.^[134]^ The active trial in Egypt is evaluating the effects of milrinone in patients undergoing surgery for mitral valve disease, who also have sPAP ≥ 55 mmHg at TTE.

8. Discussion

The data about PH-LHD epidemiology largely vary across studies in different regions of the world. This discrepancy may have several causes. Investigators may tend to focus on the most relevant type of LHD in a certain area—for example, RHD is a major health issue in Africa—whereas aortic stenosis or cardiac amyloidosis are objects of intense research in industrialized countries because of the treatment options that have been developed in the last years. This leads to a reporting bias. Methodological heterogeneity should be also considered; local availability will dictate reliance on RHC vs. TTE, which in turn affects the accuracy of PH diagnosis. It is possible that patients come to medical attention at different phases of LHD. Since PH becomes more common with LHD progression, the timing of assessment may influence the frequency of PH detection. Supporting the hypothesis that the way studies are conducted influence the estimates of PH-LHD prevalence, we found a fluctuating proportion of patients with PH-RHD only in Africa.

Nonetheless, it cannot be excluded that the burden of PH-LHD is different across the globe due to ethnical and social factors, such as genetic susceptibility, influence of diet, and promptness and completeness of therapy. Intriguingly, there is also a clear imbalance in the geographical distribution of PH-LHD clinical trials. High-income countries normally have well-structured health care systems, ensuring diagnostic capacity, resources for patient recruitment and follow-up, and control of competing diseases, such as infections. These characteristics are preconditions for the successful completion of a clinical study, and it is expected that they are looked for by sponsors and clinical research organizations.

Studies assessing PH with the same approach in similarly selected cohorts worldwide are needed to obtain reliable information about PH-LHD epidemiology. Involvement of centers of excellence in low-income nations may facilitate the design of more inclusive trials. The creation of partnerships between hospitals and funding agencies in high- and low-income nations is another possible strategy to overcome the selection bias in PH-LHD trials.

9. Conclusions

The epidemiology of PH-LHD is characterized by apparent regional variability, with PH-LHD due to mitral stenosis and RHD prevailing in low- and middle-income countries, and PH due to other LHD types being predominant in high-income countries. A bias toward reporting only the most common forms of PH-LHD in a certain area likely enforces these differences. Enrollment in PH-LHD clinical trials has mostly been limited to patients in high-income countries, arguably because of the better context that these offer as compared to low-income nations. At present, there is no global consistency in the evidence informing PH-LHD knowledge and management.

Funding

Italo Porto was supported by the Italian Ministry of University and Research (PRIN 2022 PNRR funded by the European Union - Next Generation EU; project P20225BYWX, CUP D53D23020960001).

Author contributions

Suela Vani and Filippo Novarese contributed to literature search, data synthesis, and writing. Matteo Toma and Italo Porto helped with the design of the study and critically reviewed the article draft. Pietro Ameri conceived the article and contributed to literature search, data synthesis, and writing. All authors read and approved the final manuscript.

Conflicts of interest

Italo Porto received speaker and/or consultant fees from Medtronic, Abbott Vascular, Edwards, ABIOMED, GE, Siemens Healthcare, Sanofi, Amgen, Daiichi-Sankyo, Astra Zeneca, Bayer, PIAM, and Chiesi. Pietro Ameri received speaker and/or advisor fees from Astra Zeneca, Boehringer Ingelheim, Bayer, Daiichi Sankyo, MSD, Janssen, and Gossamer Bio. The Department of Internal Medicine of the University of Genova received fees from Bayer for scientific consultancy performed by Pietro Ameri.