Vutrisiran in Patients with Transthyretin Amyloidosis with Cardiomyopathy.

BACKGROUND: Transthyretin amyloidosis with cardiomyopathy (ATTR-CM) is a progressive, fatal disease. Vutrisiran, a subcutaneously administered RNA interference therapeutic agent, inhibits the production of hepatic transthyretin. METHODS: In this double-blind, randomized trial, we assigned patients with ATTR-CM in a 1:1 ratio to receive vutrisiran (25 mg) or placebo every 12 weeks for up to 36 months. The primary end point was a composite of death from any cause and recurrent cardiovascular events. Secondary end points included death from any cause, the change from baseline in the distance covered on the 6-minute walk test, and the change from baseline in the Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS) score. The efficacy end points were assessed in the overall population and in the monotherapy population (the patients who were not receiving tafamidis at baseline) and were tested hierarchically. RESULTS: A total of 655 patients underwent randomization; 326 were assigned to receive vutrisiran and 329 to receive placebo. Vutrisiran treatment led to a lower risk of death from any cause and recurrent cardiovascular events than placebo (hazard ratio in the overall population, 0.72; 95% confidence interval [CI], 0.56 to 0.93; P = 0.01; hazard ratio in the monotherapy population, 0.67; 95% CI, 0.49 to 0.93; P = 0.02) and a lower risk of death from any cause through 42 months (hazard ratio, 0.65; 95% CI, 0.46 to 0.90; P = 0.01). A primary end-point event occurred in 163 patients in the vutrisiran group and in 202 in the placebo group. In the overall population, treatment with vutrisiran resulted in less of a decline in the distance covered on the 6-minute walk test than placebo (least-squares mean difference, 26.5 m; 95% CI, 13.4 to 39.6; P<0.001) and less of a decline in the KCCQ-OS score (least-squares mean difference, 5.8 points; 95% CI, 2.4 to 9.2; P<0.001). Similar benefits were observed in the monotherapy population. The incidence of adverse events was similar in the two groups (99% in the vutrisiran group and 98% in the placebo group); serious adverse events occurred in 62% of the patients in the vutrisiran group and in 67% of those in the placebo group. CONCLUSIONS: Among patients with ATTR-CM, treatment with vutrisiran led to a lower risk of death from any cause and cardiovascular events than placebo and preserved functional capacity and quality of life. (Funded by Alnylam Pharmaceuticals; HELIOS-B ClinicalTrials.gov number, NCT04153149.).

Right Heart Adaptation to Exercise in Pulmonary Hypertension: An Invasive Hemodynamic Study.

BACKGROUND: Right heart failure (RHF) is associated with a dismal prognosis in patients with pulmonary hypertension (PH). Exercise right heart catheterization may unmask right heart maladaptation as a sign of RHF. We sought to (1) define the normal limits of right atrial pressure (RAP) increase during exercise; (2) describe the right heart adaptation to exercise in PH owing to heart failure with preserved ejection fraction (PH-HFpEF) and in pulmonary arterial hypertension (PAH); and (3) identify the factors associated with right heart maladaptation during exercise. METHODS AND RESULTS: We analyzed rest and exercise right heart catheterization from patients with PH-HFpEF and PAH. Right heart adaptation was described by absolute or cardiac output (CO)-normalized changes of RAP during exercise. Individuals with noncardiac dyspnea (NCD) served to define abnormal RAP responses (>97.5th percentile). Thirty patients with PH-HFpEF, 30 patients with PAH, and 21 patients with NCD were included. PH-HFpEF were older than PAH, with more cardiovascular comorbidities, and a higher prevalence of severe tricuspid regurgitation (P < .05). The upper limit of normal for peak RAP and RAP/CO slope in NCD were >12 mm Hg and ≥1.30 mm Hg/L/min, respectively. PH-HFpEF had higher peak RAP and RAP/CO slope than PAH (20 mm Hg [16-24 mm Hg] vs 12 mm Hg [9-19 mm Hg] and 3.47 mm Hg/L/min [2.02-6.19 mm Hg/L/min] vs 1.90 mm Hg/L/min [1.01-4.29 mm Hg/L/min], P < .05). A higher proportion of PH-HFpEF had RAP/CO slope and peak RAP above normal (P < .001). Estimated stressed blood volume at peak exercise was higher in PH-HFpEF than PAH (P < .05). In the whole PH cohort, the RAP/CO slope was associated with age, the rate of increase in estimated stressed blood volume during exercise, severe tricuspid regurgitation, and right atrial dilation. CONCLUSIONS: Patients with PH-HFpEF display a steeper increase of RAP during exercise than those with PAH. Preload-mediated mechanisms may play a role in the development of exercise-induced RHF.

Pediatric pulmonary arterial hypertension due to a novel homozygous GDF2 missense variant affecting BMP9 processing and activity.

Pulmonary arterial hypertension (PAH) is a rare and severe disorder characterized by progressive pulmonary vasculopathy. Growth differentiation factor (GDF)2 encodes the pro-protein bone morphogenetic protein (BMP) 9, activated after cleavage by endoproteases into an active mature form. BMP9, together with BMP10, are high-affinity ligands of activin receptor-like kinase 1 (ALK1) and BMP receptor type II (BMPR2). GDF2 mutations have been reported in idiopathic PAH with most patients being heterozygous carriers although rare homozygous cases have been described. The link between PAH occurrence and BMP9 or 10 expression level is still unclear. In this study, we describe a pediatric case of PAH also presenting with telangiectasias and epistaxis. The patient carries the novel homozygous GDF2 c.946A > G mutation, replacing the first arginine of BMP9's cleavage site (R316) by a glycine. We show that this mutation leads to an absence of circulating mature BMP9 and mature BMP9-10 heterodimers in the patient's plasma although pro-BMP9 is still detected at a similar level as controls. In vitro functional studies further demonstrated that the mutation R316G hampers the correct processing of BMP9, leading to the secretion of inactive pro-BMP9. The heterozygous carriers of the variant were asymptomatic, similarly to previous reports, reinforcing the hypothesis of modifiers preventing/driving PAH development in heterozygous carriers.

Eomesodermin induces Mesp1 expression and cardiac differentiation from embryonic stem cells in the absence of Activin.

The transcription factor Eomesodermin (Eomes) is involved in early embryonic patterning, but the range of cell fates that it controls as well as its mechanisms of action remain unclear. Here we show that transient expression of Eomes promotes cardiovascular fate during embryonic stem cell differentiation. Eomes also rapidly induces the expression of Mesp1, a key regulator of cardiovascular differentiation, and directly binds to regulatory sequences of Mesp1. Eomes effects are strikingly modulated by Activin signalling: high levels of Activin inhibit the promotion of cardiac mesoderm by Eomes, while they enhance Eomes-dependent endodermal specification. These results place Eomes upstream of the Mesp1-dependent programme of cardiogenesis, and at the intersection of mesodermal and endodermal specification, depending on the levels of Activin/Nodal signalling.

Left ventricular hypertrophy: do not forget Fabry disease. Diagnostic work-up and differential diagnosis.

BACKGROUND: Left ventricular (LV) hypertrophy is a common clinical finding. Differential diagnosis includes Fabry disease, a rare and progressive, but treatable storage disease caused by deficiency of α-galactosidase A. However, diagnosis of Fabry is often hampered by its clinical heterogeneity, LV hypertrophy phenocopies and unawareness of the clinician. METHODS: This review summarises clinical data, family history, electrocardiogram (ECG) and imaging (echocardiogram and cardiovascular magnetic resonance (CMR)) characteristics to differentiate aetiologies of LV hypertrophy including clues for the diagnosis of Fabry. RESULTS: LV hypertrophy is a consequence of pressure overload mostly, but differential diagnosis includes hypertrophic cardiomyopathy and infiltrative diseases. Clinical data, ECG, type and degree of LV hypertrophy, functional and tissue characteristics differ among aetiologies. LV hypertrophy in Fabry is progressive and mostly concentric but may copy any hypertrophic cardiomyopathy. Dependent on residual alfa-galactosidase A enzyme activity, degree of LV hypertrophy in Fabry may vary. Initially, low myocardial CMR T1-map values are calculated. At a later stage, midwall late gadolinium enhancement of the inferolateral LV wall may occur. Global longitudinal strain may be depressed in the inferolateral wall. Voltage criteria for LV hypertrophy and short PQ interval are common. Right ventricular (RV) hypertrophy is frequent. In addition, multisystemic symptoms including neuropathic pain, hypohidrosis, proteinuria, renal insufficiency and familial young stroke are pointing to Fabry. CONCLUSIONS: LV hypertrophy should raise suspicion of Fabry disease, especially if LV hypertrophy is unexplained and/or associated with RV hypertrophy. In Fabry, LV hypertrophy may be heterogeneous and mimic any hypertrophic cardiomyopathy. ECG, multisystemic symptoms and imaging may provide clues for Fabry.

Case report: Serious unexpected vascular events in two patients with lymphocytic variant hypereosinophilic syndrome.

Background: Lymphocytic-variant hypereosinophilic syndrome (L-HES) is a form of reactive hypereosinophilia, most commonly associated with interleukin-5 over-production by clonal, most commonly CD3-CD4+CD2hiCD5hiCD45RO+ T-cells. Patients often present with predominant cutaneous and soft-tissue manifestations, while cardiovascular involvement is uncommon. Methods: We reviewed the medical files of two L-HES patients followed in our center who developed serious vascular complications and performed a literature review for similar cases. Results: Patient 1, a 52-year-old female, presented with an ischemic stroke secondary to left middle cerebral artery dissection after 10 years of indolent L-HES. Blood eosinophilia was controlled with oral corticosteroids (OCS), but OCS-tapering attempts with hydroxyurea and pegylated interferon failed, prompting the introduction of mepolizumab with rapid normalization. Patient 2, a 62-year-old female, had been asymptomatic for 10 years without treatment when a NSTEMI occurred, due to coronary artery occlusion secondary to a large cauliflower-aneurysm of the proximal aorta and aneurysmal dilatation of several coronary arteries, requiring semi-urgent surgical management. Aortic wall staining for eosinophil major basic protein showed eosinophils in the adventitia. Blood eosinophilia was controlled with OCS. Conclusions: Patients with apparently clinically benign L-HES may develop arterial complications, consisting in dissection and/or aneurysm dilatation of medium-to-large vessels with serious consequences. The value of performing regular vascular imaging and monitoring during follow-up has yet to be determined.

Lung diffusion capacity correlates with pre-implant pulmonary hypertension and predicts outcome after LVAD implantation.

AIMS: Diffusing capacity of the lung for carbon monoxide (DLCO ) reduction is common in heart failure (HF) and is associated with a worse prognosis. Correlations between DLCO and pulmonary hypertension (PH) are unclear, and published data are conflicting; it has been shown that DLCO impairment may persist or even worsen after normalization of pulmonary pressures following left ventricle assist device (LVAD) implantation, maybe reflecting persistent pulmonary damage. We aimed to investigate the impact of pre-implant DLCO and central haemodynamics on outcome in patients with advanced HF implanted with a LVAD. METHODS AND RESULTS: We retrospectively analysed pre-implant and post-implant data from 42 patients implanted with a LVAD at our institution. Out of 42 patients, 35 had post-capillary PH before implantation, including 17 with combined post- and pre-capillary PH (Cpc-PH). Median DLCO was 59% (IQR 47-68%), and it inversely correlated with pulmonary vascular resistance (PVR) (P 0.037) and diastolic pulmonary gradient (DPG) (P 0.042). Compared with baseline, LVAD resulted in improvement in LV diameter (LVDd, P < 0.001), mitral regurgitation (P 0.022), and PH (mPAP 24 vs. 36 mmHg, P < 0.001; PAWP 12 vs. 23 mmHg, P 0.001; pulmonary artery compliance, CPA 3.1 vs. 1.9 mL/mmHg, P 0.021). Lower DLCO and Cpc-PH at baseline were associated with a better LV reverse remodelling post-implantation (P 0.027 for LVDd) but also with a smaller gain in CPA (P 0.049). CONCLUSIONS: Before LVAD implantation, DLCO impairment is associated with higher PVR and DPG, suggesting that it might be an expression of persistent pulmonary damage occurring in Cpc-PH. After LVAD implantation, both LV dimension and haemodynamics improve. Lower pre-implant DLCO is associated with better LV reverse remodelling.

Pulmonary artery wedge pressure and left ventricular end-diastolic pressure during exercise in patients with dyspnoea.

Background: Pulmonary artery wedge pressure (PAWP) during exercise, as a surrogate for left ventricular (LV) end-diastolic pressure (EDP), is used to diagnose heart failure with preserved ejection fraction (HFpEF). However, LVEDP is the gold standard to assess LV filling, end-diastolic PAWP (PAWPED) is supposed to coincide with LVEDP and mean PAWP throughout the cardiac cycle (PAWPM) better reflects the haemodynamic load imposed on the pulmonary circulation. The objective of the present study was to determine precision and accuracy of PAWP estimates for LVEDP during exercise, as well as the rate of agreement between these measures. Methods: 46 individuals underwent simultaneous right and left heart catheterisation, at rest and during exercise, to confirm/exclude HFpEF. We evaluated: linear regression between LVEDP and PAWP, Bland-Altman graphs, and the rate of concordance of dichotomised LVEDP and PAWP ≥ or < diagnostic thresholds for HFpEF. Results: At peak exercise, PAWPM and LVEDP, as well as PAWPED and LVEDP, were fairly correlated (R2>0.69, p<0.01), with minimal bias (+2 and 0 mmHg respectively) but large limits of agreement (±11 mmHg). 89% of individuals had concordant PAWP and LVEDP ≥ or <25 mmHg (Cohen's κ=0.64). Individuals with either LVEDP or PAWPM ≥25 mmHg showed a PAWPM increase relative to cardiac output (CO) changes (PAWPM/CO slope) >2 mmHg·L-1·min-1. Conclusions: During exercise, PAWP is accurate but not precise for the estimation of LVEDP. Despite a good rate of concordance, these two measures might occasionally disagree.

Mesp1: a key regulator of cardiovascular lineage commitment.

In mammals, the heart arises from the differentiation of 2 sources of multipotent cardiovascular progenitors (MCPs). Different studies indicated that an evolutionary conserved transcriptional regulatory network controls cardiovascular development from flies to humans. Whereas in Drosophila, Tinman acts as a master regulator of cardiac development, the identification of such a master regulator in mammals remained elusive for a long time. In this review, we discuss the recent findings suggesting that Mesp1 acts as a key regulator of cardiovascular progenitors in vertebrates. Lineage tracing in mice demonstrated that Mesp1 represents the earliest marker of cardiovascular progenitors, tracing almost all the cells of the heart including derivatives of the primary and second heart fields. The inactivation of Mesp1/2 indicated that Mesp genes are essential for early cardiac mesoderm formation and MCP migration. Several recent studies have demonstrated that Mesp1 massively promotes cardiovascular differentiation during embryonic development and pluripotent stem cell differentiation and indicated that Mesp1 resides at the top of the cellular and transcriptional hierarchy that orchestrates MCP specification. In primitive chordates, Mesp also controls early cardiac progenitor specification and migration, suggesting that Mesp arises during chordate evolution to regulate the earliest step of cardiovascular development. Defining how Mesp1 regulates the earliest step of MCP specification and controls their migration is essential to understand the root of cardiovascular development and how the deregulation of these processes can lead to congenital heart diseases. In addition, these findings will be very useful to boost the production of cardiovascular cells for cellular therapy, drug and toxicity screening.

Hypereosinophilic syndrome: considerations for the cardiologist.

Eosinophil-mediated endomyocardial damage is a well-known complication in patients with hypereosinophilic syndromes (HES). Although management and survival have improved significantly, some patients continue to develop severe cardiomyopathy as a direct consequence of uncontrolled hypereosinophilia. Cardiologists play a key role in early detection and treatment. At the early generally asymptomatic stage, related to subendocardial eosinophilic infiltrates, elevation of the biomarker of cardiac damage (serum troponin) and cardiac MRI are the best tools for diagnosis. As disease progresses, patients typically develop intracardiac mural thrombi and may experience variable degrees of heart failure due to valve damage and/or subendocardial fibrosis, all of which are more readily detectable with traditional echocardiographic investigation. New imaging modalities such as strain imaging and specific sequences in MRI offer the perspective of detecting subtle perturbations and distinguishing inflammatory versus fibrotic stages. Endomyocardial biopsy may help in difficult settings, namely, when blood eosinophilia is not prominent, but may be non-contributive due to sampling issues or eosinophil degranulation or replacement by fibrosis, and must always be performed after careful consideration of the risk:benefit ratio. Although treatment of the HES itself should be managed by clinicians with expertise in this rare disorder with the aim of lowering eosinophil counts to prevent and treat eosinophil-mediated organ damage and dysfunction, cardiologists play a key role in managing the associated cardiopathy. There are no consensual disease-specific guidelines for treating eosinophil-mediated thrombotic complications and cardiopathy, which should be managed according to classical international recommendations.

Summary of 2020 ESC guidelines on non-STE ACS, adult congenital heart disease, sports cardiology and atrial fibrillation.

During the ESC congress in September 2020, the new ESC guidelines were presented and are available on the ESC website. The new guidelines describe management recommendations on following cardiovascular diseases: non-STE ACS, adult congenital heart disease, sports cardiology and atrial fibrillation. The present document gives a summary of these guidelines and highlights the most important recommendations and changes in the management of these diseases. It will help to increase awareness about the new guidelines and may stimulate to consult the full document for specific items. Ultimately, the authors hope that this document will enhance implementation of new ESC guidelines in daily clinical practice.

Early-onset and severe pulmonary arterial hypertension due to a novel compound heterozygous association of rare VHL mutations: A case report and review of existing data.

Very rare cases of pulmonary arterial hypertension (PAH) have been linked to homozygous or compound heterozygous von Hippel-Lindau (VHL) tumor suppressor gene mutations, while heterozygous VHL mutations lead to VHL tumor syndrome. Although those entities are defined, the genotype-phenotype correlation is incompletely understood, and patient management recommendations are lacking. Here, we describe a case of severe early-onset PAH due to a so-far unreported compound heterozygous association of VHL mutations and review the existing data.

Impact of COVID-19 lockdown on exercise capacity in PAH patients.

The outbreak of novel coronavirus-19 disease (COVID-19) was classified as a global pandemic thanks to the rapid viral spread, and restrictive policy measures of infection containment, including "lockdown" periods and self-isolation, were first instituted in Belgium from March to June 2020. The consequent reduction in physical activity could have a negative impact on exercise capacity, especially in frail patients with pre-existing chronic diseases, such as pulmonary arterial hypertension (PAH). With the aim to define the impact of COVID-19 lockdown on functional status, we included in our observational analysis clinically stable PAH patients, who had performed at least four consecutive 6-min walking tests (6MWT) during 2019-2020, to compare their exercise performance before and after the lockdown. In the 63 patients included, a comparison between the distance covered at 6MWT after the lockdown period and the pooled mean of the previous three 6MWTs showed a mean reduction of 14 m after the lockdown (p = 0.004). Moreover, the mean distance covered at 6MWT went from 447 m in March 2020 to 434 m in June 2020, with a significant average loss of 13 m (p = 0.024). Our results showed that PAH patients were less performing at 6MWT after 3 months of reduced physical activity, despite constant clinical stability and the absence of signs of disease progression, suggesting that this confounding factor should be kept in mind when evaluating changes in 6MWT during or after COVID-19 pandemic.

An updated meta-analysis of hemodynamics markers of prognosis in patients with pulmonary hypertension due to left heart disease.

Pulmonary hypertension (PH) is associated with a poor prognosis in left heart disease (LHD). We sought to provide an updated analysis on the association of hemodynamic variables, such as pulmonary vascular resistance (PVR), pulmonary artery compliance (PAC), and diastolic pressure gradient (DPG), with prognosis in PH-LHD, through a systematic literature review. Sixteen articles were identified, including 9600 patients with LHD, heterogeneous in terms of age, sex, and etiology of cardiac disease. In this large population, PVR (hazard ratio [HR], 1.07; 95% confidence interval [CI]: 1.05-1.0), DPG (HR, 1.02; 95% CI: 1.01-1.02) and PAC (HR, 0.76; 95% CI: 0.69-0.84) were associated with an increased risk of adverse outcome, albeit with a less solid performance of DPG. Similar results were found when hemodynamic variables were analyzed according to the thresholds commonly applied in clinical practice, or subdividing cohorts according to the underlying LHD. Furthermore, cumulative metanalysis indicated that these results are consistently stable since 2018. Thus, PVR, DPG and PAC have an established prognostic value in PH-LHD. These results are consistent through the years and unlikely to change with further studies.

Exercise haemodynamics in heart failure with preserved ejection fraction: a systematic review and meta-analysis.

AIMS: Exercise right heart catheterization (RHC) is considered the gold-standard test to diagnose heart failure with preserved ejection fraction (HFpEF). However, exercise RHC is an insufficiently standardized technique, and current haemodynamic thresholds to define HFpEF are not universally accepted. We sought to describe the exercise haemodynamics profile of HFpEF cohorts reported in literature, as compared with control subjects. METHODS AND RESULTS: We performed a systematic literature review until December 2020. Studies reporting pulmonary artery wedge pressure (PAWP) at rest and peak exercise were extracted. Summary estimates of all haemodynamic variables were evaluated, stratified according to body position (supine/upright exercise). The PAWP/cardiac output (CO) slope during exercise was extrapolated. Twenty-seven studies were identified, providing data for 2180 HFpEF patients and 682 controls. At peak exercise, patients with HFpEF achieved higher PAWP (30 [29-31] vs. 16 [15-17] mmHg, P < 0.001) and mean right atrial pressure (P < 0.001) than controls. These differences persisted after adjustment for age, sex, body mass index, and body position. However, peak PAWP values were highly heterogeneous among the cohorts (I2  = 93%), with a relative overlap with controls. PAWP/CO slope was steeper in HFpEF than in controls (3.75 [3.20-4.28] vs. 0.95 [0.30-1.59] mmHg/L/min, P value < 0.0001), even after adjustment for covariates (P = 0.007). CONCLUSIONS: Despite methodological heterogeneity, as well as heterogeneity of pooled haemodynamic estimates, the exercise haemodynamic profile of HFpEF patients is consistent across studies and characterized by a steep PAWP rise during exercise. More standardization of exercise haemodynamics may be advisable for a wider application in clinical practice.

Current Limitations of Invasive Exercise Hemodynamics for the Diagnosis of Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Exercise hemodynamics can differentiate heart failure with preserved ejection fraction (HFpEF) from noncardiac dyspnea. However, respiratory pressure swings may impact hemodynamic measurements, potentially leading to misdiagnosis of HFpEF. Moreover, threshold values for abnormal hemodynamic response indicative of HFpEF are not universally accepted. Thus, we sought to evaluate the impact of respiratory pressure swings on hemodynamic data interpretation as well as the concordance among 3 proposed exercise hemodynamic criteria for HFpEF: (1) end-expiratory pulmonary artery wedge pressure (PAWPexp) ≥25 mm Hg; (2) PAWPexp/cardiac output slope >2 mm Hg/L per minute; and (3) respiratory-averaged (avg) mean pulmonary artery pressure >30 mm Hg, total pulmonary resistanceavg >3 WU, PAWPavg ≥20 mm Hg. METHODS: Fifty-seven patients with unexplained dyspnea (70% women, 70±9 years) underwent exercise cardiac catheterization. The difference between end-expiratory and averaged hemodynamic values, as well as the concordance among the 3 hemodynamic definitions of HFpEF, were assessed. RESULTS: End-expiratory hemodynamics measurements were higher than values averaged across the respiratory cycle. During exercise, a larger proportion of patients exceeded the threshold of 25 mm Hg for PAWPexp rather than for PAWPavg (70% versus 53%, P<0.01). The concordance of 3/3 HFpEF exercise hemodynamic criteria was recorded in 70% of patients. PAWPexp/cardiac output slope identified HFpEF more frequently than the other 2 criteria (81% versus 64% to 69%), incorporating over 97% of abnormal responses to the latter. Patients with 3/3 positive criteria had worse clinical, gas-exchange, and hemodynamic profiles. CONCLUSIONS: Respiratory pressure swings impact on the exercise hemodynamic definitions of HFpEF that provide discordant results in 30% of patients. Equivocal diagnoses of HFpEF might be limited by adopting the most sensitive and inclusive criterion alone (ie, PAWPexp/cardiac output slope).