Recurrent angina and cardiac ischaemia as a presentation of pheochromocytoma: a case report.

Background: We present a case of a pregnant patient with recurrent angina, in which her symptoms were initially attributed to coronary artery spasm. However, during follow-up, she was diagnosed as having pheochromocytoma, a rare neuroendocrine tumour. Case summary: The 35-year-old patient was admitted to the hospital because of chest pain and elevated cardiac troponins after the use of MDMA. Physical examination, electrocardiogram, echocardiography, coronary angiogram, and cardiac MRI were normal. Symptoms were attributed to coronary spasm, and a calcium antagonist was started. Ten months later, when 36 weeks pregnant, her symptoms returned. One week later, the patient was readmitted to the hospital with signs of acute left ventricular (LV) failure, highly elevated troponins, and severe global LV dysfunction. Urgent section caesarean was performed due to maternal morbidity and foetal tachycardia. During section, flushes and marked variability in blood pressure were noted. Laboratory metanephrines testing was performed. LV function recovered within 3 days without any therapeutic intervention. However, chest pain reoccurred, now accompanied with headaches, malignant hypertension, and accelerated idiopathic ventricular rhythms. (Nor)metanephrines tests were positive. A solid lesion in the right adrenal on CT scan confirmed the diagnosis of pheochromocytoma. Fluid repletion and alpha-blocker therapy were started. Due to persistent symptoms, urgent laparoscopic adrenalectomy was performed. Hereafter, the patient remained without symptoms. Discussion: A pheochromocytoma may present with recurrent angina and can result in a catecholamine-induced cardiomyopathy. It is important to timely recognize this diagnosis in order to minimize morbidity and mortality.

The impact of unilateral pulmonary artery stenosis on right ventricular to pulmonary arterial coupling in patients with transposition of the great arteries.

BACKGROUND: Unilateral pulmonary artery (PA) stenosis is common in the transposition of the great arteries (TGA) after arterial switch operation (ASO) but the effects on the right ventricle (RV) remain unclear. AIMS: To assess the effects of unilateral PA stenosis on RV afterload and function in pediatric patients with TGA-ASO. METHODS: In this retrospective study, eight TGA patients with unilateral PA stenosis underwent heart catheterization and cardiac magnetic resonance (CMR) imaging. RV pressures, RV afterload (arterial elastance [Ea]), PA compliance, RV contractility (end-systolic elastance [Ees]), RV-to-PA (RV-PA) coupling (Ees/Ea), and RV diastolic stiffness (end-diastolic elastance [Eed]) were analyzed and compared to normal values from the literature. RESULTS: In all TGA patients (mean age 12 ± 3 years), RV afterload (Ea) and RV pressures were increased whereas PA compliance was reduced. RV contractility (Ees) was decreased resulting in RV-PA uncoupling. RV diastolic stiffness (Eed) was increased. CMR-derived RV volumes, mass, and ejection fraction were preserved. CONCLUSION: Unilateral PA stenosis results in an increased RV afterload in TGA patients after ASO. RV remodeling and function remain within normal limits when analyzed by CMR but RV pressure-volume loop analysis shows impaired RV diastolic stiffness and RV contractility leading to RV-PA uncoupling.

Clinical-imaging-pathological correlation in pulmonary hypertension associated with left heart disease.

Pulmonary hypertension (PH) is highly prevalent in patients with left heart disease (LHD) and negatively impacts prognosis. The most common causes of PH associated with LHD (PH-LHD) are left heart failure and valvular heart disease. In LHD, passive backward transmission of increased left-sided filling pressures leads to isolated post-capillary PH. Additional pulmonary vasoconstriction and remodelling lead to a higher vascular load and combined pre- and post-capillary PH. The increased afterload leads to right ventricular dysfunction and failure. Multimodality imaging of the heart plays a central role in the diagnostic work-up and follow-up of patients with PH-LHD. Echocardiography provides information about the estimated pulmonary artery pressure, morphology and function of the left and right side of the heart, and valvular abnormalities. Cardiac magnetic resonance imaging is the gold standard for volumetric measurements and provides myocardial tissue characterisation. Computed tomography of the thorax may show general features of PH and/or LHD and is helpful in excluding other PH causes. Histopathology reveals a spectrum of pre- and post-capillary vasculopathy, including intimal fibrosis, media smooth muscle cell hyperplasia, adventitial fibrosis and capillary congestion. In this paper, we provide an overview of clinical, imaging and histopathological findings in PH-LHD based on three clinical cases.

Post-implantation CMR imaging to study biventricular pacing effects on the right ventricle in left bundle branch block patients.

Cardiac resynchronization therapy (CRT) is an established treatment for heart failure patients with left ventricular dysfunction and a left bundle branch block. However, its impact on right ventricular (RV) function remains uncertain. This cardiac magnetic resonance imaging study found that CRT did not improve RV volumes and function, and CRT-off during follow-up had an immediate detrimental effect on the RV, which may suggest potential unfavorable RV remodeling with RV pacing during CRT.

Right ventricular to pulmonary arterial coupling in patients with repaired tetralogy of Fallot: a case series.

Background: In repaired tetralogy of Fallot (ToF) patients with residual right ventricular (RV) outflow tract obstructions (RVOTO), risk stratification and timing of re-interventions are based on RVOTO gradients. However, this might be insufficient to prevent RV dysfunction. Instead, assessment of RV to pulmonary arterial (RV-PA) coupling allows integrated assessment of RV function in relationship to its afterload and could be of additional value in clinical decision-making. Case summary: Two patients with repaired ToF and residual RVOTO without pulmonary regurgitation underwent right heart catheterization (RHC) and cardiac magnetic resonance imaging. We determined RV end-systolic elastance (Ees), arterial elastance (Ea) and RV-PA coupling (Ees/Ea) using single-beat RV pressure-volume analysis. Patient 1 was asymptomatic despite severely increased RV pressures and a left pulmonary artery (LPA) stenosis (invasive gradient 20 mmHg). Right ventricular volumes and function were preserved. The Ea and Ees were increased but RV-PA coupling was relatively maintained. Of interest, RV end-diastolic pressure and RV diastolic stiffness were increased. After LPA plasty, RV function was preserved during long-term follow-up. Patient 2 was symptomatic despite mildly elevated RV pressures and a supravalvular RV-PA conduit stenosis (invasive gradient 30 mmHg). The RV showed severe RV dilatation and dysfunction. The Ea was increased but Ees was decreased leading to RV-PA uncoupling. Despite balloon angioplasty, RV function was unchanged during long-term follow-up. Discussion: Development of RV dysfunction might be insufficiently predicted by RVOTO severity in patients with repaired ToF. Assessment of RV remodelling and function in relationship to its afterload might help to optimize risk stratification.

Multimorbidity in Heart Failure: Leveraging Cluster Analysis to Guide Tailored Treatment Strategies.

REVIEW PURPOSE: This review summarises key findings on treatment effects within phenotypical clusters of patients with heart failure (HF), making a distinction between patients with preserved ejection fraction (HFpEF) and reduced ejection fraction (HFrEF). FINDINGS: Treatment response differed among clusters; ACE inhibitors were beneficial in all HFrEF phenotypes, while only some studies show similar beneficial prognostic effects in HFpEF patients. Beta-blockers had favourable effects in all HFrEF patients but not in HFpEF phenotypes and tended to worsen prognosis in older, cardiorenal patients. Mineralocorticoid receptor antagonists had more favourable prognostic effects in young, obese males and metabolic HFpEF patients. While a phenotype-guided approach is a promising solution for individualised treatment strategies, there are several aspects that still require improvements before such an approach could be implemented in clinical practice. Stronger evidence from clinical trials and real-world data may assist in establishing a phenotype-guided treatment approach for patient with HF in the future.

Upfront combination therapy reduces right ventricular volumes in pulmonary arterial hypertension.

In pulmonary arterial hypertension (PAH), upfront combination therapy is associated with better clinical outcomes and a greater reduction in N-terminal pro-brain natriuretic peptide (NT-proBNP) than monotherapy. NT-proBNP levels reflect right ventricular (RV) wall stress, which increases when the right ventricle dilates. This study explored the impact of upfront combination therapy on RV volumes compared with monotherapy in PAH patients.This retrospective study involved 80 incident PAH patients (New York Heart Association class II and III) who were treated with upfront combination therapy (n=35) (i.e. endothelin receptor antagonists (ERAs) plus phosphodiesterase-5-inhibitors (PDE5Is)) or monotherapy (n=45) (i.e. either ERAs or PDE5Is). All patients underwent right-sided heart catheterisation and cardiac magnetic resonance imaging at baseline and after 1-year follow-up.Combination therapy resulted in more significant reductions in pulmonary vascular resistance and pulmonary pressures than monotherapy. NT-proBNP was decreased by ∼77% in the combination therapy group compared with a ∼51% reduction after monotherapy (p<0.001). RV volumes and calculated RV wall stress improved after combination therapy (both p<0.001) but remained unchanged after monotherapy (both p=NS). RV ejection fraction improved more in the combination therapy group than in the monotherapy group (p<0.001).In PAH patients, upfront combination therapy was associated with improved RV volumes.

Bisoprolol in idiopathic pulmonary arterial hypertension: an explorative study.

While beta-blockers are considered contraindicated in pulmonary arterial hypertension (PAH), the prognostic significance of sympathetic nervous system over-activity suggests a potential benefit of beta-blocker therapy. The aim of this randomised, placebo-controlled, crossover, single centre study was to determine the effects of bisoprolol on right ventricular ejection fraction (RVEF) in idiopathic PAH (iPAH) patients. Additional efficacy and safety parameters were explored.Patients with optimally treated, stable iPAH (New York Heart Association functional class II/III) were randomised to placebo or bisoprolol. Imaging and functional measurements were performed at baseline, crossover and end of study.18 iPAH patients were included, because inclusion faltered before enrolment of the targeted 25 patients. 17 patients completed 6 months of bisoprolol, 15 tolerated bisoprolol, one patient required intravenous diuretics. Bisoprolol was associated with a lower heart rate (17 beats per minute, p=0.0001) but RVEF remained unchanged. A drop in cardiac index (0.5 L·min(-1)·m(-2), p=0.015) was observed, along with a trend towards a decreased 6-min walking distance (6MWD).Although careful up-titration of bisoprolol was tolerated by most patients and resulted in a decreased heart rate, no benefit of bisoprolol in iPAH was demonstrated. Decreases in cardiac index and 6MWD suggest a deteriorated cardiac function. The results do not favour the use of bisoprolol in iPAH patients.

The right ventricle and pulmonary hypertension.

In patients with pulmonary hypertension (PH), the primary cause of death is right ventricular (RV) failure. Improvement in RV function is therefore one of the most important treatment goals. In order to be able to reverse RV dysfunction and also prevent RV failure, a detailed understanding of the pathobiology of RV failure and the underlying mechanisms concerning the transition from a pressure-overloaded adapted right ventricle to a dilated and failing right ventricle is required. Here, we propose that insufficient RV contractility, myocardial fibrosis, capillary rarefaction, and a disturbed metabolism are important features of a failing right ventricle. Furthermore, an overview is provided about the potential direct RV effects of PH-targeted therapies and the effects of RV-directed medical treatments.

Predicting pulmonary hypertension with standard computed tomography pulmonary angiography.

The most common feature of pulmonary hypertension (PH) on computed tomography pulmonary angiography (CTPA) is an increased diameter-ratio of the pulmonary artery to the ascending aorta (PA/AAAX). The aim of this study was to investigate whether combining PA/AAAX measurements with ventricular measurements improves the predictive value of CTPA for precapillary PH. Three predicting models were analysed using baseline CTPA scans of 51 treatment naïve precapillary PH patients and 25 non-PH controls: model 1: PA/AAAX only; model 2: PA/AAAX combined with the ratio of the right ventricular and left ventricular diameter measured on the axial view (RV/LVAX); model 3: PA/AAAX combined with the RV/LV-ratio measured on a four chamber view (RV/LV4CH). Prediction models were compared using multivariable binary logistic regression, ROC analyses and decision curve analyses (DCA). Multivariable binary logistic regression showed an improvement of the predictive value of model 2 (-2LL = 26.48) and 3 (-2LL = 21.03) compared to model 1 (-2LL = 21.03). ROC analyses showed significantly higher AUCs of model 2 and 3 compared to model 1 (p = 0.011 and p = 0.007, respectively). DCA showed an increased clinical benefit of model 2 and 3 compared to model 1. The predictive value of model 2 and 3 were almost equal. We found an optimal cut-off value for the RV/LV-ratio for predicting precapillary PH of RV/LV ≥ 1.20. The predictive value of CTPA for precapillary PH improves when ventricular and pulmonary artery measurements are combined. A PA/AAAX ≥ 1 or a RV/LVAX ≥ 1.20 needs further diagnostic evaluation to rule out or confirm the diagnosis.

Signs of right ventricular deterioration in clinically stable patients with pulmonary arterial hypertension.

BACKGROUND: Even after years of stable response to therapy, patients with idiopathic pulmonary arterial hypertension (IPAH) may show an unexpected clinical deterioration due to progressive right ventricular (RV) failure. Therefore, the aim of this study was to assess in 5-year clinically stable patients with IPAH whether initial differences or subsequent changes in RV volumes precede late clinical progression. METHODS: Included were 22 clinically stable patients with IPAH as reflected by stable or improving New York Heart Association functional class II-III and exercise capacity during 5 years of follow-up. Twelve patients subsequently remained stable during a total follow-up of 10 years, whereas 10 other patients showed late progression leading to death or lung transplantation after a follow-up of 8 years. All patients underwent right-sided heart catheterization and cardiac MRI at baseline and at 1½, 3½, 6½, and, if still alive, 10 years follow-up. RESULTS: Baseline hemodynamics were comparable in both groups and remained unchanged during the entire follow-up period. Baseline RV end-systolic volume (RVESV) was higher and RV ejection fraction (RVEF) was lower in late-progressive patients. Late-progressive patients demonstrated a gradually increased RV end-diastolic volume and RVESV and a decline in RVEF, whereas long-term stable patients did not show any RV changes. CONCLUSIONS: In patients with stable IPAH for 5 years, subsequent late disease progression is preceded by changes in RV volumes. The results indicate that monitoring RV volumes anticipates clinical worsening, even at a time of apparent clinical stability.

Contractile dysfunction of left ventricular cardiomyocytes in patients with pulmonary arterial hypertension.

BACKGROUND: After lung transplantation, increased left ventricular (LV) filling can lead to LV failure, increasing the risk of post-operative complications and mortality. LV dysfunction in pulmonary arterial hypertension (PAH) is characterized by a reduced LV ejection fraction and impaired diastolic function. OBJECTIVES: The pathophysiology of LV dysfunction in PAH is incompletely understood. This study sought to assess the contribution of atrophy and contractility of cardiomyocytes to LV dysfunction in PAH patients. METHODS: LV function was assessed by cardiac magnetic resonance imaging. In addition, LV biopsies were obtained in 9 PAH patients and 10 donors. The cross-sectional area (CSA) and force-generating capacity of isolated single cardiomyocytes was investigated. RESULTS: Magnetic resonance imaging analysis revealed a significant reduction in LV ejection fraction in PAH patients, indicating a reduction in LV contractility. The CSA of LV cardiomyocytes of PAH patients was significantly reduced (~30%), indicating LV cardiomyocyte atrophy. The maximal force-generating capacity, normalized to cardiomyocyte CSA, was significantly reduced (~25%). Also, a reduction in the number of available myosin-based cross-bridges was found to cause the contractile weakness of cardiomyocytes. This finding was supported by protein analyses, which showed an ~30% reduction in the myosin/actin ratio in cardiomyocytes from PAH patients. Finally, the phosphorylation level of sarcomeric proteins was reduced in PAH patients, which was accompanied by increased calcium sensitivity of force generation. CONCLUSIONS: The contractile function and the CSA of LV cardiomyocytes is substantially reduced in PAH patients. We propose that these changes contribute to the reduced in vivo contractility of the LV in PAH patients.

State of the art: advanced imaging of the right ventricle and pulmonary circulation in humans (2013 Grover Conference series).

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by remodeling and vasoconstriction of the pulmonary vasculature, ultimately leading to right ventricular (RV) failure and death. Recent developments in echocardiography, cardiovascular magnetic resonance imaging, computed tomography, and positron emission tomography allow advanced, noninvasive, in vivo assessment of the RV and have contributed to the identification of risk factors, prognostic factors, and monitoring of therapeutic responses in patients with PAH. Although far from reaching its future potential, these techniques have not only provided global RV assessment but also allowed evaluation of changes in cellular and molecular tissue processes, such as metabolism, oxygen balance and ischemia, angiogenesis, and apoptosis. Integrated application of these techniques could provide full insights into the different pathophysiological aspects of a failing RV in the setting of PAH. Recent advances in hybrid imaging have implemented simultaneous measurements of myocardial and vascular interactions and will be one of the most important potential future developments.

Changes in right ventricular function measured by cardiac magnetic resonance imaging in patients receiving pulmonary arterial hypertension-targeted therapy: the EURO-MR study.

BACKGROUND: Most measures that predict survival in pulmonary hypertension (PH) relate directly to, or correlate with, right ventricular (RV) function. Direct assessment of RV function using noninvasive techniques such as cardiac MRI may therefore be an appropriate way of determining response to therapy and monitoring disease progression in PH. METHODS AND RESULTS: In this pan-European study, 91 patients with PH (mean pulmonary arterial pressure 46±15 mm Hg) underwent clinical and cardiac MRI assessments at baseline and after 12 months of disease-targeted therapy (predominantly endothelin receptor antagonists [47.3%] or phosphodiesterase type-5 inhibitors [25.3%]). At month 12, functional class had improved in 21 patients, was unchanged in 63 patients, and had deteriorated in 7 patients. Significant improvements were achieved in RV and left ventricular ejection fraction (P<0.001 and P=0.0007, respectively), RV stroke volume index (P<0.0001), and left ventricular end-diastolic volume index (P=0.0015). Increases in 6-minute walk distance were significant (P<0.0001) and correlated with change in RV ejection fraction and left ventricular end-diastolic volume, although correlation coefficients were low (r=0.28, P=0.01 and r=0.26, P=0.02, respectively). CONCLUSIONS: On-treatment changes in cardiac MRI-derived variables from left and right sides of the heart reflected changes in functional class and survival in patients with PH. Direct measurement of RV function using cardiac MRI can fully assess potential benefits of treatment in PH.