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PURPOSE: Obstructive sleep apnea (OSA) is a prevalent and multifaceted disease. To date, the presence and severity of objectively identified comorbidities and their association with specific OSA phenotypes, CPAP adherence, and survival remain to be elucidated. The aim of this study is to cluster patients with OSA based on 10 clinically important objectively identified comorbidities, and to characterize the comorbidity clusters in terms of clinical and polysomnographic characteristics, CPAP adherence, and survival. STUDY DESIGN AND METHODS: Seven hundred ten consecutive patients starting CPAP for moderate-to-severe OSA were included. Comorbidities were based on generally accepted cutoffs identified in the peer-reviewed literature. Self-organizing maps were used to order patients based on presence and severity of their comorbidities and to generate clusters. RESULTS: The majority of patients were men (80%). They were generally middle-aged (52 years) and obese (BMI: 31.5 kg/m2). Mean apnea-hypopnea index (AHI) was 41 ± 20 per h of sleep. More than 94% of the patients had one or more comorbidities with arterial hypertension, dyslipidemia, and obesity being the most prevalent. Nine comorbidity clusters were identified. The clinical relevance of these comorbidity clusters was highlighted by the difference in symptoms, PSG parameters, and cardiovascular risk. Also, differences in CPAP adherence, improvements in ESS, and long-term survival were present between the clusters. CONCLUSION: Comorbidity prevalence in patients with OSA is high, and different comorbidity clusters, demonstrating differences in cardiovascular risk, CPAP adherence, and survival, can be identified. These results further substantiate the need for a comprehensive assessment of patients with OSA beyond the AHI. ispartof: SLEEP AND BREATHING vol:26 issue:1 pages:195-204 ispartof: location:Germany status: published

According to the US Centers for Disease Control and Prevention (CDC), patients with underlying health conditions, including all types of lung and cardiovascular diseases, have an increased risk of developing serious disease when infected by SARS-CoV-2 [1]. Based on prior publications on the effects of acute right heart failure superimposed on systemic infection [2–5], Ryan et al. [6] suggested that right heart failure and concomitant COVID-19 infection may result in increased mortality in pulmonary arterial hypertension (PAH) patients. Surprisingly, the number of hospitalised PAH-COVID-19 patients remained rather low in Italy and the USA so far [7]. In late March 2020, experts from over 32 US PH expert centres answered a query endorsed by the US Pulmonary Hypertension Association. COVID-19 infection was reported in 13 PAH patients, among whom three required intubation and one died. This is consequently raising the question whether and why PAH patients appear to be at lower risk of developing severe COVID-19 [7]., This international survey highlights that a limited number of PAH and CTEPH patients suffered from severe #COVID19 infection https://bit.ly/3jGuBQq

Background:Exertional intolerance is a limiting and often crippling symptom in patients with chronic thromboembolic pulmonary hypertension (CTEPH). Traditionally the pathogenesis has been attributed to central factors, including ventilation/perfusion mismatch, increased pulmonary vascular resistance, and right heart dysfunction and uncoupling. Pulmonary endarterectomy and balloon pulmonary angioplasty provide substantial improvement of functional status and hemodynamics. However, despite normalization of pulmonary hemodynamics, exercise capacity often does not return to age-predicted levels. By systematically evaluating the oxygen pathway, we aimed to elucidate the causes of functional limitations in patients with CTEPH before and after pulmonary vascular intervention.Methods:Using exercise cardiac magnetic resonance imaging with simultaneous invasive hemodynamic monitoring, we sought to quantify the steps of the O2transport cascade from the mouth to the mitochondria in patients with CTEPH (n=20) as compared with healthy participants (n=10). Furthermore, we evaluated the effect of pulmonary vascular intervention (pulmonary endarterectomy or balloon angioplasty) on the individual components of the cascade (n=10).Results:Peak Vo2(oxygen uptake) was significantly reduced in patients with CTEPH relative to controls (56±17 versus 112±20% of predicted;P2cascade, including O2delivery (product of cardiac output and arterial O2content), skeletal muscle diffusion capacity, and pulmonary diffusion. The total O2extracted in the periphery (ie, ΔAVo2[arteriovenous O2content difference]) was not different. After pulmonary vascular intervention, peak Vo2increased significantly (from 12.5±4.0 to 17.8±7.5 mL/[kg·min];P=0.036) but remained below age-predicted levels (70±11%). The O2delivery was improved owing to an increase in peak cardiac output and lung diffusion capacity. However, peak exercise ΔAVo2was unchanged, as was skeletal muscle diffusion capacity.Conclusions:We demonstrated that patients with CTEPH have significant impairment of all steps in the O2use cascade, resulting in markedly impaired exercise capacity. Pulmonary vascular intervention increased peak Vo2by partly correcting O2delivery but had no effect on abnormalities in peripheral O2extraction. This suggests that current interventions only partially address patients’ limitations and that additional therapies may improve functional capacity.

BACKGROUND Right heart failure (RHF) in pulmonary hypertension (PH) patients is manifested by increased right atrial (RA) pressure. We hypothesized liver relaxation times measured at cardiovascular magnetic resonance (CMR) can be used to noninvasively assess increased right-sided filling pressure. METHODS Forty-five consecutive patients, that is, 37 PH patients and 8 chronic thromboembolic pulmonary disease patients without PH underwent right heart catheterization and CMR. CMR findings were compared to 40 control subjects. Native T1, T2, and extracellular volume (ECV) liver values were measured on the cardiac maps. RESULTS Patients with increased RA pressure (i.e.,≥8 mm Hg)(n = 19, RA+ group) showed higher NT-proBNP and CRP values, lower LVEF, MAPSE values, larger atrial size, and higher native T1 and T2 values of the myocardium than patients with normal RA pressure (RA- group, n = 26). Liver T1, T2 and ECV was significantly higher in RA+ than RA- patients and controls, that is, T1: 684 ± 129 ms vs 563 ± 72 ms and 540 ± 34 ms; T2: 60 ± 10 ms vs 49 ± 6 ms and 46 ± 4 ms; ECV: 36 ± 8% vs 29 ± 4% and 30 ± 3%. A positive correlation was found between liver T1, T2 and ECV and RA pressure, that is, r2 of 0.61, 0.82, and 0.58, respectively (p < 0.001). ROC analysis to depict increased RA pressure showed an AUC of 0.847, 0.904, 0.816, and 0.645 for liver T1, T2, NT-proNBP and gamma-glutamyl transpeptidase, respectively. Excellent intra- and inter-observer agreement was found for assessment of T1/T2/ECV liver values. CONCLUSIONS Assessment of liver relaxation times as part of a comprehensive CMR exam in PH patients may provide valuable information with regard to the presence of passive liver congestion.

Data concerning sleep-disordered breathing (SDB) after lung transplantation (LTX) are scarce. This study aims to analyze prevalence, associated factors, and impact on survival of moderate to severe SDB in a large cohort of consecutive LTX patients (n = 219). Patients underwent a diagnostic polysomnography 1 year after LTX. Moderate to severe SDB was present in 57.5% of patients, with the highest prevalence in chronic obstructive pulmonary disease/emphysema (71.1%) and pulmonary fibrosis (65.1%). SDB patients were older, mostly male, and had higher body mass index and neck circumference. Nocturnal diastolic and 24-hour blood pressures were higher in SDB patients. In 45 patients, polysomnography was also performed pre-LTX. Compared to pre-LTX, mean apnea/hypopnea index (AHI) increased significantly after LTX. A significant correlation was seen between lung function parameters and AHI, suggesting a role of decreased caudal traction on the pharynx. Presence of SDB had no impact on mortality or prevalence of chronic lung allograft dysfunction. However, survival was better in continuous positive airway pressure (CPAP) compliant SDB patients compared to SDB patients without CPAP treatment. These findings may be pertinent for systematic screening of SDB after LTX. ispartof: AMERICAN JOURNAL OF TRANSPLANTATION vol:21 issue:1 pages:281-290 ispartof: location:United States status: published

Rationale: Cardiovascular comorbidities are prevalent in patients after lung transplantation (LTX). While sleep apnea is known to be associated with cardiovascular problems, data concerning sleep apnea (SA) after LTX are scarce. The aim of this study is to analyze prevalence, associated factors and impact on survival of moderate to severe SA in a large cohort of consecutive LTX patients. Methods: Patients (n=219, 50,2% females) transplanted between February 2013 and March 2017 underwent a diagnostic polysomnography 1 year after LTX. Results: Moderate to severe SA was present in 57.5% of patients. SA patients were older, mostly male (57.9%) and had a higher BMI and neck circumference. The prevalence of moderate to severe SA was highest in COPD/emphysema patients (86/121; 71.1%) and pulmonary fibrosis (28/43; 65.1%). Nighttime diastolic and 24-hour blood pressures were higher in SA patients. Compared to pre-LTX, mean apnoea/hypopnoea index (AHI) increased significantly after LTX. A significant correlation was seen between lung function parameters and AHI. Presence of SA had no significant impact on mortality or prevalence of chronic lung allograft dysfunction. However, survival was significantly better in CPAP compliant SA patients compared to SA patients without CPAP treatment. Conclusion: The prevalence of SA one year after LTX was high, especially in patients with pre-LTX emphysema and pulmonary fibrosis. SA after LTX was associated with anthropometric, lung function parameters and higher blood pressure. CPAP compliant patients had a better survival than SA patients without CPAP treatment. These findings may ask for systemic screening of SA after LTX.

INTRODUCTION Continuous positive airway pressure (CPAP)-therapy is the first-line treatment for moderate to severe obstructive sleep apnoea (OSA). A significant limitation of CPAP treatment is the poor therapy adherence, compromising the beneficial effects. OBJECTIVE This study evaluates three different educational approaches and their effect on therapy adherence. METHOD This single-center, retrospective study compared three groups of 100 consecutive, CPAP-naive patients with moderate to severe OSA who were started on CPAP therapy. Group 1 and 2 received the same individual structured education on two consecutive days with an extra phone call 7 to 10 days after CPAP start in group 2. Group 3 received individual structured education on the first day and participated in a group education using a slide presentation open for discussion on the second day. Re-evaluation was performed after 24 weeks. RESULTS Baseline characteristics did not differ significantly between groups. During the 24 weeks follow-up there was a drop-out rate of 16% (group 1), 12% (group 2) and 5% (group 3). In the patients still on CPAP after 24 weeks, the mean nightly CPAP usage was, respectively, 4.7 ± 1.8, 5.2 ± 2.3 and 5.7 ± 2.1 h/night. In group 3 both the drop-out rate and mean CPAP usage were significantly different (P values, respectively, P

PURPOSE: To evaluate the safety and efficacy of balloon pulmonary angioplasty (BPA) for nonoperable chronic thromboembolic pulmonary hypertension (CTEPH) patients during the initial experience of a single center. METHODS: A total of 18 CTEPH patients (5 with residual pulmonary hypertension after pulmonary endarterectomy) were treated with BPA during the period 2014-2018 and were retrospectively reviewed. Mean age was 61 ± 19 years; 55% were female; mean pulmonary artery pressure was 44 ± 12 mmHg; cardiac output was 4.3 ± 1.0 l/min; and pulmonary vascular resistance was 8.4 ± 3.6 WU. Patients were evaluated by New York Heart Association functional class, 6-minute walk distance, N-terminal pro b-type natriuretic peptide, echocardiography, right heart catheterization, and before and after completions of BPA. RESULTS: A total of 91 procedures were performed, with a median number of 4 BPA sessions per patient (range, 2-8). There were no deaths or major complications requiring extracorporeal support or (non)invasive ventilation. The most common complication was self-limiting hemoptysis (3%). According to Society of Interventional Radiology classification, 4 mild, 4 moderate, and 1 severe adverse events were noted. Invasive hemodynamics significantly improved, with a cardiac index increase of 15% (P = .0333), decrease of mean pulmonary artery pressure of 30% (P = .0013), and decrease of pulmonary vascular resistance of 45% (P = .0048). Stroke volume index (P = .0171) and pulmonary arterial compliance (P = .0004) were also significantly enhanced. CONCLUSIONS: BPA significantly improves cardiopulmonary hemodynamics with an acceptable safety profile. Further studies assessing the long-term efficacy of BPA are required. ispartof: JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY vol:30 issue:8 pages:1265-1272 ispartof: location:United States status: published

Chronic thromboembolic pulmonary hypertension (CTEPH) is a severe disease characterized by unresolved and organized thrombi obstructing the pulmonary arterial bed, resulting in PH and right ventricular (RV) failure. We previously found that repeated embolization and fibrinolysis inhibition induced CTEPH in rabbits. Neovascularization may play a role in resolving venous thrombi. We hypothesized that inhibition of angiogenesis may prevent clot resolution and promote CTEPH progression. We aimed to investigate whether repeated embolization with blood clots containing an inhibitor of angiogenesis may induce CTEPH in rabbits. Adult male New Zealand rabbits were weekly embolized (x 7) with autologous blood clots containing Sugen, an inhibitor of VEGF receptor, or not. Right heart catheterization was performed 8 weeks after the last embolization. RV function was assessed by transthoracic echocardiography at baseline, after the last embolization and before sacrifice. RV hypertrophy and lung vessel morphometry were analyzed. Repeated embolization with clots containing Sugen resulted in a 44% increase in mean pulmonary arterial pressure, a 2-fold increase in pulmonary vascular resistance index without any change in cardiac output and a 37 % increase in RV diameter compared to baseline; it also induced fibro-thrombotic lesions in large proximal pulmonary arteries and remodeling of distal pulmonary arteries. Embolization with autologous blood clots containing Sugen promoted CTEPH development in rabbits. Obstruction of large proximal pulmonary arteries by fibro-thrombotic lesions highlights the similarity with the human pathology of CTEPH.

Transplant type for end-stage pulmonary vascular disease remains debatable. We compared recipient outcome after heart-lung (HLT) versus double-lung (DLT) transplantation. Single-center analysis (38 HLT-30 DLT; 1991-2014) for different causes of precapillary pulmonary hypertension (PH): idiopathic (22); heritable (two); drug-induced (nine); hepato-portal (one); connective tissue disease (four); congenital heart disease (CHD) (24); chronic thromboembolic PH (six). HLT decreased from 91.7% [1991-1995] to 21.4% [2010-2014]. Re-intervention for bleeding was higher after HLT; (P = 0.06) while primary graft dysfunction grades 2 and 3 occurred more after DLT; (P

Pulmonary arterial hypertension is a severe disease with a 1-year mortality of over 10%. Since it is a rare disease, it is usually managed in expert centres. However, life-threatening complications can occur at any moment and place and should be adequately taken care of to prevent avoidable deaths. Therefore, based on an analysis of the causes of death, this chapter describes the most important complications and their management: right heart failure, arrhythmias, haemoptysis, pericardial effusion, pulmonary arterial dilation with as a consequence left main coronary artery compression, and pulmonary artery dissection, as well as treatment-related adverse events.

OBJECTIVES: This study was a comprehensive evaluation of cardiopulmonary function in patients with chronic thromboembolic (pulmonary vascular) disease (CTED) during exercise. BACKGROUND: Exertional dyspnea is frequent following pulmonary embolism, but only a minority of patients eventually develops chronic thromboembolic pulmonary hypertension (CTEPH). Better understanding of the factors that limit exercise capacity in patients with persistent pulmonary artery obstruction could help to further define the entity of CTED. METHODS: Fifty-two subjects (13 healthy control subjects, 14 CTED patients, and 25 CTEPH patients) underwent cardiopulmonary exercise testing and exercise cardiac magnetic resonance with simultaneous invasive pressure registration. Pulmonary vascular function and right ventricular contractile reserve were assessed through combined invasive pressure measurements and magnetic resonance imaging volume measures. RESULTS: Exercise capacity was reduced by 29% and 57% in patients with CTED and CTEPH respectively, compared with control subjects. Both CTED (3.48 [interquartile range: 2.24 to 4.36] mm Hg × l-1 × min-1) and CTEPH patients (8.85 [interquartile range: 7.18 to 10.4] mm Hg × l-1 × min-1) had abnormal total pulmonary vascular resistance. Right ventricular contractile reserve was reduced in CTED patients compared with control subjects (2.23 ± 0.55 vs. 3.72 ± 0.94), but was still higher than that in CTEPH patients (1.34 ± 0.24; p < 0.001). As opposed to patients with CTEPH in whom right ventricular ejection fraction declined with exercise, right ventricular ejection fraction still increased in patients with CTED, albeit to a lesser extent than in healthy control subjects (interaction p < 0.001), which illustrated the distinct patterns of ventricular-arterial coupling. CONCLUSIONS: CTED represents an intermediate clinical phenotype. Exercise imaging unmasks cardiovascular dysfunction not evident at rest and identifies hemodynamically significant disease that results from reduced contractile reserve or increased vascular load. ispartof: JACC-Cardiovascular Imaging vol:12 issue:8 pages:1-3 ispartof: location:United States status: Published online

Background: There is a high prevalence of poor sleep quality in patients with pulmonary arterial hypertension (PAH). However, the impact of insomnia on exercise capacity and quality of life (QOL) in these patients is unclear. Moreover, there is a lack of data on the use of sleep medication and the effects of cognitive behavioural therapy for insomnia (CBTI) in PAH. Methods: Patients who visited the outpatient clinic of a tertiary centre from September 2015 to March 2016 were asked to complete the Pittsburgh Sleep Quality Index, the Insomnia Severity Index, the Epworth Sleepiness Scale, the Depression Anxiety Stress Scales and the 36-Item Short Form Survey. Exercise capacity was assessed by six-minute walk distance (6MWD). Results: Seventy-two PAH patients (median age 60y, 75% female) were enrolled. More than half (52%) of the patients had a poor sleep quality, 13% had clinical insomnia. Patients with poor sleep quality had a significant lower 6MWD (479 vs 368 m, p=0.003). A significantly higher Borg score was found in patients with insomnia (5 vs 7, p=0.019). Insomnia patients were significantly more depressed, had a worse NYHA class and a lower QOL. Benzodiazepines, z-drugs and antidepressants use was twice as high for insomnia patients. A total of 40% of all PAH patients used psychotropics. Only 5% of the patients with poor sleep quality agreed to follow CBTI. In these patients an improvement in NYHA class and the 6MWD was seen after three months. Conclusion: The high prevalence of poor sleep quality and insomnia in patients with PAH warrants regular screening and appropriate treatment. Treating sleep problems may contribute to improve the QOL and exercise capacity in PAH.

Alkylating agents can induce pulmonary veno-occlusive disease (PVOD) in animals and human. Mitomycin, used to treat anal and renal cancer, can induce PVOD in rats and human. The aim of the study was to investigate the effects of mitomycin on pulmonary hemodynamics and vessel remodeling in rabbits. Mitomycin (n=14) or saline (controls; n=5) was injected intraperitoneally in female rabbits twice at one-week interval in the presence or not of an antiemetic (maropitant citrate or metoclopramide). Animals underwent right heart catheterization (RHC) 5 weeks after the second injection; lungs and heart were collected. Fulton index was calculated to evaluate right ventricular hypertrophy. Sections of pulmonary tissue were stained with trichrome-Masson and immunohistochemistry against α-smooth muscle actin was performed. RHC was performed in 8 animals; lungs and heart were collected from 11 animals. Mean pulmonary arterial pressure (mPAP) was significantly increased in mitomycin-treated rabbits compared to controls animals (35 vs. 14 mmHg). mPAP was significantly correlated with Fulton index in mitomycin treated animals (r=0.71, p=0.009). Remodeling (muscularization, media thickening) of pulmonary arteries and fibrosis of pulmonary veins were observed. Mortality decreased from 75% to 28% in the presence of an antiemetic. In animals which did not receive any antiemetic, infiltration of inflammatory cells (macrophages and lymphocytes) was found. To conclude, mitomycin-treated female rabbits developed signs of pulmonary hypertension characterized by an elevated mPAP and distal arteriopathy, and of PVOD as indicated by venous fibrosis, suggesting that this animal model could serve as a model of PVOD.

We read with great interest the article by Perros et al,1 which reported mitomycin C (MMC)–induced pulmonary veno-occlusive disease (PVOD) in patients displaying anal squamous cancer and in a rat preclinical model. We would like to share our experience with 2 more patients with pulmonary hypertension related to MMC exposure who did not show radiological evidence of PVOD. It concerns a 59-year-old man with an anal carcinoma and a 53-year-old woman with an anorectal spinocellular carcinoma. Both were treated by radiochemotherapy (MMC plus 5-fluoruracil) and developed dyspnea on exertion within 4 years and 1 year. Echocardiogram showed increased systolic pulmonary arterial pressure, right ventricular dilatation …

OBJECTIVE: To analyze the implication of the beta3-adrenoceptor (beta3-AR) pathway in human septic myocardium and a murine model of sepsis, a condition associated with myocardial depression. METHODS AND RESULTS: beta3-AR and eNOS protein abundance were increased (332+/-66.4% and 218+/-39.3; P

It is known that adenosine excess due to monophosphate deaminase deficiency (AMPD1) can be linked to muscle problems. Recently, Perumal et al., 2014 reported a first case of possible impact of AMPD1 on sleep, REM sleep and cholinergic neurotransmission. We report a second patient with similar sleep complaints: long sleep duration with residual daytime sleepiness and a need to sleep after exercise. On polysomnography we observed a long sleep duration, with high sleep efficiency and a SOREMP; on MSLT a shortened sleep latency and 4 SOREMPS were observed. Frequency power spectral heart rate analysis during slow wave sleep, REM sleep and wakefulness revealed an increased parasympathetic tone. In conclusion, AMPD1 could have a profound influence on cholinergic neurotransmission and sleep; further studies are mandatory.

The mammalian heart expresses all three isoforms of nitric oxide synthases (NOS) in diverse cell types of the myocardium. Despite their apparent promiscuity, the NOS isoforms support specific signaling because of their subcellular compartmentation with colocalized effectors and limited diffusibility of NO in muscle cells. eNOS and nNOS sustain normal EC coupling and contribute to the early and late phases of the Frank-Starling mechanism of the heart. They also attenuate the beta1-/beta2-adrenergic increase in inotropy and chronotropy, and reinforce the pre- and post-synaptic vagal control of cardiac contraction. By doing so, the NOS protect the heart against excessive stimulation by catecholamines, just as an "endogenous beta-blocker". In the ischemic and failing myocardium, induced iNOS further reinforces this effect, as does eNOS coupled to overexpressed beta3-adrenoceptors. nNOS expression also increases in the aging and infarcted heart, but its role (compensatory or deleterious) is less clear. In addition to their direct regulation of contractility, the NOS modulate oxygen consumption, substrate utilization, sensitivity to apoptosis, hypertrophy and regenerative potential, all of which illustrate the pleiotropic effects of this radical on the cardiac cell biology.

Background— β1-2-adrenergic receptors (AR) are key regulators of cardiac contractility and remodeling in response to catecholamines. β3-AR expression is enhanced in diseased human myocardium, but its impact on remodeling is unknown. Methods and Results— Mice with cardiac myocyte-specific expression of human β3-AR (β3-TG) and wild-type (WT) littermates were used to compare myocardial remodeling in response to isoproterenol (Iso) or Angiotensin II (Ang II). β3-TG and WT had similar morphometric and hemodynamic parameters at baseline. β3-AR colocalized with caveolin-3, endothelial nitric oxide synthase (NOS) and neuronal NOS in adult transgenic myocytes, which constitutively produced more cyclic GMP, detected with a new transgenic FRET sensor. Iso and Ang II produced hypertrophy and fibrosis in WT mice, but not in β3-TG mice, which also had less re-expression of fetal genes and transforming growth factor β1. Protection from Iso-induced hypertrophy was reversed by nonspecific NOS inhibition at low dose Iso, and by preferential neuronal NOS inhibition at high-dose Iso. Adenoviral overexpression of β3-AR in isolated cardiac myocytes also increased NO production and attenuated hypertrophy to Iso and phenylephrine. Hypertrophy was restored on NOS or protein kinase G inhibition. Mechanistically, β3-AR overexpression inhibited phenylephrine-induced nuclear factor of activated T-cell activation. Conclusions— Cardiac-specific overexpression of β3-AR does not affect cardiac morphology at baseline but inhibits the hypertrophic response to neurohormonal stimulation in vivo and in vitro, through a NOS-mediated mechanism. Activation of the cardiac β3-AR pathway may provide future therapeutic avenues for the modulation of hypertrophic remodeling.

The role of nitric oxide (NO) as a regulator of cardiac contraction was suggested in the early nineties, but a consensual view of its main functions in cardiac physiology has only recently emerged with the help of experiments using genetic deletion or overexpression of the three nitric oxide synthase (NOS) isoforms in cardiomyocytes. Contrary to the effects of exogenous, pharmacologic NO donors, signaling by endogenous NO is restricted to intracellular effectors co-localized with NOS in specific subcellular compartments. This both ensures coordinate signaling by the three NOS isoforms on different aspects of the cardiomyocyte function and helps to reconcile previous apparently contradictory observations based on the use of non-isoform-specific NOS inhibitors. This review will emphasize the role of NOS on excitation-contraction coupling in the normal and diseased heart. Endothelial NOS and neuronal NOS contribute to maintain an adequate balance between adrenergic and vagal input to the myocardium and participate in the early and late phases of the Frank-Starling adaptation of the heart. At the early phases of cardiac diseases, inducible NOS reinforces these effects, which may become maladaptive as disease progresses.

Background— The therapeutic effects of nonspecific β-blockers are limited by vasoconstriction, thus justifying the interest in molecules with ancillary vasodilating properties. Nebivolol is a selective β 1 -adrenoreceptor antagonist that releases nitric oxide (NO) through incompletely characterized mechanisms. We identified endothelial β 3 -adrenoreceptors in human coronary microarteries that mediate endothelium- and NO-dependent relaxation and hypothesized that nebivolol activates these β 3 -adrenoreceptors. Methods and Results— Nebivolol dose-dependently relaxed rodent coronary resistance microarteries studied by videomicroscopy (10 μmol/L, −86±6% of prostaglandin F2α contraction); this was sensitive to NO synthase (NOS) inhibition, unaffected by the β 1-2 -blocker nadolol, and prevented by the β 1-2-3 -blocker bupranolol ( P 3 -adrenoreceptor–deficient mice. Nebivolol (10 μmol/L) also relaxed human coronary microvessels (−71±5% of KCl contraction); this was dependent on a functional endothelium and NO synthase but insensitive to β 1-2 -blockade (all P 3 -adrenoreceptor– or endothelial NOS–deficient mice. In cultured endothelial cells, 10 μmol/L nebivolol increased NO release by 200% as measured by electron paramagnetic spin trapping, which was also reversed by NOS inhibition. In parallel, endothelial NOS was dephosphorylated on threonine 495 , and fura-2 calcium fluorescence increased by 91.8±23.7%; this effect was unaffected by β 1-2 -blockade but abrogated by β 1-2-3 -blockade (all P Conclusions— Nebivolol dilates human and rodent coronary resistance microarteries through an agonist effect on endothelial β 3 -adrenoreceptors to release NO and promote neoangiogenesis. These properties may prove particularly beneficial for the treatment of ischemic and cardiac failure diseases through preservation of coronary reserve.

Background— In the heart, nitric oxide synthases (NOS) modulate cardiac contraction in an isoform-specific manner, which is critically dependent on their cellular and subcellular localization. Defective NO production by NOS3 (endothelial NOS [eNOS]) in the failing heart may precipitate cardiac failure, which could be reversed by overexpression of NOS3 in the myocardium. Methods and Results— We studied the influence of NOS3 in relation to its subcellular localization on the function of cardiomyocytes isolated from transgenic mice overexpressing NOS3 under the α-myosin heavy chain promoter (NOS3-TG). Immunoblot analysis demonstrated moderate (5-fold) NOS3 overexpression in cardiomyocytes from NOS3-TG heterozygotes. Caveolar localization of transgenic eNOS was demonstrated by immunofluorescence, coimmunoprecipitation with caveolin-3, sucrose gradient fractionation, and immunogold staining revealed by electron microscopy. Compared with wild-type littermate, contractility of NOS3-TG cardiomyocytes analyzed by videomicroscopy revealed a lower incidence of spontaneous arrhythmic contractions (n=32, P −7 mol/L: 62.1±7.8% versus 90.8±8.0% of maximum Ca 2+ response; n=10 to 17; P −8 mol/L: −63.9±14% versus −27.7±5.6% of basal rate; n=8 to 10; P P P Conclusions— Moderate overexpression of NOS3 , targeted to caveolae in murine cardiomyocytes, potentiates the postsynaptic muscarinic response and attenuates the effect of high concentrations of catecholamines. Cardiomyocyte NOS3 may represent a promising therapeutic target to restore the sympathovagal balance and protect the heart against arrhythmia.