Julian Strange

Phosphodiesterase Type 5 as a Target for the Treatment of Hypoxia-Induced Pulmonary Hypertension

Background—Phosphodiesterase type 5 (PDE5) is a novel therapeutic target for the treatment of pulmonary hypertension. This study examined the distribution of PDE5 in normal and hypoxic lung and the effect of chronic PDE5 inhibition with sildenafil, initiated before and during exposure to hypoxia, on pulmonary artery pressure (PAP) and structure. Methods and Results—Sprague-Dawley rats were exposed to hypoxia (10% O2) for up to 42 days. PAP, measured continuously by telemetry, increased gradually by 20 to 40 mm Hg, reaching a plateau between 10 and 14 days, and declined to normal levels on return to normoxia. PDE5 immunoreactivity was localized to smooth muscle cells in the medial layer of pulmonary arteries and veins in the normal lung and in distal muscularized arteries (<25 &mgr;m diameter) after hypoxia-induced pulmonary hypertension. Sildenafil (25 or 75 mg · kg−1 · d−1) given before hypoxia produced marked dose-dependent inhibition in the rise of PAP (60% to 90% reduction; P <0.0001) and vascular muscularization (28.4±5.0% reduction; P <0.001). When begun after 14 days of hypoxia, sildenafil significantly reduced PAP (30% reduction; P <0.0001) and partially reversed pulmonary artery muscularization (39.9±4.9% reduction; P <0.001). Conclusions—PDE5 is found throughout the muscularized pulmonary vascular tree, including in newly muscularized distal pulmonary arteries exposed to hypoxia. PDE5 inhibition attenuates the rise in PAP and vascular remodeling when given before chronic exposure to hypoxia and when administered as a treatment during ongoing hypoxia-induced pulmonary hypertension.

Beneficial Effects of Phosphodiesterase 5 Inhibition in Pulmonary Hypertension Are Influenced by Natriuretic Peptide Activity

Background—Phosphodiesterase type 5 (PDE5) inhibitors (eg, sildenafil) are a novel, orally active approach to the treatment of pulmonary arterial hypertension. The role of natriuretic peptides in the response to sildenafil was examined in mice lacking NPR-A, a guanylyl cyclase-linked natriuretic peptide receptor, in which pulmonary hypertension was induced by hypoxia. Methods and Results—Mice homozygous for NPR-A (NPR-A+/+) and null mutants (NPR-A−/−) were studied. Sildenafil inhibited the pressor response to acute hypoxia in the isolated perfused lungs of both genotypes. This effect was greater in the presence of atrial natriuretic peptide in the perfusate in NPR-A+/+ mice but not NPR-A−/− animals. In vivo, NPR-A mutants had higher basal right ventricular (RV) systolic pressures (RVSPs) than did NPR-A+/+ mice, and this was not affected by 3 weeks of treatment with sildenafil (25 mg · kg−1 · d−1). Both genotypes exhibited a rise in RVSP and RV weight with chronic hypoxia (10% O2 for 21 days); RVSP and RV weight were reduced by continuous sildenafil administration in NPR-A+/+ mice, but only RVSP showed evidence of a response to the drug in NPR-A−/− mice. The effect of sildenafil on hypoxia-induced pulmonary vascular muscularization and cyclic GMP levels was also blunted in NPR-A−/− mice. Conclusions—The natriuretic peptide pathway influences the response to PDE5 inhibition in hypoxia-induced pulmonary hypertension, particularly its effects on RV hypertrophy and vascular remodeling.

Role of Cardiovascular Magnetic Resonance as a Gatekeeper to Invasive Coronary Angiography in Patients Presenting With Heart Failure of Unknown Etiology

Background— In patients presenting with new-onset heart failure of uncertain etiology, the role of coronary angiography (CA) is unclear. Although conventionally performed to differentiate underlying coronary artery disease from dilated cardiomyopathy, CA is associated with a risk of complications and may not detect an ischemic cause resulting from arterial recanalization or an embolic episode. In this study, we assessed the diagnostic accuracy of a cardiovascular magnetic resonance (CMR) protocol incorporating late gadolinium enhancement (LGE) and magnetic resonance CA as a noninvasive gatekeeper to CA in determining the etiology of heart failure in this subset of patients. Methods and Results— One hundred twenty consecutive patients underwent CMR and CA. The etiology was ascribed by a consensus panel that used the results of the CMR scans. Similarly, a separate consensus group ascribed an underlying cause by using the results of CA. The diagnostic accuracy of both strategies was compared against a gold-standard panel that made a definitive judgment by reviewing all clinical data. The study was powered to show noninferiority between the 2 techniques. The sensitivity of 100%, specificity of 96%, and diagnostic accuracy of 97% for LGE-CMR were equivalent to CA (sensitivity, 93%; specificity, 96%; and diagnostic accuracy, 95%). As a gatekeeper to CA, LGE-CMR was also found to be a cheaper diagnostic strategy in a decision tree model when United Kingdom–based costs were assumed. The economic merits of this model would change, depending on the relative costs of LGE-CMR and CA in any specific healthcare system. Conclusion— This study showed that LGE-CMR is a safe, clinically effective, and potentially economical gatekeeper to CA in patients presenting with heart failure of uncertain etiology.

A Prospective Randomized Trial of Everolimus-Eluting Stents Versus Bare-Metal Stents in Octogenarians: The XIMA Trial (Xience or Vision Stents for the Management of Angina in the Elderly)

OBJECTIVES The aim of this study was to determine whether drug-eluting stents (DES) are superior to bare-metal stents (BMS) in octogenarian patients with angina. BACKGROUND Patients ≥80 years of age frequently have complex coronary disease warranting DES but have a higher risk of bleeding from prolonged dual antiplatelet therapy. METHODS This multicenter randomized trial was conducted in 22 centers in the United Kingdom and Spain. Patients ≥80 years of age underwent stent placement for angina. The primary endpoint was a 1-year composite of death, myocardial infarction, cerebrovascular accident, target vessel revascularization, or major hemorrhage. RESULTS In total, 800 patients (83.5 ± 3.2 years of age) were randomized to BMS (n = 401) or DES (n = 399) for treatment of stable angina (32%) or acute coronary syndrome (68%). Procedural success did not differ between groups (97.7% for BMS vs. 95.4% for DES; p = 0.07). Thirty-eight percent of patients had ≥2-vessel percutaneous coronary intervention, and 66% underwent complete revascularization. Patients who received BMS had shorter stent implants (24.0 ± 13.4 mm vs. 26.6 ± 14.3 mm; p = 0.01). Rates of dual antiplatelet therapy at 1 year were 32.2% for patients in the BMS group and 94.0% for patients in the DES group. The primary endpoint occurred in 18.7% of patients in the BMS group versus 14.3% of patients in the DES group (p = 0.09). There was no difference in death (7.2% vs. 8.5%; p = 0.50), major hemorrhage (1.7% vs. 2.3%; p = 0.61), or cerebrovascular accident (1.2% vs. 1.5%; p = 0.77). Myocardial infarction (8.7% vs. 4.3%; p = 0.01) and target vessel revascularization (7.0% vs. 2.0%; p = 0.001) occurred more often in patients in the BMS group. CONCLUSIONS BMS and DES offer good clinical outcomes in this age group. DES were associated with a lower incidence of myocardial infarction and target vessel revascularization without increased incidence of major hemorrhage. (Xience or Vision Stent-Management of Angina in the Elderly [XIMA]; ISRCTN92243650).

Myocardial tissue characterization and the role of chronic anemia in sickle cell cardiomyopathy

To use cardiovascular magnetic resonance (CMR) techniques to examine possible causes for the left ventricular (LV) dilatation that occurs in sickle cell disease (SCD), including the effects of chronic anemia, iron‐induced cardiomyopathy, and regional fibrosis due to sludge infarcts that occur during sickle crises.

A novel approach to the management of occlusive in-stent restenosis (ISR).

AIMS Chronic total occlusions (CTO) secondary to in-stent restenosis (ISR) represent challenging lesions with low PCI success rates. The CrossBoss is an over-the-wire blunt catheter which has emerged as a useful tool in occlusive ISR. We aimed to review the utility of this device in the treatment of occlusive ISR within the United Kingdom. METHODS AND RESULTS The CrossBoss catheter was used as the primary strategy in 30 patients (31 CTOs) with a median CTO duration of 24 months, a mean CTO length of 39 mm and a previous unsuccessful PCI attempt in 48% of cases. Procedural success was 90% (27/30) and the CrossBoss catheter directly facilitated success in 81% of cases, with direct lumen-to-lumen crossing of the catheter in most cases. Identifiable predictors of failure were evident in the unsuccessful cases. When successful, crossing time was short (median eight minutes, range one to 40 minutes), as were procedural time (mean 99±29 minutes) and fluoroscopy time (mean 26.9±12.2 minutes), whilst radiation dose (median 5,738 cGycm2, range 3,430-64,122 cGycm2) and contrast dose (mean 271±79 mL) were low. There were no procedural complications. CONCLUSIONS In our experience, use of the CrossBoss catheter is associated with high procedural success rates, short crossing times and low complication rates in the setting of occlusive ISR.

Impact of proctoring on success rates for percutaneous revascularisation of coronary chronic total occlusions.

Objective To assess the impact of proctoring for chronic total occlusion (CTO) percutaneous coronary intervention (PCI) in six UK centres. Methods We retrospectively analysed 587 CTO procedures from six UK centres and compared success rates of operators who had received proctorship with success rates of the same operators before proctorship (pre-proctored) and operators in the same institutions who had not been proctored (non-proctored). There were 232 patients in the pre-proctored/non-proctored group and 355 patients in the post-proctored group. Complexity was assessed by calculating the Japanese CTO (JCTO) score for each case. Results CTO PCI success was greater in the post-proctored compared with the pre-proctored/non-proctored group (77.5% vs 62.1%, p<0.0001). In more complex cases where JCTO≥2, the difference in success was greater (70.7% vs 49.5%, p=0.0003). After proctoring, there was an increase in CTO PCI activity in centres from 2.5% to 3.5%, p<0.0001 (as a proportion of total PCI), and the proportion of very difficult cases with JCTO score ≥3 increased from 15.3% (35/229) to 29.7% (105/354), p<0.0001. Conclusions Proctoring resulted in an increase in procedural success for CTO PCI, an increase in complex CTO PCI and an increase in total CTO PCI activity. Proctoring may be a valuable way to improve access to CTO PCI and the likelihood of procedural success.

Spontaneous multivessel coronary intramural hematoma: an insight with OCT.

Spontaneous coronary arterial intramural hematoma is a rarely diagnosed cause of acute myocardial infarction. The underlying pathophysiology is poorly understood. A historical series of intramedial dissecting hematomas, published in 1965 ([1][1]), postulated that rupture of the vasa vasorum or

Percutaneous intervention for chronic total occlusion: integrating strategies to address an unmet need

Chronic total occlusion (CTO) remains a challenging lesion subset when considering percutaneous coronary intervention (PCI). Until recently, CTO lesions were associated with relatively low procedural success rates ranging between 60–70% despite evidence of considerable case selection1 ,2 However, the emergence of new techniques and technologies is revolutionising the field, such that procedural success rates in excess of 90% have been described by specialist operators.3 While it has long been appreciated that CTO revascularisation can improve symptoms,4 there is an increasing body of evidence to suggest prognostic benefit may follow.5 In this issue of Heart , Michael et al describe outcomes following CTO PCI among patients with previous coronary artery bypass graft surgery (CABG).6 They demonstrate that prior CABG remains a challenge in CTO PCI, with lower procedural success rates than CTO lesions in previously ungrafted patients. However, the most powerful aspect of their data is that the reporting US centres are consistently achieving high rates of procedural success (85%) despite treating increasingly complex patients. In their cohort 37% of patients had undergone prior CABG, a substantially greater proportion than any other reported registry. This suggests greater patient selection among previous registries, where CTO patients with more complex disease may have been excluded from revascularisation, a situation likely to reflect real world clinical practice. Patients who have symptoms, significant ischaemia, and/or myocardial viability may often be excluded from revascularisation on the basis of feasibility of percutaneous revascularisation —that is, anatomy rather than clinical need. Although chronic occlusions may be present in up to 35% of patients undergoing coronary angiography,7 CTO PCI accounts for only around 5% of all elective PCI procedures.8 Many patients with single vessel de novo CTO are not offered revascularisation at all. Among patients with multivessel disease undergoing PCI, the …

Towards a contemporary, comprehensive scoring system for determining technical outcomes of hybrid percutaneous chronic total occlusion treatment: The RECHARGE score

This study sought to create a contemporary scoring tool to predict technical outcomes of chronic total occlusion (CTO) percutaneous coronary intervention (PCI) from patients treated by hybrid operators with differing experience levels.