David Hutchings

Phosphodiesterase type-5 inhibitor use in type 2 diabetes is associated with a reduction in all-cause mortality

Objective Experimental evidence has shown potential cardioprotective actions of phosphodiesterase type-5 inhibitors (PDE5is). We investigated whether PDE5i use in patients with type 2 diabetes, with high-attendant cardiovascular risk, was associated with altered mortality in a retrospective cohort study. Research design and methods Between January 2007 and May 2015, 5956 men aged 40–89 years diagnosed with type 2 diabetes before 2007 were identified from anonymised electronic health records of 42 general practices in Cheshire, UK, and were followed for 7.5 years. HRs from multivariable survival (accelerated failure time, Weibull) models were used to describe the association between on-demand PDE5i use and all-cause mortality. 10.1136/heartjnl-2015-309223.supp1 Supplementary appendix Results Compared with non-users, men who are prescribed PDE5is (n=1359) experienced lower percentage of deaths during follow-up (19.1% vs 23.8%) and lower risk of all-cause mortality (unadjusted HR=0.69 (95% CI: 0.64 to 0.79); p<0.001)). The reduction in risk of mortality (HR=0.54 (0.36 to 0.80); p=0.002) remained after adjusting for age, estimated glomerular filtration rate, smoking status, prior cerebrovascular accident (CVA) hypertension, prior myocardial infarction (MI), systolic blood pressure, use of statin, metformin, aspirin and β-blocker medication. PDE5i users had lower rates of incident MI (incidence rate ratio (0.62 (0.49 to 0.80), p<0.0001) with lower mortality (25.7% vs 40.1% deaths; age-adjusted HR=0.60 (0.54 to 0.69); p=0.001) compared with non-users within this subgroup. Conclusion In a population of men with type 2 diabetes, use of PDE5is was associated with lower risk of overall mortality and mortality in those with a history of acute MI.

Takotsubo cardiomyopathy in association with endogenous and exogenous thyrotoxicosis

### Case 1 A 79-year-old woman from Sri Lanka, with a history of hyperthyroidism, presented with chest pain and breathlessness following an episode of extreme anxiety after missing her connecting flight. She had been unable to take carbimazole during the preceding 3 months due to local shortages. Examination revealed signs of acute heart failure, with an electrocardiogram (ECG) showing anterior T-wave inversion, a 12-h cardiac Troponin I of 4.1 ng/ml and thyroid function tests demonstrating thyrotoxicosis (free thyroxine [fT4] 40.4 pmol/l, thyroid-stimulating hormone [TSH] 0.04 mU/l). Coronary angiography showed only minor disease in the left anterior descending and circumflex arteries. Ventriculography revealed classical apical ballooning and left ventricular dysfunction. Cardiovascular magnetic resonance (CMR) imaging on Day 3 confirmed this finding on cine imaging and without evidence of delayed gadolinium hyperenhancement (Figure 1). Her symptoms resolved within 4 …

Repeat percutaneous coronary revascularization: Indications and outcomes in a “Real World” cohort†

Objectives: To investigate rates of and reasons for second and subsequent stent procedures in an unselected, “real‐world” population. Background: Repeat stenting is the primary difference reported in clinical trials of alternative revascularization strategies. The incidence, indication, and outcome for repeat stenting in contemporary practice outside the more selective populations of trials and registries has not been described. Method: All patients undergoing a first percutaneous coronary intervention (PCI) procedure with stenting from January 2001 to August 2009 (10,509) from a large UK tertiary referral and district general hospital were identified. Mortality and the incidence, timing, and indication for repeat revascularization in this population were investigated from patient records. Results: Of 10,509 patients undergoing a first PCI and stent implant 23.5% underwent repeat angiography of which 11.2% required repeat PCI and 2% coronary artery bypass grafting (median follow‐up of 3.8 years). A total of 1.3% went on to a third PCI. The commonest indication for repeat stenting was disease progression remote from the original stent (46%) and planned staged PCI (23%); 21% had a stent‐related indication. Functional assessment before repeat stenting was used in one‐third of stable patients. Mortality was 2.5% per annum. Conclusions: In contemporary practice, patients undergoing a first stenting procedure have a low subsequent mortality, and the substantial majority (86.4%) requires no further revascularization over a median 3.8 year follow‐up. For those who do require repeat stenting, this is most commonly at a site remote from the first stent.

Phosphodiesterase-5 inhibitors and the heart: compound cardioprotection?

Novel cardioprotective agents are needed in both heart failure (HF) and myocardial infarction. Increasing evidence from cellular studies and animal models indicate protective effects of phosphodiesterase-5 (PDE5) inhibitors, drugs usually reserved as treatments of erectile dysfunction and pulmonary arterial hypertension. PDE5 inhibitors have been shown to improve contractile function in systolic HF, regress left ventricular hypertrophy, reduce myocardial infarct size and suppress ischaemia-induced ventricular arrhythmias. Underpinning these actions are complex but increasingly understood cellular mechanisms involving the cyclic GMP activation of protein kinase-G in both cardiac myocytes and the vasculature. In clinical trials, PDE5 inhibitors improve symptoms and ventricular function in systolic HF, and accumulating epidemiological data indicate a reduction in cardiovascular events and mortality in PDE5 inhibitor users at high cardiovascular risk. Here, we focus on the translation of underpinning basic science to clinical studies and report that PDE5 inhibitors act through a number of cardioprotective mechanisms, including a direct myocardial action independent of the vasculature. We conclude that future clinical trials should be designed with these mechanisms in mind to identify patient subsets that derive greatest treatment benefit from these novel cardioprotective agents.

Effects of phosphodiesterase-5 inhibition with sildenafil on calcium waves in cardiac myocytes

Abstract Background Diastolic Ca 2 + waves in cardiac myocytes lead to arrhythmias by inducing delayed after-depolarisations. Waves occur when sarcoplasmic reticulum (SR) content reaches a threshold level. The phosphodiesterase-5 inhibitor, sildenafil, is antiarrhythmic in mammalian myocardial ischaemia models, and in rat myocytes it reduces Ca 2 + transient amplitude and SR Ca 2 + content. We sought to determine effects of sildenafil on propensity to Ca 2 + waves in the large mammal. Methods Sheep ventricular myocytes were voltage clamped and Ca 2 + fluorescence measured using fura-2. Cells were paced at 0·5 Hz with depolarisations from −40mV to +10mV. When at steady state, waves were induced with 7·5–15 mM Ca 2 + . Upon regular waving, sildenafil (1 μM) was applied. To determine threshold SR Ca 2 + content, caffeine (10 mM) was added immediately after a wave, and both wave and caffeine-induced Na + /Ca 2 + exchanger current ( I NCX )were integrated. Findings Increasing external Ca 2 + increased SR content and induced diastolic waves. Sildenafil abolished waves in seven of 11 cells. In cells where sildenafil terminated waves, SR content was reduced below threshold. In addition, sildenafil treatment was associated with reduced rate constant of SERCA (k SERCA −68·4% of control, p I NCX tail current (+190%, p=0·022), and reduced sarcolemmal influx via L-type Ca 2 + current ( I Ca-L ) (−29·8%, p=0·0015). In cells continuing to wave in sildenafil, SR threshold for waves was unchanged (123·8 μmol/L sildenafil vs 150·7, p=0·57). In unstimulated cells spontaneously waving in 10–15 mM Ca 2 + , sildenafil reduced wave frequency (6·3 waves per 20 s vs 2·7, p=0·0034). The effect of sildenafil on both wave models was abolished when cells were preincubated with the protein kinase G inhibitor, KT5823. Interpretation Sildenafil suppresses waves induced by elevated external Ca 2 + via a protein kinase G-dependent mechanism. This suppression is mediated by reduced SR content, which itself is caused by reduced SERCA function and possible reduced I Ca-L . These findings highlight novel antiarrhythmic properties of phosphodiesterase-5 inhibition. Funding British Heart Foundation.

Phosphodiesterase-5 inhibition with sildenafil suppresses calcium waves by reducing sarcoplasmic reticulum content

Rationale: Occurrence of diastolic Ca2+ waves in cardiac myocytes leads to arrhythmias by inducing delayed after-depolarisations. Waves are initiated when sarcoplasmic reticulum (SR) content reaches a critical threshold level. The phosphodiesterase-5 inhibitor sildenafil (Sil) is antiarrhythmic in mammalian myocardial ischaemia models, while Sil reduces Ca2+ transient amplitude and sarcoplasmic reticulum (SR) Ca2+ content in rat myocytes. Objective: To determine effects of Sil on propensity to Ca2?+ waves in the large mammal. Methods: Sheep ventricular myocytes were voltage clamped and intracellular Ca2+ measured using Fura-2. Cells were paced at 0.5 Hz with depolarisations from −40 mV to+10 mV. When at steady state, waves were induced with 10–15 mM Ca2+. Upon regular waving, Sil (1µM) was applied. To determine threshold SR content, caffeine (10 mM) was added immediately following a wave, and both wave and caffeine-induced I NCX integrated. Differences between groups were determined using students paired t tests. Results: Increasing external Ca2+ to 10–15 mM increased SR content and induced diastolic waves. Sildenafil abolished waves in 9/15 cells. In cells where Sil terminated waves, SR content was reduced below threshold. In addition, Sil treatment was associated with a reduced rate constant of SERCA (kSERCA−66.0±9.9% of control, p<0.005), an initial (first 4 s) increase in sarcolemmal efflux via the I NCX tail current (+142± 36.4%, p<0.01), and reduced sarcolemmal influx via I Ca-L (–30.5±5.6%, p<0.005). In cells continuing to wave in Sil, SR threshold for waves was unchanged (126.9 µmolL-1 ctrl vs 147.2 µmolL-1 Sil, p=0.6). In unstimulated cells spontaneously waving in 10–15 mM Ca²+, sildenafil reduced wave frequency (6.3 waves per 20 s vs 2.7, p<0.005). The protective effect of sildenafil on both wave models was abolished when cells were pre-incubated with the PKG inhibitor, KT5823. Sildenafil suppression of waves was also observed in cells from animals in end-stage heart failure, while Sil suppressed ventricular ectopy and episodes of torsades de pointes in vivo in a sheep model of LQT2. Conclusions: Sildenafil suppresses waves induced by elevated external Ca2+ via a PKG-dependent mechanism, and mediated by a reduction in SR content, which itself is caused by reduced SERCA function ± reduced I Ca-L. These findings highlight novel antiarrhythmic properties of PDE5 inhibition and translate to suppression of triggered arrhythmias in vivo. Funding: British Heart Foundation.

Echocardiographic images of organised pericardial thrombus in type A aortic dissection.

A 70-year-old woman with a background of hypertension was admitted with severe stabbing central chest pain and epigastric discomfort. Initial examination was unremarkable. Observations revealed blood pressure (BP) of 152/87 mm Hg, heart rate 89/min and normal O2 saturations. 12-lead ECG and chest X-ray (CXR) were normal (figure 1). Serum cardiac troponin I was borderline elevated at 0.07 12 h after admission (RR <0.04 ng/mL). CT of the thorax showed no evidence of aortic dissection on arterial phase and no pulmonary embolism on venous phase. Transthoracic echo demonstrated normal left ventricular function and inconsequential …

Effects of phosphodiesterase type 5A inhibition on intracellular calcium handling and its implications for cardioprotection and antiarrhythmogenesis

Abstract Phosphodiesterase type 5A inhibition with sildenafil improves cardiac function in heart failure. In addition, sildenafil in animal models of myocardial infarction has direct cardioprotective and antiarrhythmic effects. Sildenafil reduces L-type calcium current ( I ca-L ) and attenuates adrenergically driven inotropism, but effects on calcium handling are largely undetermined. Isolated adult rat ventricular myocytes were voltage clamped and calcium fluorescence measured with the indicator fura-2. Cells were paced at 0·5 Hz with depolarisations from −60 mV to +10 mV. Sarcoplasmic reticulum (SR) content was determined by application of caffeine (10–20 mmol/L) and integration of inward sodium-calcium exchanger current. Rate constants for calcium extrusion from the cell (K caff ) and calcium uptake into the SR (K SERCA ) were determined by fitting first order exponentials to decay phases of the respective calcium transients. Following the initial control protocol, a therapeutically relevant dose of sidenafil (1 μM) was applied. Differences were determined with students paired t tests. Sildenafil reduced SR content by 26·5% (n=9, p SERCA (–2.3% with sildenafil, p=0·97, n=5). Peak and integrated I ca-L were also reduced with sildenafil (–9·1% and −6·0%, respectively, n=9, p ca-L was also seen in adult dog ventricular myocytes (reducing peak and integrated I ca-L by 15·9% and 26·4%, respectively, p Sildenafil substantially reduced SR content with no reduction in K SERCA , and thus may be mediated through ryanodine receptor modulation. Such reduction in SR load may reduce proarrhythmic SR calcium release, indicating a novel mechanism through which sildenafil exerts an antiarrhythmic effect. Acute reductions in calcium transient amplitude and I ca-L with sildenafil indicate acute negative inotropic effects and may contribute to our understanding of its cardioprotective effects in the setting of hyperadrenergic drive in heart failure. Funding British Heart Foundation.