Robert Cooper

Mechanisms of Myocardial Ischemia in Hypertrophic Cardiomyopathy: Insights From Wave Intensity Analysis and Magnetic Resonance

Background Angina is common in hypertrophic cardiomyopathy (HCM) and is associated with abnormal myocardial perfusion. Wave intensity analysis improves the understanding of the mechanics of myocardial ischemia. Objectives Wave intensity analysis was used to describe the mechanisms underlying perfusion abnormalities in patients with HCM. Methods Simultaneous pressure and flow were measured in the proximal left anterior descending artery in 33 patients with HCM and 20 control patients at rest and during hyperemia, allowing calculation of wave intensity. Patients also underwent quantitative first-pass perfusion cardiac magnetic resonance to measure myocardial perfusion reserve. Results Patients with HCM had a lower coronary flow reserve than control subjects (1.9 ± 0.8 vs. 2.7 ± 0.9; p = 0.01). Coronary hemodynamics in HCM were characterized by a very large backward compression wave during systole (38 ± 11% vs. 21 ± 6%; p < 0.001) and a proportionately smaller backward expansion wave (27% ± 8% vs. 33 ± 6%; p = 0.006) compared with control subjects. Patients with severe left ventricular outflow tract obstruction had a bisferiens pressure waveform resulting in an additional proximally originating deceleration wave during systole. The proportion of waves acting to accelerate coronary flow increased with hyperemia, and the magnitude of change was proportional to the myocardial perfusion reserve (rho = 0.53; p < 0.01). Conclusions Coronary flow in patients with HCM is deranged. Distally, compressive deformation of intramyocardial blood vessels during systole results in an abnormally large backward compression wave, whereas proximally, severe left ventricular outflow tract obstruction is associated with an additional deceleration wave. Perfusion abnormalities in HCM are not simply a consequence of supply/demand mismatch or remodeling of the intramyocardial blood vessels; they represent a dynamic interaction with the mechanics of myocardial ischemia that may be amenable to treatment.

Original InvestigationMechanisms of Myocardial Ischemia in Hypertrophic Cardiomyopathy: Insights From Wave Intensity Analysis and Magnetic Resonance

Background Angina is common in hypertrophic cardiomyopathy (HCM) and is associated with abnormal myocardial perfusion. Wave intensity analysis improves the understanding of the mechanics of myocardial ischemia. Objectives Wave intensity analysis was used to describe the mechanisms underlying perfusion abnormalities in patients with HCM. Methods Simultaneous pressure and flow were measured in the proximal left anterior descending artery in 33 patients with HCM and 20 control patients at rest and during hyperemia, allowing calculation of wave intensity. Patients also underwent quantitative first-pass perfusion cardiac magnetic resonance to measure myocardial perfusion reserve. Results Patients with HCM had a lower coronary flow reserve than control subjects (1.9 ± 0.8 vs. 2.7 ± 0.9; p = 0.01). Coronary hemodynamics in HCM were characterized by a very large backward compression wave during systole (38 ± 11% vs. 21 ± 6%; p < 0.001) and a proportionately smaller backward expansion wave (27% ± 8% vs. 33 ± 6%; p = 0.006) compared with control subjects. Patients with severe left ventricular outflow tract obstruction had a bisferiens pressure waveform resulting in an additional proximally originating deceleration wave during systole. The proportion of waves acting to accelerate coronary flow increased with hyperemia, and the magnitude of change was proportional to the myocardial perfusion reserve (rho = 0.53; p < 0.01). Conclusions Coronary flow in patients with HCM is deranged. Distally, compressive deformation of intramyocardial blood vessels during systole results in an abnormally large backward compression wave, whereas proximally, severe left ventricular outflow tract obstruction is associated with an additional deceleration wave. Perfusion abnormalities in HCM are not simply a consequence of supply/demand mismatch or remodeling of the intramyocardial blood vessels; they represent a dynamic interaction with the mechanics of myocardial ischemia that may be amenable to treatment.

Radiofrequency ablation of the interventricular septum to treat outflow tract gradients in hypertrophic obstructive cardiomyopathy: a novel use of CARTOSound® technology to guide ablation.

AIMS Septal reduction is needed for hypertrophic obstructive cardiomyopathy (HOCM) patients with severe left ventricular outflow tract (LVOT) gradients and symptoms despite medication. Myectomy cannot be performed in all. Alcohol septal ablation cannot be performed in 5-15% due to technical difficulties. A method of delivering percutaneous tissue damage to the septum that is not reliant on coronary anatomy is desirable. To directly ablate the interventricular septum at the mitral valve (MV) systolic anterior motion (SAM)-septal contact point using radiofrequency (RF) energy guided by CARTOSound. METHODS AND RESULTS Five patients underwent RF ablation (RFA); we describe follow-up at 6 months in four patients. Intracardiac echocardiography (ICE) images are merged with CARTO to create a shell of the cardiac chambers. The SAM-septal contact area is marked from ICE images and mapped on to the CARTO shell; this becomes the target for RF delivery. Conduction tissue is mapped and avoided where possible. Twenty-eight to 42 min of RF energy was delivered to the target area using retrograde aortic access and SmartTouch catheters. Resting LVOT gradient improved from 64.2 (±50.6) to 12.3 (±2.5) mmHg. Valsalva/exercise-induced gradient reduced from 93.5 (±30.9) to 23.3 (±8.3) mmHg. Three patients improved New York Heart Association status from III to II, one patient improved from class III to I. Exercise time on bicycle ergometer increased from 612 to 730 s. Cardiac magnetic resonance shows late gadolinium enhancement up to 8 mm depth at LV target myocardium. One patient died following a significant retroperitoneal haemorrhage. CONCLUSION Radiofrequency ablation using CARTOSound(®) guidance is accurate and effective in treating LVOT gradients in HOCM in this preliminary group of patients.

Outcome of Alcohol Septal Ablation in Mildly Symptomatic Patients With Hypertrophic Obstructive Cardiomyopathy: A Long‐Term Follow‐Up Study Based on the Euro‐Alcohol Septal Ablation Registry

Background The long‐term efficacy and safety of alcohol septal ablation (ASA) in patients with highly symptomatic hypertrophic obstructive cardiomyopathy has been demonstrated. The aim of this study was to evaluate the long‐term outcomes of mildly symptomatic patients with hypertrophic obstructive cardiomyopathy treated with ASA. Methods and Results We retrospectively evaluated consecutive patients enrolled in the Euro‐ASA registry (1427 patients) and identified 161 patients (53±13 years; 27% women) who were mildly symptomatic (New York Heart Association [NYHA] class II) pre‐ASA. The median (interquartile range) follow‐up was 4.8 (1.7–8.5) years. The clinical outcome was assessed and compared with the age‐ and sex‐matched general population. The 30‐day mortality after ASA was 0.6% and the annual all‐cause mortality rate was 1.7%, which was similar to the age‐ and sex‐matched general population (P=0.62). A total of 141 (88%) patients had resting left ventricular outflow tract gradient at the last clinical checkup ≤30 mm Hg. Obstruction was reduced from 63±32 to 15±19 mm Hg (P<0.01), and the mean NYHA class decreased from 2.0±0 to 1.3±0.1 (P<0.01); 69%, 29%, and 2% of patients were in NYHA class I, II, and III at the last clinical checkup, respectively. Conclusions Mildly symptomatic hypertrophic obstructive cardiomyopathy patients treated with ASA had sustained symptomatic and hemodynamic relief with a low risk of developing severe heart failure. Their survival is comparable to the general population.

Computed tomography angiography planning identifies the target vessel for optimum infarct location and improves clinical outcome in alcohol septal ablation for hypertrophic obstructive cardiomyopathy

AIMS Alcohol septal ablation (ASA) is an established treatment option in hypertrophic obstructive cardiomyopathy (HOCM). ASA is ineffective in some: inaccurate infarct and inability to identify a vessel contribute. We aimed to improve accuracy of infarct using CT angiography guidance and provide a more predictable and satisfactory outcome. METHODS AND RESULTS Twenty-one successive patients with symptomatic LVOT obstruction refractory to medication underwent CT angiography planning to guide ASA. CT was performed using a dual-source CT system. Alcohol was delivered to the artery identified from CT: in 17/21 this was a sub-branch of a septal artery, in 2/21 the septal vessel was identified from the circumflex artery. Peak gradient improved from 98 (IQR 89.50-111.50) mmHg to 14 (IQR 8.50-22) mmHg (p=0.003). Systolic anterior motion (SAM) improved in 18/20 patients. NYHA class improved by ≥1 in 18/20. Peak VO2 improved from 79.19% of predicted value (±14.01) to 91.62% (±12.02) predicted (p<0.0001). Success at the first procedure is greater with CT guidance, 17/20 vs. 50/75 with traditional methods (pre-CT guidance) (p=0.02); 9/20 had six-month CMR with target septum infarct in all. ASA-related RBBB reduced from 62% to 13% (p=0.0004). CONCLUSIONS CT angiography planning improves localisation of infarct and procedural success at the first attempt in ASA when compared to traditional methods. Follow-up to six months suggests a symptomatic, functional and haemodynamic improvement.

Central venous spasm during pacemaker insertion

An 83-year-old female presented with syncope. She was found to be in complete heart block with an escape rhythm of 40 bpm. Following admission she remained haemodynamically stable with no prolonged pauses; she was therefore listed for pacemaker implantation the next morning. Initial attempts at venous access were right-sided due to recent left shoulder …

Hypertrophic Cardiomyopathy—Past, Present and Future

Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiomyopathy with a prevalence of 1 in 500 in the general population. Since the first pathological case series at post mortem in 1957, we have come a long way in its understanding, diagnosis and management. Here, we will describe the history of our understanding of HCM including the initial disease findings, diagnostic methods and treatment options. We will review the current guidelines for the diagnosis and management of HCM, current gaps in the evidence base and discuss the new and promising developments in this field.

New Developments in Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy is the leading cause of sudden death in young individuals and an important cause of heart failure at any age. In this review we discuss advances in investigation and management of this heterogenous disease. Improved cardiac imaging has allowed us to detail many of the structural abnormalities whereas the use of new techniques, predominantly in cardiac magnetic resonance imaging, has given us a greater insight in to tissue architecture, mechanism of contractile abnormalities, and function. Risk stratification remains challenging because of the low event rate in clinical studies. Multicentre registries have improved risk stratification for sudden cardiac death and multiple models can be used to aid decision-making for implantable defibrillator therapy. We discuss the current state of nonsurgical septal reduction therapy and results of multicentre registries. New approaches to septal reduction therapy including refinement of alcohol ablation and noncoronary interventions such as radiofrequency ablation of the septum show great promise. Surgical myectomy remains a major part of treatment; a greater recognition of abnormalities of the mitral valve apparatus can allow improved surgical options. Myocardial perfusion abnormalities are known to predict adverse outcome in hypertrophic cardiomyopathy and we discuss underlying mechanisms and relevance to management. The off-label use of currently licensed medicines such as ranolazine, perhexiline, calcium channel blockers, and renin-angiotensin system antagonists are discussed. A novel approach to medical treatment of the underlying sarcomeric disorder has been investigated and shows great potential.

Wave intensity analysis and assessment of myocardial perfusion abnormalities in patients with hypertrophic cardiomyopathy

Background Coronary perfusion pressure is a combination of proximal perfusion pressure and distal coronary artery pressure resulting from contraction and relaxation of the myocardium and the consequences on the microcirculation. Wave intensity analysis (WIA) defines dominant waves causing coronary filling during the cardiac cycle and allows separation of proximally and distally originating waves.Reduced myocardial perfusion has been shown to predict mortality in hypertrophic cardiomyopathy (HCM), however no study has assessed the relationship between coronary filling patterns and downstream absolute myocardial perfusion.

Can RAS inhibitors affect the course of hypertrophic cardiomyopathy

Modulators of the renin-angiotensin system (RAS) have shown promise in animal and pilot human studies in hypertrophic cardiomyopathy. The possibility of reversing hypertrophy and improving diastolic function is attractive and certainly deserves further investigation. The investigators of the INHERIT placebo-controlled trial, the results of which are reported in The Lancet Diabetes & Endocrinology, set out to investigate the eff ects of the angiotensin II receptor blocker losartan in patients with hypertrophic cardiomyopathy recruited from a tertiary referral centre in Denmark. The primary outcome measure of left ventricular mass after 12 months of treatment was a sensible choice, and the imaging modalities used—cardiac magnetic resonance imaging (CMR) and CT—are well validated in hypertrophic cardiomyopathy. The investigators decided to avoid fi brosis as assessed by cardiac MRI as a primary outcome, which would have excluded most patients with an implantable cardioverter defi brillator and hence missed a high-risk patient group. Cardiac fi brosis was, however, measured as a secondary outcome. Change in left ventricular mass after 12 months did not diff er signifi cantly between the placebo group and the losartan group (mean diff erence 1 g/m2, 95% CI –3 to 6; p=0·60), although systolic blood pressure in the losartan group was decreased, as expected. Although many readers would label this a negative trial, useful information can still be taken from these fi ndings. The INHERIT results show that losartan does not seem to reduce left ventricular mass or the extent of left ventricular fi brosis in patients with hypertrophic cardiomyopathy. This study is the most comprehensive assessment of angiotensin modulators to date and the results are at odds with earlier work. The results also show that losartan is safe in patients with a left ventricular outfl ow tract gradient. A long-held assumption has been that RAS inhibitors would exacerbate left ventricular outfl ow tract gradients and lead to syncope. RAS modulators have often been grouped with nitrates as vasodilators and proposed to put patients at risk of syncope; they are therefore largely avoided in patients with hypertrophic obstructive cardiomyopathy. Clinicians sometimes face the problem of concurrent diagnoses of hypertrophic cardiomyopathy with obstruction and hypertension. Furthermore, results from septal reduction studies have shown that not all of the hypertrophy in hypertrophic cardiomyopathy is genetically determined, since removal of the gradient and afterload results in regression of hypertrophy away from the septum and improves diastolic function. Any cause of increased afterload must therefore be treated, meaning that hypertension must therefore be controlled. The results of INHERIT show that treatment with losartan is safe and reduces blood pressure in patients with hypertrophic cardiomyopathy. The extent of fi brosis in hypertrophic cardiomyopathy is believed to be a risk factor for sudden cardiac death. Studies of fi brosis in patients with hypertrophic cardiomyopathy are often based on a measurement at a single timepoint then monitoring for an outcome such as death or ventricular arrhythmia. With INHERIT, there is the benefi t of serial imaging and the observation of change over 12 months. The presence of fi brosis in 83% patients is perhaps slightly higher than in other studies, but the 4 percentage point increase in fi brotic left ventricular mass over the study period is a useful fi nding. This result provides us with an insight into the natural history of hypertrophic cardiomyopathy, and further serial imaging and clinical monitoring of this group of patients would represent another success for the INHERIT team. This trial represents a rare success in clinical research of hypertrophic cardiomyopathy: a well designed and well executed randomised controlled trial. Few precedents exist of randomised studies on the topic, and none involved as many patients as were recruited in the INHERIT trial (n=133). The investigators were helped by a solid clinical structure for recruitment, and by choosing an outcome that did not rely on events such as death or cardiac arrest—the Achilles heel for statistical power in many proposed studies into hypertrophic cardiomyopathy. However, the use of surrogate outcomes has its problems and an association with hard clinical outcomes is usually assumed rather than proven beyond doubt. Other issues such as the heterogeneous Lancet Diabetes Endocrinol 2014