Franco Cecchi

2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy: the Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC)

2D : two-dimensional 99mTc-DPD : 99mTechnetium-3,3-diphosphono- 1,2-propanodi-carboxylic acid ACE : angiotensin-converting enzyme AF : atrial fibrillation AL : amyloid light chain AR : aortic regurgitation ARB : angiotensin receptor blocker ATTR : amyloidosis-transthyretin type AV : atrioventricular BiVAD : biventricular assist device BNP : brain natriuretic peptide BPM : Beats per minute CCS : Canadian Cardiovascular Society CFC : cardiofacialcutaneous CHA2DS2-VASc : Congestive Heart failure, hypertension, Age ≥75 (doubled), Diabetes, Stroke (doubled), Vascular disease, Age 65–74, and Sex (female) CMR : cardiac magnetic resonance CRT : cardiac resynchronization therapy CRT-D : cardiac resynchronization therapy-defibrillator CRT-P : Cardiac resynchronization therapy with a pacemaker CT : computed tomography DC : direct current DNA : deoxyribonucleic acid E/A : ratio of mitral peak velocity of early filling (E) to mitral peak velocity of late filling (A) E/e’ : ratio of early transmitral flow velocity (E) to early mitral annulus velocity (e’) EACTS : European Association for Cardio-Thoracic Surgery ECG : electrocardiogram EF : ejection fraction EPS : electrophysiological study ESC : European Society of Cardiology FDA : (US) Food and Drug Administration FHL1 : four and a half LIM domains 1 HAS-BLED : hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile INR, elderly (>65 years), drugs/alcohol concomitantly HCM : hypertrophic cardiomyopathy hs-cTnT : high sensitivity cardiac troponin T HTS : high throughput sequencing ICD : implantable cardioverter defibrillator ILR : implantable loop recorder INR : international normalized ratio IUD : intrauterine device LA : left atrium LAMP-2 : lysosome-associated membrane protein 2 LBBB : left bundle branch block LEOPARD : Lentigines, ECG abnormalities, Ocular hypertelorism, Pulmonary stenosis, Abnormal genitalia, Retardation of growth, and sensory-neural Deafness LGE : late gadolinium enhancement LV : left ventricular LVAD : left ventricular assist device LVH : left ventricular hypertrophy LVOTO : left ventricular outlow tract obstruction MADIT-RIT : Multicenter Automatic Defibrillator Implantation Trial—Reduce Inappropriate Therapy MAPK : mitogen activated protein kinase MELAS : mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes MERFF : myoclonic epilepsy with ragged red fibres MRA : mineralocorticoid receptor antagonist MYBPC3 : myosin-binding protein C, cardiac-type MYH7 : myosin-7 (s-myosin heavy chain) MYL3 : myosin light chain 3 NOAC : new oral anticoagulants NSVT : non-sustained ventricular tachycardia NT-proBNP : N-terminal pro brain natriuretic peptide NYHA : New York Heart Association OAC : oral anticoagulants o.d. : omni die (every day) PC-CMR : phase contrast cardiac magnetic resonance PDE5 : phosphodiesterase type 5 PET : positron emission tomography PRKAG2 : gamma-2 sub-unit of the adenosine monophosphate-activated protein kinase RAAS : renin angiotensin aldosterone system RV : right ventricular SAM : systolic anterior motion SCD : sudden cardiac death SAA : septal alcohol ablation S-ICD™ : Subcutaneous lead implantable cardioverter defibrillator SPECT : single photon emission computed tomography SSFP : steady-state free precession SVT : supraventricular tachycardia TOE : transoesophageal echocardiography TNNI3 : troponin I, cardiac muscle TNNT2 : troponin T, cardiac muscle TPM1 : tropomyosin alpha-1 chain TTE : transthoracic echocardiography TTR : transthyretin VF : ventricular fibrillation VKA : vitamin K antagonist VT : ventricular tachycardia WHO : World Health Organization Guidelines summarize and evaluate all available evidence at the time of the writing process, on a particular issue with the aim of assisting health professionals in selecting the best management strategies for an individual patient, with a given condition, taking into account the impact on outcome, as well as the risk-benefit-ratio of particular diagnostic or therapeutic means. Guidelines and recommendations should help the health professionals to make decisions in their daily practice. However, the final decisions concerning an individual patient must be made by the responsible health professional(s) in consultation with the patient and caregiver as appropriate. A great number of Guidelines have been issued in recent years by the European Society of Cardiology (ESC) as well as by other societies and organisations. Because of the impact on clinical practice, quality criteria for the development of guidelines have been established in order to make all decisions transparent to the user. The recommendations for formulating and issuing ESC Guidelines can be found on the ESC website (http://www.escardio.org/guidelines-surveys/esc-guidelines/about/Pages/rules-writing.aspx). ESC Guidelines represent the official position of the ESC on a given topic and are regularly updated. Members of this Task Force were selected by the ESC to represent professionals involved with the medical care of patients with this pathology. Selected experts in the field undertook a comprehensive review of the published evidence for management (including diagnosis, treatment, prevention and rehabilitation) of a given condition according to ESC Committee for Practice Guidelines (CPG) policy. A critical evaluation of diagnostic and therapeutic procedures was performed including assessment of the risk-benefit-ratio. Estimates of expected health outcomes for larger populations were included, where data exist. The level of evidence and the strength of recommendation of particular management options were weighed and graded according to predefined scales, as outlined in Tables 1 and 2 . The experts of …

Epidemiology of Hypertrophic Cardiomyopathy–Related Death Revisited in a Large Non–Referral-Based Patient Population

BACKGROUND Death resulting from hypertrophic cardiomyopathy (HCM), particularly when sudden, has been reported to be largely confined to young persons. These data emanated from tertiary HCM centers with highly selected referral patterns skewed toward high-risk patients. METHODS AND RESULTS The present analysis was undertaken in an international population of 744 consecutively enrolled and largely unselected patients more representative of the overall HCM spectrum. HCM-related death occurred in 86 patients (12%) over 8+/-7 years (mean+/-SD). Three distinctive modes of death were as follows: (1) sudden and unexpected (51%; age, 45+/-20 years); (2) progressive heart failure (36%; age, 56+/-19 years); and (3) HCM-related stroke associated with atrial fibrillation (13%; age, 73+/-14 years). Sudden death was most common in young patients, whereas heart failure- and stroke-related deaths occurred more frequently in midlife and beyond. However, neither sudden nor heart failure-related death showed a statistically significant, disproportionate age distribution (P=0.06 and 0.5, respectively). Stroke-related deaths did occur disproportionately in older patients (P=0.002). Of the 45 patients who died suddenly, most (71%) had no or mild symptoms, and 7 (16%) participated in moderate to severe physical activities at the time of death. CONCLUSIONS HCM-related cardiovascular death occurred suddenly, or as a result of heart failure or stroke, largely during different phases of life in a prospectively assembled, regionally based, and predominantly unselected patient cohort. Although most sudden deaths occurred in adolescents and young adults, such catastrophes were not confined to patients of these ages and extended to later phases of life. This revised clinical profile suggests that generally held epidemiological tenants for HCM have been influenced considerably by skewed reporting from highly selected populations. These data are likely to importantly affect risk stratification and treatment strategies importantly for the prevention of sudden death in HCM.

Hypertrophic Cardiomyopathy Is Predominantly a Disease of Left Ventricular Outflow Tract Obstruction

Background— Nonobstructive hypertrophic cardiomyopathy (HCM) has been regarded as the predominant hemodynamic form of the disease on the basis of assessment of outflow gradient under resting conditions. We sought to prospectively define the prevalence, clinical profile, and significance of left ventricular (LV) outflow tract obstruction under resting conditions and with physiological exercise in a large HCM cohort. Methods and Results— We prospectively analyzed 320 consecutive HCM patients (age, 47±17 years), measuring LV outflow gradient at rest, with Valsalva maneuver, and with exercise echocardiography. LV outflow obstruction was present at rest and/or with exercise in 225 patients (70%); 119 had rest gradients ≥50 mm Hg and were not exercised. Of the other 201 patients with gradients <50 mm Hg at rest (average, 4±9 mm Hg), 106 developed mechanical obstruction to LV outflow resulting from mitral valve–septal contact after exercise (80±43 mm Hg), including 76 with marked gradients ≥50 mm Hg and 46 with heart failure symptoms. The remaining 95 patients (30%) had no or small gradients (<30 mm Hg) both at rest and with exercise. Valsalva maneuver underestimated the presence and magnitude of exercise-induced obstruction. Conclusions— Among those patients who come to clinical evaluation, HCM is a predominantly obstructive disease in which LV outflow gradients, frequently associated with heart failure symptoms and often identified only with exercise, are evident in most patients (ie, 70%). Identification of LV outflow obstruction with exercise echocardiography may broaden management options in HCM by identifying symptomatic patients not otherwise regarded as potential candidates for septal reduction therapy. Assessment of subaortic gradients with exercise should be a routine component of the evaluation of HCM patients without outflow obstruction under resting conditions.

Prognostic Value of Quantitative Contrast-Enhanced Cardiovascular Magnetic Resonance for the Evaluation of Sudden Death Risk in Patients With Hypertrophic Cardiomyopathy

Background— Hypertrophic cardiomyopathy (HCM) is the most common cause of sudden death in the young, although not all patients eligible for sudden death prevention with an implantable cardioverter-defibrillator are identified. Contrast-enhanced cardiovascular magnetic resonance with late gadolinium enhancement (LGE) has emerged as an in vivo marker of myocardial fibrosis, although its role in stratifying sudden death risk in subgroups of HCM patients remains incompletely understood. Methods and Results— We assessed the relation between LGE and cardiovascular outcomes in 1293 HCM patients referred for cardiovascular magnetic resonance and followed up for a median of 3.3 years. Sudden cardiac death (SCD) events (including appropriate defibrillator interventions) occurred in 37 patients (3%). A continuous relationship was evident between LGE by percent left ventricular mass and SCD event risk in HCM patients (P=0.001). Extent of LGE was associated with an increased risk of SCD events (adjusted hazard ratio, 1.46/10% increase in LGE; P=0.002), even after adjustment for other relevant disease variables. LGE of ≥15% of LV mass demonstrated a 2-fold increase in SCD event risk in those patients otherwise considered to be at lower risk, with an estimated likelihood for SCD events of 6% at 5 years. Performance of the SCD event risk model was enhanced by LGE (net reclassification index, 12.9%; 95% confidence interval, 0.3–38.3). Absence of LGE was associated with lower risk for SCD events (adjusted hazard ratio, 0.39; P=0.02). Extent of LGE also predicted the development of end-stage HCM with systolic dysfunction (adjusted hazard ratio, 1.80/10% increase in LGE; P<0.03). Conclusions— Extensive LGE measured by quantitative contrast enhanced CMR provides additional information for assessing SCD event risk among HCM patients, particularly patients otherwise judged to be at low risk.

Myofilament protein gene mutation screening and outcome of patients with hypertrophic cardiomyopathy.

OBJECTIVE To determine the influence of a positive genetic test for hypertrophic cardiomyopathy (HCM) on clinical outcome. PATIENTS AND METHODS A cohort of 203 unrelated patients with HCM (mean +/- SD age, 50+/-18 years) was enrolled from January 1, 2002, through December 31, 2003. They were followed up for a mean +/- SD time of 4.0+/-1.7 years after genetic testing of the 8 HCM-susceptibility genes that encode key sarcomeric/myofilament proteins. The clinical phenotype of those with a positive genetic test (myofilament-positive HCM) was compared with those with a negative genetic test (myofilament-negative HCM). RESULTS In this cohort of 203 patients, 87 mutations were identified in 126 patients (myofilament-positive HCM, 62%); the remaining 77 patients (38%) were myofilament-negative. Despite similar baseline features, patients with myofilament-positive HCM showed increased risk of the combined end points of cardiovascular death, nonfatal stroke, or progression to New York Heart Association class III or IV compared with the patients with myofilament-negative HCM (25% vs 7%, respectively; independent hazard ratio, 4.27; P=.008). These end points occurred at any age among patients with myofilament-positive HCM (range, 14-86 years), but only in those aged 65 years and older among patients with myofilament-negative HCM. Moreover, patients with myofilament-positive HCM showed greater probability of severe left ventricular systolic and diastolic dysfunction, defined as an ejection fraction of less than 50% and a restrictive filling pattern (P=.02 and P<.02, respectively, vs myofilament-negative HCM). CONCLUSION Screening for sarcomere protein gene mutations in HCM identifies a broad subgroup of patients with increased propensity toward long-term impairment of left ventricular function and adverse outcome, irrespective of the myofilament (thick, intermediate, or thin) involved.

Hypertrophic cardiomyopathy in Tuscany : clinical course and outcome in an unselected regional population

OBJECTIVES Our aim was to study a population of patients with hypertrophic cardiomyopathy from the well defined geographic region of Tuscany in central Italy, a group virtually free of selective referral bias and therefore probably closely representative of the true patient population with this disease. BACKGROUND Most available information on clinical course, natural history and prognosis of hypertrophic cardiomyopathy is based on data generated from tertiary referral centers and therefore constitutes a potentially biased perspective of the disease process in this complex and diverse condition. METHODS The study group comprised 202 patients aged 1 to 74 years (mean +/- SD 41 +/- 17) at initial diagnosis and followed up for 1 to 30 years (mean 10 +/- 5). RESULTS Largely with the use of single or multiple drug therapy, the vast majority of patients (n = 154 [76%]) were asymptomatic or mildly symptomatic and in stable or improved condition over the period of follow-up, whereas the remaining patients (n = 48 [24%]) experienced deterioration, had substantial functional impairment or died. Of the 13 patients (6%) who died of cardiovascular causes related to hypertrophic cardiomyopathy, 11 had progressive congestive heart failure (including 6 in the end-stage phase) and only 2 died suddenly. The annual mortality rate for cardiovascular disease was 0.6% and that due to sudden cardiac death was only 0.1%; the cumulative survival rate was 97%, 95% and 92%, respectively, at 5, 10 and 15 years of follow-up. Atrial fibrillation proved to be a relatively common (n = 57 [28%]) and particularly unfavorable clinical feature, with premature death occurring in 9 of the 57 patients. The cumulative survival rate after 15 years was 76% for patients with atrial fibrillation versus 97% for patients with sinus rhythm. Syncope occurred in 33 patients (16%) but did not appear to be of prognostic significance. CONCLUSIONS In an unselected regional population, hypertrophic cardiomyopathy had a relatively benign prognosis inconsistent with its prior characterization as a generally progressive disorder, based primarily on the experience of selected referral institutions. Sudden unexpected cardiac death was distinctly uncommon, although a sizable proportion of patients (particularly the subset prone to atrial fibrillation), did experience clinical deterioration.

Clinical profile of stroke in 900 patients with hypertrophic cardiomyopathy

OBJECTIVES We sought to assess the occurrence and clinical significance of stroke and peripheral arterial embolizations at non-central nervous system sites in a large, community-based cohort with hypertrophic cardiomyopathy (HCM). BACKGROUND Such vascular events are insufficiently appreciated complications of HCM for which there is limited information on occurrence, clinical profile and determinants. METHODS We assessed the clinical features of patients with stroke and other peripheral vascular events in a consecutive group of patients with HCM from four regional cohorts not subject to significant tertiary referral bias. RESULTS Of the 900 patients, 51 (6%) patients experienced stroke or other vascular events over 7 +/- 7 years, including 44 patients with stroke; 21 (41%) of these 51 patients died or were permanently disabled. The overall incidence was 0.8%/year and 1.9% for patients >60 years old. Age at first event ranged from 29 to 86 years (mean 61 +/- 14 years). Most (n = 37; 72%) events occurred in those >50 years, although 14 (28%) younger patients (< or = 50 years) also had events. Multivariate analysis showed stroke and other peripheral vascular events to be independently associated with congestive symptoms and advanced age, as well as with atrial fibrillation (in 45 [88%] of 51 patients), at the initial evaluation. The cumulative incidence of these events among patients with atrial fibrillation was significantly higher in non-anticoagulated patients as compared with patients receiving warfarin (31% vs. 18%; p < 0.05). CONCLUSIONS Stroke and peripheral embolizations showed a 6% prevalence rate and an incidence of 0.8%/year in a large, unselected HCM group. These profound complications of HCM, which may lead to disability and death, were substantially more common in the elderly, occurred almost exclusively in patients with paroxysmal or chronic atrial fibrillation and appeared to be reduced in frequency by anticoagulation.

Clinical Features and Outcome of Hypertrophic Cardiomyopathy Associated With Triple Sarcomere Protein Gene Mutations

OBJECTIVES The aim of this study was to describe the clinical profile associated with triple sarcomere gene mutations in a large hypertrophic cardiomyopathy (HCM) cohort. BACKGROUND In patients with HCM, double or compound sarcomere gene mutation heterozygosity might be associated with earlier disease onset and more severe outcome. The occurrence of triple mutations has not been reported. METHODS A total of 488 unrelated index HCM patients underwent screening for myofilament gene mutations by direct deoxyribonucleic acid sequencing of 8 genes, including myosin binding protein C (MYBPC3), beta-myosin heavy chain (MYH7), regulatory and essential light chains (MYL2, MYL3), troponin-T (TNNT2), troponin-I (TNNI3), alpha-tropomyosin (TPM1), and actin (ACTC). RESULTS Of the 488 index patients, 4 (0.8%) harbored triple mutations, as follows: MYH7-R869H, MYBPC3-E258K, and TNNI3-A86fs in a 32-year-old woman; MYH7-R723C, MYH7-E1455X, and MYBPC3-E165D in a 46-year old man; MYH7-R869H, MYBPC3-K1065fs, and MYBPC3-P371R in a 45-year old woman; and MYH7-R1079Q, MYBPC3-Q969X, and MYBPC3-R668H in a 50-year old woman. One had a history of resuscitated cardiac arrest, and 3 had significant risk factors for sudden cardiac death, prompting the insertion of an implantable cardioverter-defibrillator in all, with appropriate shocks in 2 patients. Moreover, 3 of 4 patients had a severe phenotype with progression to end-stage HCM by the fourth decade, requiring cardiac transplantation (n=1) or biventricular pacing (n=2). The fourth patient, however, had clinically mild disease. CONCLUSIONS Hypertrophic cardiomyopathy caused by triple sarcomere gene mutations was rare but conferred a remarkably increased risk of end-stage progression and ventricular arrhythmias, supporting an association between multiple sarcomere defects and adverse outcome. Comprehensive genetic testing might provide important insights to risk stratification and potentially indicate the need for differential surveillance strategies based on genotype.

PROGNOSTIC VALUE OF SYSTEMIC BLOOD PRESSURE RESPONSE DURING EXERCISE IN A COMMUNITY-BASED PATIENT POPULATION WITH HYPERTROPHIC CARDIOMYOPATHY

OBJECTIVES The present study was designed to prospectively evaluate the prognostic relevance of abnormal blood pressure response to exercise (ABPR), defined as hypotension or failed blood pressure increase (<20 mm Hg) with exercise, in a community-based hypertrophic cardiomyopathy (HCM) population representative of the overall disease spectrum. BACKGROUND Abnormal blood pressure response to exercise has been proposed as a marker for hemodynamic instability and increased risk for disease-related mortality in highly selected patient populations with HCM. METHODS The study population comprised 126 patients (aged 42+/-14 years) who underwent maximal symptom-limited cycloergometer exercise testing as part of the standard evaluation at our institution, and who were followed systematically for 4.7+/-3.7 years after testing. RESULTS Of the 126 study patients, 98 (78%) had a normal blood pressure response during exercise, whereas the other 28 (22%) had ABPR, including nine with hypotension and 19 with failed blood pressure rise. During the follow-up period, nine patients (7%) died of HCM-related causes (three suddenly and six heart failure-related), of whom four had ABPR. In those patients aged < or =50 years, survival analysis after exercise testing showed a significantly increased risk for cardiovascular mortality associated with ABPR compared with a normal exercise response (p = 0.04), with an odds ratio of 4.5 (95% confidence interval: 1.1, 20.1). However, ABPR showed low positive predictive accuracy for cardiovascular mortality (i.e., 14%), whereas negative predictive accuracy was high (i.e., 95%). CONCLUSIONS A hypotensive blood pressure response during exercise occurred in over 20% of a community-based patient cohort with HCM, and was associated with adverse long-term prognosis in patients <50 years old. However, the positive predictive accuracy of this blood pressure response is too low to justify modifications of clinical management or to allow identification of the high-risk patient based solely on an abnormal test result. By virtue of its high negative predictive accuracy for HCM-related mortality, the blood pressure response to exercise appears to be most valuable (in conjunction with the absence of other well recognized risk factors) as a screening test for the identification of low-risk subsets of patients.

Assessment and Significance of Left Ventricular Mass by Cardiovascular Magnetic Resonance in Hypertrophic Cardiomyopathy

OBJECTIVES Our aim was to assess the distribution and clinical significance of left ventricular (LV) mass in patients with hypertrophic cardiomyopathy (HCM). BACKGROUND Hypertrophic cardiomyopathy is defined echocardiographically by unexplained left ventricular wall thickening. Left ventricular mass, quantifiable by modern cardiovascular magnetic resonance techniques, has not been systematically assessed in this disease. METHODS In 264 HCM patients (age 43 +/- 18 years; 75% men), LV mass by cardiovascular magnetic resonance was measured, indexed by body surface area, and compared with that in 606 healthy control subjects. RESULTS The LV mass index in HCM patients significantly exceeded that of control subjects (104 +/- 40 g/m(2) vs. 61 +/- 10 g/m(2) in men and 89 +/- 33 g/m(2) vs. 47 +/- 7 g/m(2) in women; both p < 0.0001). However, values were within the normal range (< or = mean +2 SDs for control subjects) in 56 patients (21%), and only mildly increased (mean +2 to 3 SDs) in 18 (16%). The LV mass index showed a modest relationship to maximal LV thickness (r(2) = 0.38; p < 0.001), and was greater in men (104 +/- 40 g/m(2) vs. 89 +/- 33 g/m(2) in women; p < 0.001) and in patients with resting outflow obstruction (121 +/- 43 g/m(2) vs. 96 +/- 37 g/m(2) in nonobstructives; p < 0.001). During a 2.6 +/- 0.7-year follow-up, markedly increased LV mass index proved more sensitive in predicting outcome (100%, with 39% specificity), whereas maximal wall thickness >30 mm was more specific (90%, with 41% sensitivity). CONCLUSIONS In distinction to prior perceptions, LV mass index was normal in about 20% of patients with definite HCM phenotype. Therefore, increased LV mass is not a requirement for establishing the clinical diagnosis of HCM. The LV mass correlated weakly with maximal wall thickness, and proved more sensitive in predicting outcome.