Pathophysiology and Treatment of Hypertrophic Cardiomyopathy: New Perspectives.

PURPOSE OF REVIEW: We provide a state of the art of therapeutic options in hypertrophic cardiomyopathy (HCM), focusing on recent advances in our understanding of the pathophysiology of sarcomeric disease. RECENT FINDINGS: A wealth of novel information regarding the molecular mechanisms associated with the clinical phenotype and natural history of HCM have been developed over the last two decades. Such advances have only recently led to a number of controlled randomized studies, often limited in size and fortune. Recently, however, the allosteric inhibitors of cardiac myosin adenosine triphosphatase, countering the main pathophysiological abnormality associated with HCM-causing mutations, i.e. hypercontractility, have opened new management perspectives. Mavacamten is the first drug specifically developed for HCM used in a successful phase 3 trial, with the promise to reach symptomatic obstructive patients in the near future. In addition, the fine characterization of cardiomyocyte electrophysiological remodelling has recently highlighted relevant therapeutic targets. Current therapies for HCM focus on late disease manifestations without addressing the intrinsic pathological mechanisms. However, novel evidence-based approaches have opened the way for agents targeting HCM molecular substrates. The impact of these targeted interventions will hopefully alter the natural history of the disease in the near future.

Comparison of long-term outcome in anthracycline-related versus idiopathic dilated cardiomyopathy: a single centre experience.

AIMS: Cardiac dysfunction is a severe complication of anthracycline-containing anticancer therapy. The outcome of anthracycline-induced cardiomyopathy (AICM) compared with other non-ischaemic causes of heart failure (HF), such as idiopathic dilated cardiomyopathy (IDCM), is unresolved. The aim of this study was to compare the survival of AICM patients with an IDCM cohort followed at our centre from 1990 to 2016. METHODS AND RESULTS: We included 67 patients (67% female, 50 ± 15 years) with AICM, defined as onset of otherwise unexplained left ventricular ejection fraction (LVEF) ≤50% following anthracycline therapy, and 488 IDCM patients (28% female, 55 ± 12 years). Patients were followed with constantly optimized HF therapy, for 7.6 ± 5.5 and 8.1 ± 5.5 years, respectively. In both cohorts, 25% of patients reached the combined endpoint of death/heart transplantation. Overall survival rates at 5 and 10 years were similar (AICM: 86% and 61%, IDCM: 88% and 75%; P = 0.61), and so was cardiovascular survival (AICM: 91% and 76%, IDCM: 91% and 80%; P = 0.373), also after 1:1 propensity matching (P = 0.27) and adjusting for age, LVEF and left ventricular size. A trend toward higher all-cause mortality was present in AICM patients [hazard ratio (HR) 1.67, 95% confidence interval (CI) 0.95-2.92, P = 0.076]. No differences were observed between AICM and IDCM with regard to pharmacological HF therapy, but AICM patients were less likely to receive devices (13% vs. 41.8% in IDCM, P < 0.001). CONCLUSION: Cardiovascular mortality in patients with AICM did not differ from that of a matched IDCM cohort, despite cancer-related morbidity and less prevalent use of devices. These data suggest that patients with AICM should be treated with appropriate guideline-directed medical therapies similar to other non-ischaemic dilated cardiomyopathies.

Coronary microvascular dysfunction is an early feature of cardiac involvement in patients with Anderson-Fabry disease.

AIMS: Male patients with Anderson-Fabry disease (AFD) often exhibit cardiac involvement, characterized by LV hypertrophy (LVH), associated with severe coronary microvascular dysfunction (CMD). Whether CMD is present in patients without LVH, particularly when female, remains unresolved. The aim of the study was to investigate the presence of CMD by positron emission tomography (PET) in AFD patients of both genders, with and without evidence of LVH. METHODS AND RESULTS: We assessed myocardial blood flow following dipyridamole infusion (Dip-MBF) with 13N-labelled ammonia by PET in 30 AFD patients (age 51 ± 13 years; 18 females) and in 24 healthy controls. LVH was defined as echocardiographic maximal LV wall thickness ≥13 mm. LVH was present in 67% of patients (n = 20; 10 males and 10 females). Dip-MBF was reduced in all patients compared with controls (1.8 ± 0.5 and 3.2 ± 0.5 mL/min/g, respectively, P < 0.001). For both genders, flow impairment was most severe in patients with LVH (1.4 ± 0.5 mL/min/g in males and 1.9 ± 0.5 mL/min/g in females), but was also evident in those without LVH (1.8 ± 0.3 mL/min/g in males and 2.1 ± 0.4 mL/min/g in females; overall P = 0.064 vs. patients with LVH). Analysis of variance (ANOVA) for the 17 LV segments showed marked regional heterogeneity of MBF in AFD (F = 4.46, P < 0.01), with prevalent hypoperfusion of the apical region. Conversely, controls showed homogeneous LV perfusion (F = 1.25, P = 0.23). CONCLUSIONS: Coronary microvascular function is markedly impaired in AFD patients irrespective of LVH and gender. CMD may represent the only sign of cardiac involvement in AFD patients, with potentially important implications for clinical management.

[New evidences on the use of aldosterone receptor antagonists in left ventricular dysfunction: from myocardial infarction to heart failure]. / Nuove evidenze sull'impiego degli antialdosteronici nella disfunzione ventricolare sinistra: spironolattone ed eplerenone. Dal postinfarto allo scompenso cardiaco.

Heart failure and myocardial infarction result in considerable consumption of healthcare resources. Therefore, there is interest in the availability of drug therapies that can favorably modify their prognosis in the post-acute phase, reducing mortality and rehospitalization rates. Aldosterone antagonists represent a class of drugs which offer advantages in these settings, in addition to those obtained with beta-blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, even though attention should be drawn to their potential adverse effects. In particular, eplerenone exhibits a better safety profile than spironolactone. Since it has very little affinity for glucocorticoid, androgen and progesterone receptors, eplerenone has less antiandrogenic and progestagenic effects, resulting in a lower incidence of gynecomastia. The EPHESUS study showed that eplerenone can reduce mortality in the short and long term and the rate of new hospitalizations after a myocardial infarction complicated by heart failure. In addition, in the EMPHASIS-HF study eplerenone reduced cardiovascular mortality and hospitalizations after mild heart failure (NYHA class IIa). Despite these important results, which confirmed those obtained with spironolactone in severe heart failure in the RALES study, aldosterone antagonists are still underutilized. In particular, eplerenone is not yet available in Italy, although it is recommended by the latest European Society of Cardiology guidelines.

[Prevalence and subtypes of systemic hypertension in an unselected patient population with severe obesity undergoing bariatric surgery]. / Prevalenza e tipologie di ipertensione arteriosa in una popolazione di pazienti non selezionati affetti da obesità morbigena in previsione di intervento di chirurgia bariatrica.

BACKGROUND: Obesity plays a pivotal role in the development of systemic hypertension and the two diseases are often related. Severe obesity is getting more and more prevalent in our country. The aim of this study was to evaluate the prevalence of systemic hypertension in an unselected population of obese patients observed in the Regional Referral Center for Surgical Obesity of our hospital. METHODS: 233 consecutive patients (52 male, 181 female, mean age 42 years, mean weight 120 kg, mean body mass index [BMI] 43.7 kg/m2) were screened in order to plan a surgical procedure for severe obesity. Each patient underwent cardiovascular clinical evaluation, ECG and echocardiographic examination, blood pressure ambulatory monitoring, and 24h Holter monitoring. RESULTS: Thirty-five percent of patients were under drug treatment for hypertension or were at least aware of being hypertensive; among the remaining 65% of patients who declared having normal blood pressure, 33% suffered from systemic hypertension, 11% had isolated clinical hypertension, and 14% had masked hypertension. Thus, the global prevalence of systemic hypertension in this population raised to 72.5%. ECG and echocardiographic findings were normal in about 90% of the whole population, whereas 24h Holter monitoring showed minor or major abnormalities in approximately 25% of patients. At a follow-up of at least 18 months, a subgroup of 48 patients showed a decrease in body weight from 129 to 92 kg, BMI from 47 to 33 kg/m 2, blood pressure from 134.4/86.4 to 127.7/81.1 mmHg, and heart rate from 79.7 to 69.4 bpm. CONCLUSIONS: The prevalence of systemic hypertension in an unselected population of severely obese patients is much higher than in the general population. The surgical procedures performed in the Regional Referral Center for Surgical Obesity of our hospital were virtually free from serious adverse events and proved to be effective in reducing not only body weight and BMI but also blood pressure. We believe that ambulatory blood pressure and 24h Holter monitoring are the most relevant examinations to be performed in these patients in the preoperative period.

Rotational mechanics of the left ventricle in AL amyloidosis.

AIMS: The aim of this study was to investigate whether alterations in left ventricular (LV) twisting and untwisting motion could be induced by cardiac involvement in patients with immunoglobulin light-chain (AL) systemic amyloidosis. METHODS AND RESULTS: Forty-five patients with AL amyloidosis and 26 control subjects were evaluated. After standard echocardiographic measurement and two-dimensional (2D) speckle tracking echocardiography, LV rotation at both basal and apical planes, twisting, twisting rate, and longitudinal strain were measured. Tissue Doppler imaging (TDI) derived early diastolic peak velocity at septal mitral annulus (E') was also evaluated. Twenty-six of 45 patients with systemic amyloidosis were classified as having cardiac amyloidosis (CA) if the mean value of the LV wall thickness was ≥ 12 mm or not (NCA) if this value was not reached. In NCA patients, both LV twist and untwisting rate were increased while they were decreased in CA patients making them similar to the control group. Longitudinal strain was reduced only in CA patients. Impaired relaxation as indicated by E' values was progressively reduced in the course of the disease. CONCLUSIONS: Both twisting and untwisting motions are increased in patients with AL systemic amyloidosis with no evidence of cardiac involvement while they are reduced in patients with evident amyloidosis cardiac involvement. This finding suggests that impaired LV relaxation induces a compensatory mechanism in the early phase of the disease, which fails in more advanced stage when both twisting and untwisting rates are reduced. The increase in LV rotational mechanics could be a marker of subclinical cardiac involvement.

The role of N-terminal PRO-brain natriuretic peptide and echocardiography for screening asymptomatic left ventricular dysfunction in a population at high risk for heart failure. The PROBE-HF study.

BACKGROUND: Screening for asymptomatic left ventricular dysfunction (ALVD) in subjects at risk for heart failure (HF) can affect clinical management. The aim of the present study is to examine the role of NT-pro BNP in the diagnosis of ALVD in subjects with hypertension and diabetes from primary care. METHODS AND RESULTS: A total of 1012 subjects with hypertension and/or diabetes and no symptoms or signs of HF were assessed by B-type natriuretic peptide (NT-proBNP) assay and echocardiography. Diastolic dysfunction was present in 368/1012 subjects (36.4%): 327 (32.4%) with mild diastolic dysfunction and 41 (4%) with a moderate-to-severe diastolic dysfunction. Systolic dysfunction was present in 11/1012 (1.1%). NT-proBNP levels were 170 +/- 206 and 859 +/- 661 pg/mL, respectively, in diastolic and systolic dysfunction and 92 +/- 169 in normal subjects (P < .0001). Pooling moderate-to-severe diastolic with systolic dysfunction, a total of 52 subjects (5.1 %) were obtained: best cutoff value of NT-proBNP was 125 pg/mL (males <67 years: sensitivity [Sens] 87.5%, specificity [Spec] 92.7%, negative predictive value [NPV] 99.5%, positive predictive value [PPV] 33.3%; females <67 years: Sens 100%, Spec 84.1%, NPV 100%, PPV 33.3%; males >or=67 years: Sens 100%, Spec 77.1%, NPV 100%, PPV 32.5%; females >or=67 years: Sens 100%, Spec 59.9%, NPV 100%, PPV 23%). CONCLUSIONS: The prevalence of ALVD in subjects at risk for HF is 5.1%. Because of its excellent NPV, NT-proBNP can be used by general practitioners to rule out ALVD in hypertensive or diabetic patients.

Tissue Doppler and strain imaging: a new tool for early detection of cardiac amyloidosis.

Using traditional echocardiography, the diagnosis of cardiac amyloidosis (CA) is often only possible in advanced stage when recommended therapies may have adverse effects. The aim of our study was to evaluate whether additional information can be derived from Tissue and strain Doppler imaging (TDI and SDI). Forty patients with systemic amyloidosis and 24 healthy subjects underwent traditional, tissue and strain Doppler echocardiography. Patients were classified having CA if mean wall thickness (mT), was half of the sum septum and posterior wall thickness, was > or =12 mm. The following parameters were evaluated: peak early diastolic velocity (Em) as index of ventricular relaxation, mitral E-wave to Em ratio (E/Em) as index of left ventricular (LV) filling pressure and mean LV strain peak curves (mSt) as global long-axis contraction index. In non cardiac amyloidosis (NCA), both Em and mSt were lower than in age matched controls (p < 0.01, p < 0.05, respectively) and higher than in CA (p < 0.01 and p < 0.01, respectively). Both Em and mSt were related to mT (p < 0.001). A significant (p < 0.01) nonlinear relation was observed between plasma terminal of pro B-natriuretic peptide and mT, Em, E/Em and mSt. TDI and SDI are able to detect amyloid myocardial involvement in such an early stage that cannot be evidenced by using traditional echocardiography.

Therapeutic implications of contractile reserve elicited by dobutamine echocardiography in symptomatic, low-gradient aortic stenosis.

BACKGROUND: In patients with heart failure, poor ejection fraction and estimated severe aortic stenosis because of a reduced aortic valve area (AVA) and low gradients, dobutamine echocardiography (DE) was proposed to distinguish afterload mismatch from primary left ventricular dysfunction. In this setting the feasibility and safety of DE and the outcome following management based on DE results were investigated. METHODS: Forty-eight patients (mean age 73 +/- 9 years; 79% males; AVA 0.7 +/- 0.2 cm2; mean aortic gradient 22 +/- 6 mmHg; ejection fraction 0.28 +/- 0.07; NYHA functional class 2.9 +/- 0.8) underwent DE and were followed up for 24 +/- 21 months. Aortic valve replacement (AVR) was offered to patients with left ventricular contractile reserve (ejection fraction increase > or = 30% at peak DE) and fixed aortic stenosis (AVA increase < or = 0.25 cm2). RESULTS: DE elicited a left ventricular contractile reserve in 38 patients (79%). Among these, fixed aortic stenosis was present in 28 patients, among whom 19 underwent AVR and 9 declined surgery. The 20 patients without contractile reserve or with relative stenosis (AVA increase > 0.25 cm2) were not considered eligible for surgery. During follow-up, 23 cardiovascular deaths occurred: 2/19 among operated patients, 7/9 among patients who declined surgery and 14/20 among non-eligible patients. Patients with AVR showed a significantly more favorable outcome and improved functional status as compared to the other two groups (NYHA class 1.2 +/- 0.4 vs 2.7 +/- 0.6 at baseline; p < 0.001). Conversely, non-surgical management was the strongest independent predictor of an adverse outcome (relative risk 3.6, 95% confidence interval 1.8-7.3; p < 0.0001). CONCLUSIONS: In patients with heart failure and estimated severe aortic stenosis, DE could identify a subgroup with a left ventricular contractile reserve and fixed aortic stenosis who gained great benefit from AVR. The clinical outcome of patients who were not operated upon was unfavorable.

Familial amyloid polyneuropathy with genetic anticipation associated to a gly47glu transthyretin variant in an Italian kindred.

The most frequent localization of amyloid in transthyretin (TTR) mutations is in the peripheral nerve, causing familial amyloidpolyneuropathy (FAP). It is generally accompanied by involvement of other organs such as the myocardium and kidney. To date, over 70 TTR point mutations have been reported in literature, with different phenotypes depending on the location of the mutation in the TTR gene. This paper deals with a point mutation in exon 2 position 47 of the TTR gene, encoding the substitution of glycine with glutamate. The mutation was found in an Italian family with 5 patients over 3 generations. The phenotype was characterised by peripheral neuropathy and autonomic dysfunction, associated in some patients with cardiomyopathy and renal involvement. The symptoms were very severe and the patients did not survive long, thus suggesting the aggressive nature of the pathological process. Moreover, in the succeeding generations of this family, there was genetic anticipation in the age of onset of the disease.