ß Blockers for prevention of exercise-induced left ventricular outflow tract obstruction in patients with hypertrophic cardiomyopathy.

Whether treatment with ß blockers (BBs) is of benefit to patients with hypertrophic cardiomyopathy (HC) and provocable outflow obstruction (with none or with only mild heart failure symptoms) is largely unresolved. Thus, we prospectively studied 27 patients with HC (age 36 ± 15 years; 81% men) with New York Heart Association class I or II, without obstruction at rest, but with exercise-induced left ventricular outflow tract (LVOT) gradient of ≥ 30 mm Hg. Patients underwent exercise echocardiography at baseline and after treatment with nadolol (n = 18; 40 to 80 mg/day) or bisoprolol (n = 9; 5 to 10 mg/day), according to a prespecified protocol. Without the BBs, the postexercise LVOT gradient was 87 ± 29 mm Hg and >50 mm Hg in 25 patients (93%). After a 12 ± 4-month period of BB treatment, the postexercise LVOT gradient had decreased to 36 ± 22 mm Hg (p <0.001) and was virtually abolished (to 0 or <30 mm Hg) in 14 patients (52%), substantially blunted (≥ 20 mm Hg reduction) in 9 (33%), and unchanged in only 4 (15%). Severe postexercise obstruction (range 58 to 80 mm Hg) persisted in 6 patients (22% compared to 93% without BBs; p <0.001). Nonresponders (residual postexercise gradient of ≥ 30 mm Hg with BBs) were characterized by an increased body mass index (hazard ratio 2.03/1 kg/m(2), 95% confidence interval 1.2 to 3.4; p <0.05). In conclusion, in patients with HC with mild or no symptoms, treatment with BBs can prevent the development of LVOT obstruction triggered by physiologic exercise. These findings provide a rationale for the novel strategy of early prophylactic pharmacologic treatment with standard, well-tolerated doses of BBs in physically active patients with provocable gradients, aimed at effective prevention of the hemodynamic burden associated with dynamic obstruction.

Methodological approach for the assessment of ultrasound reproducibility of cardiac structure and function: a proposal of the study group of Echocardiography of the Italian Society of Cardiology (Ultra Cardia SIC) part I.

When applying echo-Doppler imaging for either clinical or research purposes it is very important to select the most adequate modality/technology and choose the most reliable and reproducible measurements. Quality control is a mainstay to reduce variability among institutions and operators and must be obtained by using appropriate procedures for data acquisition, storage and interpretation of echo-Doppler data. This goal can be achieved by employing an echo core laboratory (ECL), with the responsibility for standardizing image acquisition processes (performed at the peripheral echo-labs) and analysis (by monitoring and optimizing the internal intra- and inter-reader variability of measurements). Accordingly, the Working Group of Echocardiography of the Italian Society of Cardiology decided to design standardized procedures for imaging acquisition in peripheral laboratories and reading procedures and to propose a methodological approach to assess the reproducibility of echo-Doppler parameters of cardiac structure and function by using both standard and advanced technologies. A number of cardiologists experienced in cardiac ultrasound was involved to set up an ECL available for future studies involving complex imaging or including echo-Doppler measures as primary or secondary efficacy or safety end-points. The present manuscript describes the methodology of the procedures (imaging acquisition and measurement reading) and provides the documentation of the work done so far to test the reproducibility of the different echo-Doppler modalities (standard and advanced). These procedures can be suggested for utilization also in non referall echocardiographic laboratories as an "inside" quality check, with the aim at optimizing clinical consistency of echo-Doppler data.

Microvascular function is selectively impaired in patients with hypertrophic cardiomyopathy and sarcomere myofilament gene mutations.

OBJECTIVES: The purpose of this study was to assess myocardial blood flow (MBF) using positron emission tomography in patients with hypertrophic cardiomyopathy (HCM) according to genetic status. BACKGROUND: Coronary microvascular dysfunction is an important feature of HCM, associated with ventricular remodeling and heart failure. We recently demonstrated the increased prevalence of systolic dysfunction in patients with HCM with sarcomere myofilament gene mutations and postulated an association between genetic status and coronary microvascular dysfunction. METHODS: Maximum MBF (intravenous dipyridamole, 0.56 mg/kg; Dip-MBF) was measured using (13)N-labeled ammonia in 61 patients with HCM (age 38 ± 14 years), genotyped by automatic DNA sequencing of 8 myofilament-encoding genes (myosin-binding protein C, beta-myosin heavy chain, regulatory and essential light chains, troponin T, troponin I, troponin C, alpha-tropomyosin, and alpha-actin). In 35 patients, cardiac magnetic resonance imaging was performed. RESULTS: Fifty-three mutations were identified in 42 of the 61 patients (genotype positive; 69%). Despite similar clinical profiles, genotype-positive patients with HCM showed substantially lower Dip-MBF compared with that of genotype-negative patients (1.7 ± 0.6 ml/min/g vs. 2.4 ± 1.2 ml/min/g; p < 0.02). A Dip-MBF <1.5 ml/min/g had 81% positive predictive value for genotype-positive status and implied a 3.5-fold independent increase in likelihood of carrying myofilament gene mutations (hazard ratio: 3.52; 95% confidence interval: 1.05 to 11.7; p = 0.04). At cardiac magnetic resonance imaging, the prevalence of late gadolinium enhancement was greater in genotype-positive patients (22 of 23 [96%] compared with 8 of 12 [67%] genotype-negative patients; p = 0.038). CONCLUSIONS: Patients with HCM with sarcomere myofilament mutations are characterized by more severe impairment of microvascular function and increased prevalence of myocardial fibrosis, compared with genotype-negative individuals. These findings suggest a direct link between sarcomere gene mutations and adverse remodeling of the microcirculation in HCM, accounting for the increased long-term prevalence of ventricular dysfunction and heart failure in genotype-positive patients.

Distal extremity pain as a presenting feature of Fabry's disease.

OBJECTIVE: Fabry's disease (FD) is an X-linked lysosomal storage disease. Distal extremity pain can be an early finding and renal, cardiac, and cerebrovascular complications may lead to complications and mortality. Treatment is now available for these patients, who may not be diagnosed correctly for years if the neuropathic nature of the pain is not recognized. The aim of our study was to describe early clinical features in a cohort of patients with FD and to emphasize the importance of distal extremity pain for early diagnosis. METHODS: The medical charts of 35 patients with FD followed in a single center were reviewed. When data were incomplete, a detailed pain questionnaire was sent to patients. Nonresponders were contacted by telephone. RESULTS: Distal extremity pain was present in the majority of cases (25 of 35). The mean age at diagnosis of FD was 43.5 years (range 5-77 years). Distal extremity pain was more prevalent in males than females and occurred mostly in childhood or adolescence. When present at onset, the disease progressed with subsequent organ system involvement. Misdiagnoses were frequent and included growing pains, juvenile idiopathic arthritis, connective tissue disease, and gout. CONCLUSION: Clinical manifestations of FD, including episodes of severe pain in the feet and hands, often start in childhood. Distal extremity pain may be the only symptom for a considerable period of time. Patients may be wrongly labeled as having rheumatologic conditions, resulting in long diagnostic and therapeutic delays. Rheumatologists should be aware of the clinical aspects of FD and include it in the differential diagnosis of distal extremity pain in childhood and adolescence.

Timing and significance of exercise-induced left ventricular outflow tract pressure gradients in hypertrophic cardiomyopathy.

The relation of exercise-induced left ventricular (LV) outflow tract obstruction to functional capacity in hypertrophic cardiomyopathy (HC) is incompletely defined. Thus, we assessed the patterns of onset of physiologically provoked LV outflow gradients and exercise performance in 74 consecutive patients with HC (age 45 ± 16 years; 74% men) without LV outflow obstruction at rest. The subaortic gradients were measured serially using echocardiography in these 74 patients during maximum, symptom-limited, upright bicycle exercise testing. The time course of the provoked gradients and the relation to exercise performance were assessed. Of the 74 patients, 30 (41%) developed a dynamic LV outflow gradient of ≥30 mm Hg (mean 78 ± 37 mm Hg) during upright exercise testing that correlated highly with the gradients measured with the patients supine during the immediate recovery period (R² = 0.97). The 16 patients in whom outflow obstruction developed rapidly at low exercise levels (≤5 METs) had a significantly reduced exercise capacity (6.1 ± 1.3 vs 8.0 ± 1.6 METs; p <0.01) compared to the other 14 patients in whom obstruction appeared later at greater exercise levels of >5 METs. The timing of the gradient onset was not predictable from the baseline clinical and echocardiographic features, peak exercise LV outflow tract gradient, or symptoms. In conclusion, in patients with HC without outflow obstruction at rest, the earlier onset of LV outflow tract gradients during physiologic exercise was associated with impaired exercise performance. These findings have provided insights into the determinants of functional impairment in HC and support the potential value of exercise echocardiography in the clinical assessment of patients with HC.

[Clinical and genetic features of left ventricular noncompaction: a continuum in cardiomyopathies]. / Clinica e genetica del ventricolo sinistro non compatto: conferma di un continuum nelle cardiomiopatie.

Isolated left ventricular non-compaction (LVNC) is a rare genetic form of cardiomyopathy (CM) characterized by prominent left ventricular wall trabeculation and intertrabecular recesses communicating with the ventricular cavity. Clinical signs are variable, ranging from lack of symptoms to severe manifestations including heart failure, sustained ventricular arrhythmias, cardioembolism and sudden death. The diagnosis of LVNC is frequently missed, due to limited awareness in the medical community. Contemporary diagnostic sensitivity has been enhanced by the introduction of specific morphologic criteria by high resolution echocardiography and cardiac magnetic resonance. As a consequence, LVNC has been diagnosed more frequently in association with other disorders such as congenital heart disease or genetic CM. The clinical relevance of regional non-compaction in the context of other cardiac diseases is still uncertain. Recent evidence points to an overlapping genetic background encompassing LVNC, hypertrophic and dilated CM, suggesting a continuum of disease associated with sarcomere protein gene mutations. This concept may prove relevant to the understanding of common pathogenetic mechanisms of CM and offer novel research opportunities.

Prevalence and clinical significance of acquired left coronary artery fistulas after surgical myectomy in patients with hypertrophic cardiomyopathy.

OBJECTIVES: The relevance of iatrogenic left coronary artery fistulas complicating surgical myectomy in patients with hypertrophic cardiomyopathy is not known. We prospectively defined the echocardiographic features, prevalence, and clinical significance of left coronary artery fistulas in 40 consecutive patients with hypertrophic cardiomyopathy undergoing extended septal myectomy. METHODS: Echocardiographic analysis was performed preoperatively and 1 and 6 months after surgical intervention. Diagnosis of left coronary artery fistulas required evidence of diastolic flow draining from the left ventricular wall into the left ventricular cavity according to prespecified criteria. RESULTS: Left coronary artery fistulas were detected in 9 (23%) of the 40 study patients as a single occurrence in all except 1 patient, who had multiple fistulas. At 6 months, left coronary artery fistulas could still be detected in only 2 of the 9 patients. Of these, 1 patient remained asymptomatic but continued to show left coronary artery fistula persistence at 37 months postoperatively. The other, a woman with prior alcohol septal ablation, had progressive severe symptoms that required percutaneous closure of the fistula with a covered stent after angiographic identification of a large first septal branch fistula associated with distal left anterior descending coronary artery steal. CONCLUSIONS: In patients with hypertrophic cardiomyopathy, left coronary artery fistulas are common in the early period after surgical myectomy, although their echocardiographic prevalence is dependent on operator awareness. Most left coronary artery fistulas heal spontaneously. Occasionally, however, fistulas can persist and cause symptoms requiring therapeutic intervention.

[Atrial fibrillation in hypertrophic cardiomyopathy: determinants, clinical course and management].

Atrial fibrillation (AF) is the most common sustained arrhythmia in patients with hypertrophic cardiomyopathy (HCM), and represents an important complication in the clinical course of the disease, with adverse consequences on functional status and outcome. Studies on community-based HCM patient populations have shown that AF is associated with long-term clinical deterioration, cardioembolic stroke and increased cardiovascular mortality due to heart failure and stroke. Moreover, acute onset of AF may cause severe hemodynamic impairment and represent a trigger of potentially lethal ventricular arrhythmias. However, the consequences of AF on the long-term prognosis of HCM patients are not uniformly unfavorable, and may be compatible with an uneventful course, when properly managed. Management of AF in HCM is challenging, particularly when onset occurs at a young age. Both paroxysmal and permanent AF represent clear indications for oral anticoagulation. In most patients, maintenance of sinus rhythm is highly desirable but made difficult by the limited long-term efficacy and potentially hazardous side effects of available pharmacological options. In selected patients with HCM and severely symptomatic AF, radiofrequency catheter ablation may represent an effective therapeutic alternative, improving functional status, and reducing or postponing the need for antiarrhythmic drugs. In patients with persistent AF, in whom maintenance of sinus rhythm is not feasible, adequate ventricular rate control should be pursued aggressively by atrio-ventricular node blocking agents.

Microvascular dysfunction, myocardial ischemia, and progression to heart failure in patients with hypertrophic cardiomyopathy.

Microvascular dysfunction can be demonstrated in most patients with hypertrophic cardiomyopathy (HCM), both in the hypertrophied and nonhypertrophied myocardial walls, mostly due to intimal and medial hyperplasia of the intramural coronary arteries and subsequent lumen reduction. As a consequence, regional myocardial ischemia may be triggered by exercise, increased heart rate, or arrhythmias, in areas which are unable to increase myocardial blood flow. In patients with HCM, microvascular dysfunction leading to severe myocardial hypoperfusion during maximal hyperemia represents a strong predictor of unfavorable outcome, left ventricular remodeling with progressive wall thinning, left ventricular dysfunction, and heart failure. Accurate quantitative assessment of microvascular dysfunction and myocardial ischemia is not easily feasible in clinical practice. Although signs of inducible myocardial ischemia may be detected by electrocardiogram, echocardiography, or myocardial scintigraphy, the vasodilator response to dipyridamole by positron emission tomography is considered the method of choice for the assessment of maximal regional and global flow. Cardiac magnetic resonance provides further information, by late gadolinium enhancement (LGE), which may show areas where replacement fibrosis has occurred following microvascular ischemia and focal necrosis. LGE areas colocalize with severe regional microvascular dysfunction, are associated with increased prevalence of ventricular arrhythmias, and show more extensive distribution in the late stages of the disease, when heart failure is the dominant feature. The present review aims to provide a concise overview of the available evidence of microvascular dysfunction and ischemia eventually leading to disease progression and heart failure in HCM patients.