Which test shows cardiomyopathy
Background: Hypertrophic cardiomyopathy (HCM) is the most common hereditary cardiac disease.
Method: The following overview article summarizes the current state of knowledge regarding diagnosis and therapy of HCM on the basis of a selective literature search (new, practice-relevant publications).
Result: Several hundred mutations are known on more than 27 genes, most of which code for sarcomere proteins. HCM can thus be understood as a "sarcomere disease". A microscopic characteristic is a disorganization of the myocytes ("fiber disarray"). Depending on the presence of an obstruction of the left ventricular outflow, the more frequent (about 70%) obstructive (HOCM) can be distinguished from the non-obstructive (HNCM) form; a provocation test is essential. The symptoms include dyspnoea, anginal discomfort, palpitations, dizziness and occasionally syncope. Sudden cardiac death is the most serious complication, especially in young and asymptomatic patients. Correct diagnosis and ICD care for patients at risk are therefore essential. The drug therapy of symptomatic HNCM can be understood as heart failure treatment with preserved systolic pump function (HFNEF). Outflow gradient and symptoms in HOCM can be addressed with beta blockers or verapamil. Surgical myectomy and percutaneous septal myocardial ablation are standard procedures for drug refractory patients.
Conclusion: Almost normal life expectancy and a high quality of life are realistic therapy goals for HCM sufferers today.
The incidence of hypertrophic cardiomyopathy (HCM) is estimated to be one case per 500–1,000 people in the population. The disease is characterized by a thickening of the left, sometimes right ventricular myocardium, for which no cause (e.g. arterial hypertension) can be held responsible (illustration 1gifppt). Depending on the presence of an obstruction of the left ventricular outflow, the (approximately 70 percent) obstructive (HOCM) form can be distinguished from the non-obstructive (HNCM) form. The extent and location of the wall thickening are highly variable. The interventricular septum is often affected (1), which led to the term “asymmetrical septal hypertrophy”. An American group of experts (2) suggested defining HCM genetically and not morphologically. The European cardiomyopathy working group (3) recommends a morphological classification.
Etiology and pathogenesis
The disease has an autosomal dominant mode of inheritance with variable penetrance. Several hundred mutations in more than 27 genes are currently known. Affected proteins are mainly the beta myosin heavy chain, myosin binding protein C and troponin T, which together are responsible for about 60 to 70 percent of HCM. In 50 percent of cases, HCM is familial, otherwise a new mutation is assumed (4).
Histologically, there is typically a “fiber disarray”, whereby the cardiomyocytes, thickened by up to 100 µm, are arranged in vertebrae and branched. It is believed that the contractility disorder associated with this cell disorder and interstitial fibrosis initiates the myocardial hypertrophy process as a compensation mechanism (5, 6). Often the mitral valve leaflets appear enlarged relative to the cavum of the left ventricle.
The pump function (ejection fraction, EF) in HCM usually remains normal for years. Fibrosis (Figure 2gifppt) and hypertrophy cause - often at the time of diagnosis - a disorder of the diastolic function (7). Depending on the left ventricular morphology, dynamic obstruction with the formation of an intracavitary systolic pressure gradient can occur (Figure 3gifppt). An exercise test is mandatory, as 50 percent of HOCM patients only show this obstruction under provocation. References that the HNCM considered the more common form must be considered outdated (8). If the blood flows at high speed through a narrowed left ventricular outflow tract at the beginning of the systole, the Venturi effect causes a negative pressure or tension on the mitral leaflet in the direction of the interventricular septum ("systolic anterior movement", SAM phenomenon). If the mitral leaflets are then caught by the blood flow, an apposition to the septum results (“drag effect”) (9), so that a mechanical outflow obstacle arises and the mitral valve becomes inadequate due to its deformation. The increased LV systolic pressure provides an additional stimulus for the progression of left ventricular hypertrophy (10).
Symptoms and medical history
The spectrum ranges from asymptomatic to severely disabled patients. Dyspnoea and anginal pain under exertion, dizziness, palpitations and occasionally syncope are common (11). The most dramatic symptomatology is sudden cardiac death, often in young and hitherto completely asymptomatic patients. Death occurs mainly during or after intense physical exertion and is explained by malignant arrhythmias. HCM is the most common cause of suddenly deceased athletes (12).
Physical examination findings
The HNCM is mostly silent in auscultation. Occasionally, a 4th heart sound may be heard due to the atrial stress. In HOCM, due to the dynamic obstruction with associated mitral regurgitation, a systolic can usually be auscultated. Valsalva experiment or short-acting preload lowerers (acute nitrates) can lead to an increase in obstruction or an increase in the intensity of the auscultation phenomenon. Attention should be paid to the stigmata of systemic diseases occasionally associated with HCM (e.g. Noonan syndrome, facial dysmorphism; Fabry disease, typical maculo-papular skin lesions).
In 75 to 95 percent of HCM patients, there are EKG changes in the sense of left ventricular hypertrophy (13). 25 percent of patients have a left anterior hemiblock or a left bundle branch block. The configuration of hypervoltage and deep isosceles T-waves in the HNCM or "pseudo-infarct Q-waves" in the HOCM is typical. Acute-angled negative T waves are characteristic of the apical form of HCM (14). Peripheral low voltage suggests storage disease or cardiac amyloidosis and should trigger a myocardial biopsy (15, 16). A normal ECG does not rule out the disease, but the severity of the disease is usually mild (17).
There is a wide range of morphological findings, from the isolated thickening of individual myocardial segments, only a few mm from the normal wall thickness of the LV (< 12="" mm)="" abweichend,="" bis="" hin="" zur="" diffusen="" und="" massiven="" hypertrophie="" und="" wandstärken="" bis="" 60="" mm.="" eine="" maximale="" wanddicke=""> 30 mm is a risk marker for sudden cardiac death (Figure 1) (18). Right ventricular involvement is rare. Attention should be paid to the presence of an obstruction of the left ventricular outflow tract, including the SAM phenomenon. A reliable quantification of the obstruction is possible with Doppler echocardiography via the increased systolic flow velocities in the left ventricular outflow tract or calculation of the pressure gradient. A provocation is mandatory and can be carried out pharmacologically, by Valsalva maneuvers or by exercise on an ergometer. Post-extrasystolic potentiation (Brockenbrough phenomenon, Figure 3) is also typical. A consensus paper (19) recommends dynamic stress ergometry. An increase in afterload (increase in blood pressure) or negative inotropic substances weaken the gradient, which explains a possible variability of the intraventricular pressure gradient. An enlargement of the left atrium, a flattening of the EF slope of the anterior mitral leaflet, and a decrease and lengthening of the rapid filling phase indicate diastolic ventricular dysfunction. In terms of differential diagnosis, cardiac storage disorders or hypertrophy of secondary origin should be considered.
Other imaging modalities
Maximum wall thicknesses and determination of the left ventricular muscle mass can also be determined using cardio-MRI and cardio-CT. Myocardial scar tissue can be recorded as late enhancement in cardiac MRI (Figure 2). A recently published study suggests a relationship between the extent of fibrosis and the risk of ventricular arrhythmias (20). A relationship between the disturbance of the microcirculation and the resulting scarring with a tendency to arrhythmias has been described (21).
In patients with HCM, the objective resilience should be checked using spiroergometry, as the subjective assessment of complaints is often misleading due to the limitation and adaptation that have often existed for many years. In addition, information is obtained about blood pressure behavior at rest and during exercise (risk stratification) (22).
A 48-hour Holter ECG registration for the detection of non-sustained ventricular tachycardias is mandatory as part of the risk stratification. The invasive electrophysiological examination has lost importance in the last few years. The authors only carry out this when a specific question is asked (for example, if there is a suspicion of an additional WPW syndrome) (23).
Invasive diagnostics are used to exclude / prove coexistent coronary sclerosis, to show the septal vascular supply before planned septal ablation and to demonstrate prognostically relevant muscle bridges. Myocardial biopsies can be useful to rule out storage diseases (amyloidoses). An invasive gradient determination is rarely required (insufficient echo window). The end-diastolic LV pressure is usually increased as an expression of the disturbed elasticity (Figure 4gifppt). In the case of a corresponding clinic (NYHA III), an invasive investigation should be carried out in the sense of a step diagnosis.
First-degree relatives should be screened for HCM. If genetic diagnosis is not possible, adolescents between the ages of 12 and 18 should be examined annually by echocardiography and after the age of 18 five years (19).
The therapeutic recommendations are usually based on observational studies or case series. Large randomized studies - due to the relatively low prevalence of this cardiological disease - are naturally not available. So far, only medium-term studies are available on symptomatic therapy using alcohol-induced myocardial ablation. Overall, the basic principles of the recommendations drawn up by an international commission of experts in 2003 are still valid (19). An adaptation of physical activity with endurance character in the aerobic area (avoidance of competitive, strength or competitive sports) is recommended; a general ban on sports does not appear to be justified. Additional noxious substances such as nicotine or alcohol should be avoided; the latter, in higher doses, can contribute to aggravation of the outflow tract obstruction and arrhythmias. The previous indication for endocarditis prophylaxis in HOCM has now been put into perspective (24).
Because of the risk of sudden cardiac death, the identification of high-risk HCM patients from the perspective of ICD care is a particular challenge. So far, five main risk factors have been identified (25). If the positive predictive value of the individual risk factors is relatively low, their combination increases the informative value considerably (e1).
- A positive family history of sudden cardiac death caused by HCM is found in around 25 percent of affected families (< 45. lebensjahr)=""> 45.>
- Documented non-sustained ventricular tachycardias (NSVT) are a sensitive marker of an increased risk of sudden cardiac death. Due to the high negative predictive value, the absence of NSVT is also diagnostically valuable (e2).
- Syncope at rest or under exertion is an important risk marker for all age groups.
- Hypotensive blood pressure regulation during exercise is defined as an increase in systolic blood pressure by less than 20 mmHg from the initial value. In addition, a progressive drop in blood pressure during exercise or a drop in systolic value by 20 mmHg after an initial increase (e3) is particularly evident in young patients (< 40 lebensjahre)="" als="" risikorelevant="" (22)=""> 40>
- Extreme left ventricular hypertrophy with wall thicknesses> 30 mm (Figure 1) is also risk-relevant. The highest rate of sudden cardiac death was seen in adolescents with such pronounced hypertrophy (e4).
Further risk factors that have only been examined in smaller patient populations are discussed in Table 1 (gifppt) named. More recent studies see pronounced fibrosis (cardio MRI) as another risk factor (20). Table 1 shows the algorithm we used to identify HCM patients at risk. Patients without one of the risk markers mentioned have a high probability of having a good prognosis. In patients with ≥ 2 risk markers of the first rank, the authors indicate the primary prophylactic ICD implantation. For patients with a first-rate risk marker, an individualized decision must be made. Second-tier risk factors can provide additional decision-making aids. Surviving cardiac arrest or documentation of persistent ventricular tachycardia are clear indications for ICD care (e5).
Due to a lack of data, it is unclear whether drug treatment is indicated in asymptomatic patients. On the basis of pathophysiological considerations, the authors recommend starting drug therapy with a beta-blocker. A risk evaluation should be carried out especially in this patient group. Of particular importance is the tight adjustment of any coexistent arterial hypertension (reduction of the myocardial growth stimulus) (e6).
Symptomatic patients with HNCM
Due to the ubiquitous presence of diastolic dysfunction, strict frequency control using beta-blockers or calcium antagonists of the verapamil type should be aimed for. Diuretics and ACE inhibitors / AT receptor antagonists can be used for signs of congestion and accompanying hypertension, whereby close monitoring should be carried out, since in individual cases the induction of an outflow tract obstruction was also detectable in patients initially listed as HNCM. Animal studies postulate an inhibition of fibrosis with a favorable long-term effect after treatment with AT receptor antagonists (e7), statins (e8) or spironolactone (e8). In HNCM, atrial fibrillation with loss of active ventricular filling is often associated with a considerable decrease in performance and a risk with regard to cardioembolic events. Anticoagulation should be carried out at an early stage. Amiodarone can help prevent atrial fibrillation recurrence without reducing the risk of sudden cardiac death (e10). There are also various methods of atrial fibrillation ablation available, but the results are less favorable due to the diseased substrate.
Symptomatic patients with HOCM
In HOCM, pre- or afterload-lowering drugs (e.g. nitrates, ACE inhibitors, calcium antagonists of the nifedipine type) are contraindicated because of possible aggravation of the outflow tract obstruction. This often complicates the treatment of coexistent arterial hypertension. Likewise, drugs with a positive inotropic effect (e.g. digitalis preparations) should be avoided. The authors prefer beta blockers that improve LV filling by lengthening the diastole and reduce obstruction of the outflow tract due to negative inotropic effects (e11). In the case of beta blocker intolerance or insufficient effectiveness, calcium antagonists of the verapamil type can be switched to, which also improve the ventricular filling and reduce the obstruction (1). If coexistent arterial hypertension must also be treated, the exacerbation of the obstruction can usually be prevented with diuretics and / or central alpha blockers (e6).
Surgical myectomy according to Morrow defined the standard of therapy for many years in patients with HOCM who were not adequately controlled with medication. Here, part of the hypertrophied basal septum is removed or the remaining septum is thinned to 5 to 8 mm. In over 90 percent of the patients, a reduction or elimination of the gradient can be achieved with this. A clear indication is given for symptoms corresponding to NYHA class III and a gradient> 50 mmHg (rest or provocation). Perioperative mortality in designated centers is around 1 to 2 percent (e12), and the frequency of postoperative complete AV blocks is 2 to 5 percent. An improvement in the prognosis is postulated (e13), but due to the lack of randomized comparisons with conservatively treated patients, this cannot be considered proven. Figure 6 shows the echocardiographic aspect of a patient before and after myectomy.
Alternatively, attempts were made to reduce the obstruction of the left ventricular outflow tract by means of pacemaker stimulation. After euphoria in this regard in the 1990s (e14), a considerable placebo effect became apparent in more recent studies.The gradient could only be reduced by an average of 25 to 50 percent (e15). Therefore, this procedure is now only given a niche indication.
The treatment options for symptomatic HOCM patients were expanded with the introduction of percutaneous septal ablation (abbreviated as PTSMA, TASH, ASA or ESA). Here, 1 to 3 mL of 96 percent ethanol are injected into a septal branch supplying the hypertrophied myocardium (e16), which acutely causes contractile dysfunction in this area and, in the chronic course, leads to thinning. This iatrogenic chemical necrosis also results in a significant reduction or elimination of the obstruction in 90 percent (Figure 5gifppt, 6). The mortality of the procedure is to be equated to the myectomy in experienced centers (1 to 2 percent). Higher-grade AV blocks requiring pacemaker implantation initially occurred in up to 30 percent of patients (e17); meanwhile, significantly lower values of up to 5 percent have been achieved in designated centers. In contrast to myectomy, a delayed reduction in the gradient is often observed, parallel to a small but significant decrease in wall thickness in other LV areas (e18). Figure 6 (gifppt) shows a myectomy-analogous result of a septal ablation four months after the intervention. More than 3,000 septal ablations were performed between 1994 and 1999, a higher number than surgical myectomies since 1960 (e19, e20, e21). The question of whether the intervention has a favorable prognostic effect in addition to the symptomatic one is open. Fears that a new, prognostically unfavorable arrhythmogenic substrate was created as a result of septal necrotic tissue have not been substantiated by long-term observations (e22). The survival curves after myectomy and septal ablation - insofar as a non-randomized comparison is permitted - appear congruent. After myectomy or septal ablation, we recommend continuing drug therapy (beta blockers, calcium antagonists) to prevent the underlying disease from progressing.
Due to the relative rarity and complexity of the disease, patients with HCM require close care in or in cooperation with specialized centers. Every patient, even the asymptomatic one, should receive adequate risk stratification with regard to sudden cardiac death, possibly with the consequence of an ICD implantation. Symptomatic therapy for patients with HNCM corresponds to specific heart failure therapy. In symptomatic HOCM, septal ablation and surgical myectomy are now considered equivalent procedures. The choice of method will depend on the individual diagnosis situation. In addition to optimizing risk stratification, for example by integrating further imaging methods (MRT, CT), long-term observation of HCM patients treated differently remains a priority.
Conflict of interest
The authors declare that they have no conflict of interest.
submitted: November 20, 2009, revised version accepted: March 11, 2010
Address for the authors
Dr. med. Christian prince
Cardiology, Heart and Diabetes Center Bad Oeynhausen
Ruhr University Bochum, Georgstrasse 11, 32545 Bad Oeynhausen
Email: [email protected]
The Diagnosis and Treatment of Hypertrophic Cardiomyopathy
Background: Hypertrophic cardiomyopathy (HCM) is the most common hereditary disease of the heart.
Methods: In this article, we summarize the current state of the diagnosis and treatment of HCM on the basis of a selective review of recent publications with relevance to clinical practice.
Results: Several hundred mutations in more than 27 genes, most of which encode sarcomeric structures, are associated with the HCM phenotype. Thus, HCM can be thought of as a sarcomeric disease, with myocardial fiber disarray as its histological hallmark. There are two types of HCM, a more common, obstructive type (HOCM, 70%) and a less common, non-obstructive type (HNCM; in all cases of HCM, testing should be performed to detect outflow obstruction at rest and / or on provocation, and to thereby determine whether HOCM or HNCM is present. The symptoms of HCM include dyspnea, angina pectoris, palpitations, dizziness, and occasionally syncope. Because sudden cardiac death is the most serious complication of HCM, particularly in young and asymptomatic patients , it follows that correct diagnosis, followed by risk stratification of patients with regard to the need for prophylactic implantation of an implantable cardiac defibrillator (ICD), can be of life-saving importance. The pharmacotherapy of symptomatic HNCM consists of the treatment of heart failure with a normal ejection fraction (HFNEF). In HOCM, the patient's symptoms and the obstructive gradient are the guide to treatment with beta-blockers or verapamil. For patients with drug-resista nt disease, surgical myectomy and percutaneous septal ablation are now standard treatments.
Conclusion: A near-normal life expectancy and a highly satisfactory quality of life are now realistic treatment goals for patients with HCM.
Prinz C, Farr M, Hering D, Horstkotte D, Faber L: The diagnosis and treatment of hypertrophic cardiomyopathy. Dtsch Arztebl Int 2011; 108 (13): 209-15. DOI: 10.3238 / arztebl.2011.0209
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