Figure 1. Definition and Classification of Cardiomyopathies. 【Click to enlarge】

Akira Matsumori, MD, PhD, Kyoto University Graduate School of Medicine, discussed classification systems for cardiomyopathies and presented a proposed new system. The current classification systems (AHA, ESC) mix the etiologies and phenotypes of cardiomyopathies. Dr. Matsumori proposed that classification of cardiomyopathies should be based on etiology, anatomical structure, physiology (mechanical), and electrical types. For example, dilated cardiomyopathy (DCM) of viral origin would be classified etiologically as infectious (IB), anatomically as dilated left ventricle (LV) (IIAa), and physiologically as systolic failure (IIIA), resulting in a classification of IB, IIAa, IIIA (Figure 1).

In Japanese patients, asymmetrical apical hypertrophy (AAH) is characterized by deeply inverted T wave inversion more than 1.2 mV in the left precordial leads with LVH, normal intraventricular septum (IVS) and LV posterior wall (LVPW) thickness, and localized hypertrophy near the LV apex. Apical hypertrophy is characterized as having giant negative T waves, spade-like configuration, average apical thickness greater than hypertrophic obstructive cardiomyopathy (HOCM), and apical to mid-anterior free wall ratio greater than normal, HOCM, and hypertrophic non-obstructive cardiomyopathy (HNCM).

Figure 2. Viral Infection of the Heart. 【Click to enlarge】

Figure 3. Hypertrophic Obstructive Cardiomyopathy Associated with HCV Infection. 【Click to enlarge】

Figure 4. Apical Hypertrophic Cardiomyopathy Associated with HCV Infection. 【Click to enlarge】

Figure 5. Clinical Profiles of Patients with Hypertrophic Cardiomyopathy with Positive Anti-Hepatitis C Virus Antibody. 【Click to enlarge】

In US patients, the features of apical HCM are different than in Japanese patients, with IVS hypertrophy confined to the apical half, relatively mild T wave inversion, and no spade-like LV. Doi et al reported considerable differences between Japanese and Western patients with HCM in prevalence, symptoms, family history, sex, presence of giant negative T waves, and extent of apical hypertrophy.

A nationwide survey of patients with cardiomyopathy in Japan estimated prevalence to be 14.0 for DCM (N= 17,700), 17.3 for HCM (N=21,900), and 0.2 for restrictive cardiomyopathy (RCM) (N=300). A study of Japanese patients with HCM showed that the 5-year survival rate was 86.4%.

Cardiomyopathy caused by cardiac viral infection is thought to be the result of viral injury to myocytes, which results in different disorders depending on the location of the injury (Figure 2). Hepatitis C virus (HCV) has been associated with HCM and other cardiomyopathies. Figure 3 shows features of HOCM associated with HCV infection and Figure 4 shows features of apical HCM associated with HCV infection. Figure 5 shows clinical profiles of patients with HCM with positive anti-HCV antibody.

Susceptibility gene mapping for HCV-associated DCM and HCM showed that susceptibility to HCV-DCM was mapped at the locus spanning from NFKBIL1 to BAT1 loci within the HLA class III subregion. HCV-HCM was associated with DPB1 alleles. According to Dr. Matsumori, these candidate genes may encode molecules involved in immunity and inflammation.

Stress cardiomyopathy (SCM) is a syndrome of transient left ventricular (LV) dysfunction precipitated by an acute emotional or physiologic trigger. Dr. Ilan S. Wittstein, Johns Hopkins University School of Medicine, discussed the pathophysiology of SCM.

The exact pathophysiologic mechanism of SCM is not known but there is increasing evidence that exaggerated sympathetic stimulation may be involved: Most cases are precipitated by an acute trigger; ballooning variants do not correspond to vascular distribution, implying that ischemia is not involved; SCM primarily affects postmenopausal women, raising the issue of underlying susceptibility.

Figure 1. Plasma Catecholamines 【Click to enlarge】

The catecholamine hypothesis suggests that acute stress causes sympathetic activation, leading to LV dysfunction via the adrenal medullary hormonal system or the sympathoneural release of catecholamines. Dr. Wittstein’s group showed that plasma epinephrine and norepinephrine levels were highly elevated in patients with SCM triggered by emotional stress (Figure 1). The precursor dihydroxyphenylalanine, the neuronal metabolite dihydroxyphenylglycol, neuropeptide Y, and brain natriuretic peptide (BNP) were much higher in SCM patients than in MI patients.

Not all patients have elevated peripheral catecholamine levels, however. A Japanese study reported that coronary sinus norepinephrine was elevated in SCM patients, suggesting a local myocardial effect through the sympathoneural system. Another study found that heart rate parameters in SCM patients were depressed on admission, suggesting a sympathetic predominance. Additionally, MIBG is decreased at the apex and the washout rate is elevated in SCM patients, suggesting that preganglionic sympathetic innervation is increased.

A study by Dr. Wittstein et al described the development of SCM after intravenous catecholamine administration. Intravenous epinephrine has caused apical ballooning in animal models.

Figure 2. Hypotheses of Catecholamine Excess Effects. 【Click to enlarge】

Several hypotheses have been suggested for the mechanism of catecholamine excess leading to SCM (Figure 2). The data do not support the hypothesis that catecholamine excess causes plaque rupture and coronary thrombus, and most SCM patients have normal coronary arteries. Epicardial spasm is rarely seen in SCM patients. Dr. Wittstein argued against intraventricular obstruction as the primary mechanism, because many patients never develop an intracavitary gradient and it would not explain the mid-ventricular and basal variants. A Mayo Clinic study demonstrated elevated TIMI frame counts in all three coronary arteries, suggesting that SCM might be a microvascular disorder.

CT PET has shown markedly abnormal metabolic activity in the acute phase despite normal perfusion. Studies have demonstrated calcium overload and abnormal calcium handling in myocytes in animals models and SCM patients. Catecholamine mediated myocyte calcium handling abnormalities may account for transient myocardial dysfunction.

Figure 3. Proposed Mechanisms of SCM. 【Click to enlarge】

Factors that might increase susceptibility to SCM include decreased estrogen, depression/anxiety and antidepressant use, endothelial dysfunction, and genetic predisposition.

In summary, an acute stressor induces catecholamines, which together with underlying factors may lead to microvascular dysfunction, direct myocyte injury, and hemodynamic effects, resulting in SCM (Figure 3)