https://orcid.org/0000-0001-6691-8568
Abstract
The interpretation of 12-lead resting electrocardiogram (ECG) in patients with a definitive diagnosis or with the suspicion of a cardiomyopathy represents a cornerstone for the diagnostic work up and management of patients. Although low electrocardiographic QRS voltages (LQRSV) detected by 12-lead resting ECG have historically been acknowledged by physicians, in view of recent evidence on the demonstration of myocardial scar by cardiac magnetic resonance and its relevance as a cause of sudden cardiac death even in young individuals, a new interest has been raised about the utility of LQRSV in the clinical practice. Beyond their diagnostic value, LQRSV have also demonstrated a prognostic role in different cardiomyopathies. The present review summarizes the diagnostic and prognostic value of LQRSV in cardiomyopathies, reporting the new evidence, primarily based on advanced imaging studies, supporting the clinical utility of this parameter.
Introduction
The interpretation of 12-lead resting ECG in patients with a definitive diagnosis or with the suspicion of a cardiomyopathy represents a cornerstone for the diagnostic work up and management of patients.1Although low electrocardiographic QRS voltages (LQRSV) detected by 12-lead resting ECG have historically been acknowledged by physicians, in view of the recent evidence on the demonstration of myocardial scar by cardiac magnetic resonance (CMR), new attention has been raised in the identification and interpretation of this old ECG parameter.2,3 LQRSV can be found in isolation or in combination with other ECG abnormalities, such as T-wave inversion (TWI), St-T segment depression, and ventricular arrhythmias (VA). The detection of LQRSV and repolarization abnormalities, such as TWI, should be viewed as a potential red flag on the ECG of an apparently healthy adult and should warrant further investigations because it may represent the initial expression of cardiomyopathies that may clearly express their phenotype later and that may ultimately be associated with adverse outcomes. Beyond their diagnostic value, LQRSV have also a prognostic role in the clinical practice and have demonstrated to be associated with an increased mortality (63%) in individuals free of any cardiovascular disease.4
Therefore, the aim of the present review was to summarize the diagnostic and prognostic value of LQRSV in cardiomyopathies, reporting the new evidence derived from multimodality studies, primarily based on advanced imaging, supporting the clinical utility of this parameter.
Definition
In 1949, Sokolow and Lyon defined LQRSV as the sum of the S-wave amplitude in lead V1 and R wave in V5 or V6 ≤ 15 mm (1.5 mV), the so-called Sokolow/Lyon index.5 In the following years, the definition of LQRSV was simplified as a nadir-to-peak QRS amplitude <5 mm in all the limb leads and <10 mm in all precordial leads.6 Some authors also used the combined definition of QRS amplitude in each limb lead ≤5 mm (0.5 mV) or a Sokolow–Lyon index ≤15 mm.7,8 LQRSV may be noted only in the limb leads (a frequent encounter), the precordial leads, or both.
Low electrocardiographic QRS voltages are thought to be affected by conditions that impair either the generation or the transmission of electrical signals from the heart to the electrodes applied to body surface, such as infiltrative cardiomyopathies, amyloidosis, sarcoidosis, anasarca, pericardial effusion, chronic obstructive pulmonary disease, and obesity.9–11 The causes of LQRSV can be differentiated into those due to the deficient heart's generated potentials (cardiac causes) and those due to the attenuating influences of the pericardial space and pericardium, or the passive body volume conductor, enveloping the heart (extracardiac causes). However, an overlap exists: indeed, although pericardial pathology can be classified among the cardiac causes, in pericardial effusion, due to fluid accumulation, there is a short-circuiting of the cardiac potentials to the body surface.12 Occasionally, LQRSV in the ECG may not have an apparent explanation and, thus, if they are not associated with other ECG abnormalities, may be considered as a normal variant in otherwise healthy subjects with a negative family history of sudden cardiac death (SCD).
Low QRS voltages in arrhythmogenic cardiomyopathy
Arrhythmogenic cardiomyopathy (ACM) is a rare genetically determined disorder of the myocardium with a prevalence of 0.01–0.05% in the general population.13,14 The current clinical classification of ACM includes the following variants15:
the classic arrhythmogenic right ventricular (RV) cardiomyopathy phenotype, i.e. the originally reported and most common disease variant, characterized by isolated RV involvement;
the ‘biventricular disease variants’, i.e. ‘balanced’, ‘dominant-right’ or ‘dominant-left’, characterized by the parallel, predominant RV, and predominant left ventricular (LV) involvement, respectively; and
the LV phenotype characterized by isolated LV involvement (i.e. without clinically demonstrable RV involvement).
The main histopathological feature of ACM is the progressive loss of ventricular myocardium and the fibro-fatty replacement from epi- to endo-cardium. Recently, many studies extended the morphological spectrum of the disease from the original ‘triangle of dysplasia’ to a ‘quadrangle of arrhythmogenic RV cardiomyopathy’, which also includes the LV infero-lateral wall.15Indeed, in biventricular or LV dominant forms, the interventricular septum is usually spared, but fibro-fatty or fibrous scars can be typically identified in the epicardial layers of the postero-lateral free wall.16–18
Twelve-lead resting ECG is a valuable diagnostic test in ACM and up to 90% of ACM patients exhibit depolarization and/or repolarization abnormalities that are part of the minor and major diagnostic criteria for the diagnosis of this cardiomyopathy.19–21 The depolarization abnormalities result from a delayed RV activation/conduction and include: right bundle branch block (RBBB; usually incomplete and rarely complete), QRS fragmentation, prolongation of right precordial QRS duration with a delayed S-wave upstroke, terminal activation duration ≥55 ms, and epsilon waves. Depolarization abnormalities also include LQRSV in the limb leads that are frequently observed in ACM patients, particularly in those with LV late gadolinium enhancement (LGE) identified by CMR.17,18 Rather than an ECG marker of advanced RV disease, LQRSV indicate LV involvement (regardless of the severity of RV disease) and reflect the loss of myocardium/electrical voltages of the LV wall and the replacement by electrically inert fibro-fatty scar tissue.2,22,23 The decrease in LV myocardial mass mostly accounts for the generation of the electrical activity causing the depolarization current responsible for the QRS complex.18 It remains to be elucidated why it mainly affects the limb leads. The low sensitivity of LQRSV may be explained by a dose–effect relationship between myocardial replacement by fibrofatty scar and reduction in QRS amplitudes in limb leads. This is in keeping with the significantly higher number of LV segments affected by LGE in patients with LQRSV on resting ECG than in those without.18
Left dominant ACM
Left dominant ACM may present over a wide age range, from adolescence to the age of 80 years, typically with palpitations and symptoms of impaired consciousness.24 VAs with RBBB morphology and wide ectopic QRS are characteristic and often out of proportion to the degree of LV dysfunction.24 Many patients have an additional arrhythmic focus in the RV. A 12-lead ECG may show left deviation of the QRS axis or TWI in the infero-lateral leads.24 A key CMR finding is LV LGE in a subepicardial/midmyocardial and predilection for the inferior/infero-lateral LV walls that show a close agreement with patterns of fibrosis in ex vivo hearts from SCD victims and transplant recipients.25,26 De Lazzari et al.18 in a study on the relationship between ECG findings and CMR phenotypes in 79 patients with ACM showed that the extent of TWI to lateral leads predicted a more severe RV dilatation rather than LV involvement because of the leftward displacement of the dilated RV. Notably, LQRSV in limb leads predicted the presence and amount of LV LGE; the electrocardiographic pattern of LQRSV may predict LV involvement in the context of ACM with a specificity of 100%, although its sensitivity did not exceed 30%.18 Therefore, the authors concluded that LQRSV are a useful diagnostic marker of the ‘biventricular’ variant of ACM because it may predict the coexistence of LV involvement by significant fibro-fatty myocardial replacement, with important implications on clinical evaluation and monitoring over follow-up of the LV systolic function, which is a crucial parameter for the clinical outcome.18,27 Moreover, there is growing evidence that the presence of LV scar may increase the risk of life-threatening VAs and SCD, even in the absence of significant systolic dysfunction.2 In a study by Zusterzeel et al.28 summed QRS amplitude in the limb and precordial leads and TWI beyond lead V1 were associated with RV dilatation; despite not specific, this ECG sign was more frequently observed in the group of patients with advanced ACM with significant RV dilatation as compared to a control group who had been included because of unexplained dyspnoea, palpitations, or atypical chest complaints, showing a normal 12-lead ECG and echocardiographic examination. This sign can be more specific when limited to the right precordium29 or when the precordial QRS amplitude ratio was applied, i.e. the ratio between the sum of QRS amplitude in leads V1–V3 and the total sum of all precordial QRS amplitude V1–V6; in the comparison of scar area between patients with and without decreased precordial QRS amplitude ratio, a strong trend towards more scar area in patients with precordial QRS amplitude ratio ≤0.48 was found.30
The prognostic role of LQRSV in ACM has also been confirmed by Gallo et al.31: in a study on the long-term electrical progression of ACM patients, they demonstrated that the percentage of patients with LQRSV increased as a result of the progression of the disease over time (from 27 to 48 patients during 17 years of follow-up; P = 0.001). In agreement, De Lazzari et al.18 found that LQRSV predict the ACM phenotype in terms of severity and outcome. A correlation between LQRSV and the phenotypes of ACM was also confirmed by Steriotis et al.20: indeed, a significant difference was found between patients with mild and moderate forms and those with severe forms (P = 0.0002), as well as between patients with mild and moderate forms (P = 0.0003) and those with biventricular involvement.
Therefore, the current evidence and the recent CMR studies on tissue characterization in ACM patients suggest that LQRSV have a relevant role for the diagnosis of ACM and provide useful prognostic information. Low electrocardiographic QRS voltages are particularly useful in the biventricular form of ACM or in those with a predominant or isolated LV involvement where they may provide crucial information for an early diagnosis and for the suspicion of myocardial fibrosis (Figure 1). The possibility of a clinical and ECG surveillance of patients with suspected cardiac disease may further improve the relevance of repeating ECGs and identifying changes in the voltages of QRS to make a definitive diagnosis in these patients.
A 45-year-old man with a definitive diagnosis of biventricular arrhythmogenic cardiomyopathy: cardiac magnetic resonance imaging demonstrates the presence of biventricular fatty infiltration (up), late gadoliunium enhancement of left ventricular infero-lateral wall (bottom left), and right ventricular wall motion abnormalities (bottom, right). The cardiomyopathy is associated with an initial reduction in limb lead voltages, T-wave inversion in the anterior precordial leads, and ventricular arrhythmias with a right bundle branch block morphology and superior axis, suggesting an origin from the left ventricle.
Non-ischaemic left ventricular scar
In the last years, a new entity has been identified, known as idiopathic myocardial fibrosis or non-ischaemic LV scar (NLVS), which accounts for 1–3% of cases of SCD.32,33 Idiopathic fibrosis is characterized by heterogeneous interstitial fibrosis with a predilection for the inferior LV wall, not associated with classical features of a well-known cardiomyopathy.33 Replacement fibrosis is also observed; however, coronary artery disease and other structural abnormalities are absent by definition, indicating a repair process for which the primary insult is unknown. While infective myocarditis and age-related degeneration have been cited as possible causes, it has also been suggested that idiopathic myocardial fibrosis might be part of the same disease spectrum as ACM.22,24
Di Gioia et al.22 examined 281 consecutive cases of SCD of subjects aged 1–35 years. Non-ischaemic LV scar was defined as a thin, grey rim of subepicardial and/or midmyocardial scar in LV free wall and/or the septum, in the absence of significant stenosis of coronary arteries. The authors found that NLVS was the most frequent cause (25%) of SCDs occurring during sports. Myocardial scar was localized most frequently within the LV posterior wall and affected the subepicardial myocardium, often extending to the midventricular layer.22Notably, resting ECGs were available in more than half of subjects died suddenly because of NLVS and the most frequent abnormality was the presence of LQRSV (defined as <0.5 mV) in limb leads.22 In agreement with these findings, Zorzi et al.,2 in a study on NLVS in competitive athletes, showed that, in a group of 35 athletes with the evidence of isolated LV LGE at CMR, the ECG was abnormal in 13 athletes (37%) and the most common abnormalities were LQRSV in limb leads (20%) and TWI in infero-lateral leads (20%). Considering that LQRSV are very uncommon in young individuals and young athletes,34,35 the analysis of LQRSV in these subjects is crucial to early diagnose a life-threatening cardiomyopathy and prevent SCD.
ECG is an important screening test for the identification of leading causes of SCD.36 However, in the segmental NLVS, focal myocarditis or early/minor cardiomyopathies, 12-lead resting ECG may be normal while sometimes may show TWI in the inferior/lateral leads and low limb lead voltages. Echocardiography is usually normal, since the sub-epicardial involvement does not affect the morphology or function of the LV free walls. Among imaging tools, only CMR can detect this otherwise well-concealed myocardial substrate.37 However, CMR is an expensive and time-consuming imaging technique with limited access and it is usually recommended in symptomatic patients or in those with ECG and echocardiographic abnormalities.38 However, asymptomatic young athletes with a concealed NLVS usually exhibit LQRSV and VAs with an uncommon morphology for young individuals, i.e. an RBBB morphology with a wide ectopic QRS or polymorphic patterns, suggesting an origin from the LV.39–41 In a recent retrospective study on Olympic athletes, the prevalence of LQRSV was 4% and it is associated with premature ventricular beats, originating from either the LV free wall or the RV free wall.34 Particular attention should be paid also to exercise-induced VAs: indeed, it was found that competitive athletes with exercise-induced premature ventricular beats and/or complex VAs had a normal echocardiographic examination but abnormal CMR with the demonstration of NLVS in those with premature ventricular beats with an RBBB morphology feature.42 It was further confirmed that pathological myocardial substrates on CMR were observed more often in athletes with exercise-induced VAs than in those with non-exercise-induced VAs: repolarization abnormalities on resting ECG and complex exercise-induced VAs with an RBBB or polymorphic morphology identified the subgroup of athletes with the highest probability of CMR abnormalities.43 A study by Schnell et al.,44 investigating athletes undergoing CMR because of the suspicion of cardiomyopathy due to pathological TWI or complex VAs on exercise testing, found that LGE was demonstrated and localized predominantly in LV lateral wall, exclusively subepicardial or associated with transmural or intramural patches. This diagnosis was associated with the development of LV dysfunction and malignant VAs during the follow-up. Therefore, manifest subepicardial DGE detected during the workup of asymptomatic young elite athletes presenting with TWI or exercise-induced VAs is not a benign condition, even in the absence of typical features of cardiomyopathies.
The exact aetiology of LVNS remains to be elucidated: indeed, while some authors hypothesized that subepicardial LGE is the result of a previous myocarditis, others suggest that LV scar is due to an early inherited cardiomyopathy and a possible variant form of left dominant ACM.22,44,45 Irrespective of the aetiology, few clinical tools are useful for suspecting this pathological condition: LQRS voltages, exercise-induced arrhythmias, and VAs with an uncommon morphology (i.e. RBBB with ectopic wide QRS) may extremely important for the suspicion of LVNS and the indication to CMR even in young asymptomatic individuals who can be at the risk of SCD (Figure 2).
A 37-year-old male amateur runner with the demonstration of left ventricular non-ischaemic scar of the anterior wall. The scar was suspected because of the presence of ventricular arrhythmias with a right bundle branch block morphology, suggesting an origin from the left ventricle, relatively low QRS voltages, the absence of echocardiographic abnormalities, and negative family history for sudden cardiac death or cardiomyopathies.
Cardiac amyloidosis and infiltrative disorders
Cardiac amyloidosis is considered to be the prototype of the infiltrative form of restrictive cardiomyopathies. Amyloidosis is a disorder of misfolded proteins leading to the deposition of insoluble amyloid fibrils in the heart and other tissues.46 Although cardiac amyloid types share common clinical manifestations and cardiac imaging findings, these forms are very different in clinical presentation, diagnostic strategy, and prognosis, depending on the source and nature of the precursor protein.46 There are 2 main types of amyloid that commonly affect the heart: immunoglobulin light-chain-associated amyloid (AL) (previously called ‘primary systemic amyloidosis’) and transthyretin amyloid (ATTR). Transthyretin amyloid is further divided into a hereditary form due to a pathogenic transthyretin deoxyribonucleic acid mutation (ATTR-m) and the ‘wild-type’ (ATTR-wt) or the senile systemic amyloidosis, in which a mutation is not identified. Light-chain-associated amyloid results for excessive immunoglobulin light-chain production and ∼5% of patients have isolated cardiac involvement.46,47 Cardiac amyloidosis is not a simple infiltrative cardiomyopathy: direct toxicity of abnormal precursor proteins and other circulating factors contribute to myocardial dysfunction.48 In the ATTR, there is an accumulation of transthyretin, a protein produced by the liver that transports thyroid hormone and retinol. In hereditary ATTR (ATTR-m), a pathogenic mutation leads to protein instability and misfolding. These patients have primarily neurological symptoms (peripheral and/or autonomic neuropathy), primarily cardiac involvement (heart failure, conduction system, arrhythmias), or a mixed phenotype.49
Twelve-lead resting ECG reflects the generalized infiltrative nature of this disease with low limb lead voltages (Figure 3), pseudo-infarction patterns in the anterior precordial and/or inferior limb leads, and conduction abnormalities such as fascicular block or atrioventricular block of varying degree.50–52 In a study on 337 patients, divided into two groups depending on the presence (n = 233) or absence (n = 104) of heart involvement by amyloidosis AL, the presence of cardiac involvement was associated with a peculiar ECG pattern, with 52.2% of ECG signs of pseudo-infarction, defined by the presence of a pathological Q wave in two or more contiguous leads in the absence of history of ischaemic heart disease.53 Quantitative measurements of QRS voltages showed that all indices were depressed in patients with cardiac involvement, confirming the higher prevalence of LQRSV in cardiac AL amyloidosis [Sokolow–Lyon index: cardiac AL 7.0 mm (4.0–11.0) vs. non-cardiac AL 14.5 mm (10.0–18.4); P-value <0.001; peripheral QRS amplitude: cardiac AL 24.0 mm (18.9–31.3) vs. non-cardiac AL 33.7 mm (26.1–42.5); P-value <0.001].54 In cardiac AL, the presence of LQRSV in the limb leads is associated with higher heart rate, prolonged PQ interval, and shorter QT interval, although the corrected QT interval was comparable in patients with or without LQRSV.54 Patients with LQRSV presented higher septal thickness, larger LV end-diastolic diameters, more severely depressed longitudinal systolic function, and larger extent of diastolic dysfunction.54 Moreover, the presence of LQRSV was associated with higher BNP and NT pro-BNP serum concentrations, whereas troponin I concentrations were comparable in patients with or without LQRSV.54
A case of a 55-year-old man with cardiac amyloidosis (TTR-wt). A severe left ventricular hypertrophy, a severe diastolic dysfunction, and a moderate left ventricular systolic dysfunction were present and were associated with low QRS voltages in limb leads. The patient underwent cardiac transplantation 6 months after this clinical evaluation because of several hospitalizations for heart failure and worsening of systolic function.
Low electrocardiographic QRS voltages also demonstrated a prognostic value: indeed, both Mussinelli et al.54 and Kristen et al.55 showed that AL amyloidosis patients’ survival and a more severe cardiac involvement were associated with the presence or absence of LQRSV. In a study by Cyrille et al.56 on the prognostic significance of LQRSV among the three main types of cardiac amyloidosis (AL; ATTR-m; ATTR-wt), it was demonstrated that, despite being three distinct entities with regard to underlying biologic, genetic, and clinical variables, the prognostic information of ECG was comparable: indeed, most of the patients had LQRSV and this ECG finding was associated with adverse outcomes. In the same study, Cyrille et al.56 estimated the prevalence of LQRSV in limb leads (35% in AL; 37% in ATTR-m; 18% in ATTR-wt) and in the precordial voltages (15% in AL; 10% in ATTR-m; 6% in ATTR-wt). In one of the largest series comparing the three types of cardiac amyloid, Rapezzi et al.49 found different findings: indeed, the authors demonstrated that LQRSV were more common in patients with AL compared with ATTR-m (60% vs. 25%, respectively; P < 0.0001); this difference may be attributable to the phenotypic heterogeneity in the various types of genetic mutations in ATTR-m amyloidosis. Patients with ATTR-m have a significantly lower frequency of cardiac involvement and, therefore, a lower prevalence of LQRSV compared to patients with AL. Conversely, in the study by Cyrille et al.,56 the patients have either exclusively or predominately cardiac involvement; as a consequence, the prevalence of LQRSV did not differ between ATTR-m and AL patients. The prognostic value of LQRSV was also confirmed by Kristen et al.55 who found that LQRS voltages were independently associated with decreased survival in a combined cohort of patients with AL and ATTR.
Other infiltrative disorders
Among the 40 storage disorders caused by deficient enzymatic activity of lysosomal enzymes, Anderson Fabry disease, Danon disease (lysosomal-associated membrane protein-2), and protein kinase AMP-activated noncatalytic subunit gamma 2 (PRKAG2)-deficient cardiomyopathy are the principal diseases associated with cardiac involvement.57,58
In Fabry disease, ECG abnormalities include short PR interval, RBBB, LVH, and giant negative T waves.59 This disorder is usually not associated with LQRSV, as the abnormal deposition occurs in the cardiomyocyte rather than the interstitium.46 Similarly, in Danon disease, LQRSV are not present while usually increased QRS voltage and deeply inverted T-wave can be found.46 Finally, in the rare PRKAG2 deficiency, LQRSV have not been described among the ECG abnormalities related to this disease. Other infiltrative disorders include sarcoidosis, a systemic granulomatous disease of unknown aetiology, which can be associated with cardiac involvement: complete atrioventricular block and ventricular tachycardia/ventricular fibrillation are the most common arrhythmias in this disease, both associated with SCD.60 LQRS voltages can be found in most patients with cardiac sarcoidosis causing severe heart failure.61 Hemochromatosis represents an iron overload disorder or iron storage disease, characterized by the accumulation of excessive iron within the cells of various internal organs, resulting from a genetic defect (hereditary hemochromatosis) or from secondary causes (secondary hemochromatosis).57 Cardiac hemochromatosis is typically characterized by LV systolic dysfunction, with QRS complex voltage and duration generally preserved because of the absence of marked fibrosis with largely preserved cardiac myocytes and of the nonconductive property of iron; however, in the advanced stages of the disease, resting ECG can show LQRS voltages and repolarization abnormalities.62
Hypertrophic cardiomyopathy
Hypertrophic cardiomyopathy (HCM) is the most common genetically determined primary heart muscle disease, affecting 0.2–0.5% of the general population,63 and characterized by LVH in the absence of cardiac or systemic cause, with possible outflow tract obstruction. The pathological hallmarks of the disease include myocyte hypertrophy and disarray, interstitial and replacement fibrosis, small vessel abnormalities, and electrical remodelling of the cardiomyocytes.64 Although the recent technological progress in cardiovascular imaging has improved our understanding of the functional cardiac and tissue characterization and the phenotypes, the ECG remains a cornerstone in the evaluation of HCM patients.65 LQRSV are rare and may be rarely seen in patients with end-stage sarcomeric HCM, representing an ominous sign of diffuse fibrosis.66 Konno et al.67 investigated the impact of LV ejection fraction (EF) and myocardial fibrosis by CMR on QRS voltages in HCM patients: they studied 108 consecutive patients with HCM who underwent CMR and found that the total QRS voltages and Sokolow–Lyon indexes were positively correlated with LVEF. For discriminating patients with end-stage HCM from patients with HCM and preserved LVEF, receiver-operating characteristic analysis revealed an excellent area under the curve of 0.87 for the total QRS voltage index and 0.90 for the Sokolow–Lyon index, whereas the area under the curve for the Cornell index was only 0.54 (P < 0.01).67 Moreover, these two voltage indexes were negatively correlated with the extent of LGE-determined myocardial fibrosis when adjusted by LV maximal wall thickness. The authors concluded that LQRSV may reflect the extent of myocardial fibrosis and the consequent advanced stage of the disease in patients with HCM.67 Biagini et al.68 evaluated 1004 HCM patients and found that 4% had a normal ECG, 56% ST-segment depression, 33% pseudo-necrosis waves, 17% ‘pseudo-ST-segment elevation myocardial infarction (STEMI)’ pattern, 17% QRS duration ≥120 ms, 6% giant inverted T waves, and 3% LQRSV. During the follow-up, an independent predictive value of SCD was found for some ECG abnormalities, including LQRSV, increased QRS duration, and ‘pseudo-STEMI’ pattern.68 Similarly, Ledieu et al.69 analysed the clinical variables associated with a bad prognosis in HCM patients: at multivariable analysis using ECG covariates, they found that prolonged QTc interval, LQRSV, and premature ventricular beats with an RBBB morphology predicted a worse outcome, but none remained independently associated with the primary endpoint (composite of all-cause mortality, major non-fatal arrhythmic events, hospitalization for heart failure, and stroke) after adjustment on main demographic and clinical variables.
Therefore, while the diagnostic utility of 12-lead resting ECG has been extensively validated in HCM, further research is also needed to confirm its prognostic value. Although LQRSV are rare in HCM patients, they can be found in end-stage HCM and preliminary evidence seems to suggest a potential role for predicting the prognosis.
Dilated cardiomyopathy
Dilated cardiomyopathy (DCM) is defined by the presence of LV or biventricular dilatation and systolic dysfunction in the absence of abnormal loading conditions or coronary artery disease sufficient to cause global systolic impairment.70 However, under the umbrella of DCM, multiple disorders with different pathophysiological mechanisms, clinical management, and prognosis are included.1 The ECG retains an extremely powerful role in the evaluation of DCM patients and can provide diagnostic red flags useful to guide the work-up, the prognostic stratification, and the appropriate decision making.1 Low electrocardiographic QRS voltages in limb leads with normal QRS precordial amplitudes, or LQRSV in limb leads with high QRS complexes in the precordial leads with poor R-wave progression (Goldberger triad), have been described in patients with DCM.71 Loss of vital myocardium and diffuse LV fibrosis may both lead to reduced QRS amplitude, especially in precordial leads.72 Fukaya et al.73 conducted a study to determine the feasibility of recording serial changes in Sokolow–Lyon voltage in 1 year to estimate LV reverse remodelling (LVRR) and to predict the prognosis of idiopathic DCM patients. The QRS voltages were significantly lower in the LVRR vs. non-LVVR group (−26.9% vs. −9.2%, P < 0.001).73
Low electrocardiographic QRS voltages can also be useful in the differential diagnosis in challenging conditions, such as distinguishing between DCM and ACM with LV involvement: indeed, LQRSV in limb leads (59% vs. 4% in ACM and DCM, respectively; P < 0.01) and infero-lateral TWI (32% vs. 6% in ACM and DCM, respectively; P < 0.01) are more frequently found in patients with ACM-LV phenotype rather than in DCM, while an LVH pattern (2% vs. 20% in ACM and DCM, respectively; P = 0.05) and left bundle branch block (0% vs. 28% in ACM and DCM, respectively; P < 0.01) were more prevalent in DCM patients.17
Recently, cardiotoxicity has been identified as one of the causes of LV dilatation and dysfunction. The ECG analysis in patients treated with anthracyclines revealed that the electrical activity of the myocardium—and particularly QTc interval and LQRSV—can change and that prolonged QTc interval and LQRSV after anthracycline treatment could correlate with LV dysfunction on echocardiography.74
Tako-tsubo syndrome
Tako-tsubo syndrome, or transient apical ballooning syndrome of the LV, often mimics the clinical, electrocardiographic, and biological features of an acute coronary syndrome, with LV deformation and impairment of systolic function, in the absence of coronary occlusion or rupture of atheromatous plaque.75 The most common ECG abnormalities are ST-segment elevation, mimicking an STEMI, and TWI.76 A meta-analysis demonstrated that Tako-tsubo syndrome is associated with transient attenuation in the amplitude of QRS voltages77: LQRSV were found in 91.5% of patients with Tako-tsubo syndrome and attenuation of the amplitude of QRS complexes was seen in 93.5% of the patients. Low electrocardiographic QRS voltages and an attenuation of the amplitude of QRS complexes are highly prevalent in patients with Tako-tusbo syndrome and might be useful for the diagnosis and for the differential diagnosis with acute coronary syndromes.77
Guerra et al.78 demonstrated that QRS amplitude shows a time-related trend, with a first phase characterized by an initial decrease in amplitude both in Tako-tsubo patients and in those with an acute coronary syndrome and a second phase with a progressive recovery of QRS amplitude up to pre-event levels, while QRS amplitude in ischaemic patients remains substantially unchanged from admission onwards. Rise in amplitude attenuation of QRS voltage during hospitalization showed a positive linear association with LV systolic function recovery and both troponin I and CK-MB decrease in Tako-tsubo patients. Therefore, QRS amplitude attenuation in Tako-tsubo syndrome is transient and is linearly associated with systolic function recovery and cardiac biomarkers normalization.78 The first and more intuitive hypothesis to explain the temporary amplitude attenuation of QRS voltage relates to myocardial oedema that is a common feature of Tako-tsubo syndrome and is typically more prevalent in the areas where wall motion abnormalities are also found.79 Interstitial oedema provides decreased resistance to current dispersion, while increasing the transmural and longitudinal repolarization inhomogeneity.80 Another possible mechanism is transient fibrosis; indeed, it has been demonstrated that an increase in collagen-1 in extracellular matrix is present when compared to control tissue and returns to normal levels after functional recovery.81 The transient increase in collagen-1 expression is even more evident in LGE-positive patients and could indeed contribute to a reduction in myocardial impedance leading to LQRSV. Recovery of ‘lost’ QRS amplitude after the acute event could also have a prognostic value. Indeed, as QRS amplitude is positively associated with LV EF recovery and cardiac biomarker plasma level normalization, serial ECGs can be potentially used to predict the degree of improvement in LV EF or troponin and CK-MB fall with a good approximation, potentially reducing costs during the follow-up of these patients.78 An increase in QRS amplitude ≥20% from admission, being able to predict with good sensitivity and specificity the return to normal LV EF values and cardiac biomarker plasma levels, could be proposed as a cheap, reliable, and easy-to-obtain marker of clinical recovery in Tako-tsubo patients.78 Notably, while LQRSV usually last some weeks, TWI and prolonged QT interval found in Tako-tsubo syndrome may persist up to 6 months after complete recovery of both systolic dysfunction and cardiac biomarkers.82
The main cardiomyopathies associated with LQRSV are reported in Figure 4. The main ECG abnormalities associated with LQRSV are reported in the figure for each clinical entity.
Main cardiomyopathies associated with low QRS voltages. For each cardiomyopathy, the most common ECG abnormalities associated with low QRS voltages are reported separately. DCM, dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; NLV, non-ischaemic left ventricular; LBBB, left bundle branch block; LQRS, low QRS voltages; RBBB, right bundle branch block; TWI, t-wave inversion; STEMI, ST-segment elevation acute myocardial infarction; VA, ventricular arrhythmias.
Other causes
Other causes of LQRSV include pericardial effusion, myocardial infarction, chronic obstructive lung disease, and obesity. Pericardial effusion leads to LQRSV, with a short-circuiting of cardiac potentials as they are transmitted to the body surface; however, the mechanism may be more complex and may include even the intrapericardial pressure, like in tamponade, as the primary reason, along with the inflammation.9,83 Myocardial infarction may lead to LQRSV because of cancellations and diminished electromotive force generation; LQRSV and QRS notches are seen in conjunction with severe post-myocardial infarction dyssynergy.84 Myocarditis can also be associated with LQRSV: a study analysing the presence of LGE and ECG findings in myocarditis showed that a greater prevalence of patients had LGE in presence of abnormal ECG findings, including LQRSVs in 61% of the cases.85 The association of LQRSV with the presence of LGE has a sensitivity of 11% and a specificity of 94% for LQRS.85 Chronic obstructive lung disease may show LQRSV, particularly in the limb leads, because of an increased heart/chest wall distance from lung hyperinflation, which, if not offset, would be expected to augment QRS potentials by the way of an increased electrical impedance.12 For the same reasons, pneumopericardium, pneumomediastinum, and pneumothorax, particularly left sided, are associated with LQRSV.86 Low QRS voltage has been frequently listed as an ECG abnormality associated with obesity and prior studies assessing the ECG in obesity have identified T-wave abnormalities in the inferior leads and trends towards leftward axis and LQRSV as the most common ECG abnormalities.10 The main cardiac and non-cardiac causes of LQRSV are shown in Table 1.
Main cardiac and non-cardiac causes of low QRS voltages
| Mechanism | Generation |
| Cardiac causes | Arrhythmogenic cardiomyopathy |
| Non-ischaemic LV scar | |
| Hypertrophic cardiomyopathy | |
| Dilated cardiomyopathy | |
| Infiltrative cardiomyopathy | |
| Tako-tsubo syndrome | |
| Myocardial infarction | |
| Myocarditis | |
| Mechanism | Impedance |
| Cardiac causes | Pericardial effusion |
| Constrictive pericarditis | |
| Pneumopericardium | |
| Non-cardiac causes | COPD |
| Obesity | |
| Pneumothorax | |
| Pleural effusion | |
| Pulmonary edoema | |
| Pneumomediastinum | |
| Peripheral edoema |
| Mechanism | Generation |
| Cardiac causes | Arrhythmogenic cardiomyopathy |
| Non-ischaemic LV scar | |
| Hypertrophic cardiomyopathy | |
| Dilated cardiomyopathy | |
| Infiltrative cardiomyopathy | |
| Tako-tsubo syndrome | |
| Myocardial infarction | |
| Myocarditis | |
| Mechanism | Impedance |
| Cardiac causes | Pericardial effusion |
| Constrictive pericarditis | |
| Pneumopericardium | |
| Non-cardiac causes | COPD |
| Obesity | |
| Pneumothorax | |
| Pleural effusion | |
| Pulmonary edoema | |
| Pneumomediastinum | |
| Peripheral edoema |
The causes are also divided according to the mechanism, i.e. defect of generation or impedance.
LV, left ventricular.
Main cardiac and non-cardiac causes of low QRS voltages
| Mechanism | Generation |
| Cardiac causes | Arrhythmogenic cardiomyopathy |
| Non-ischaemic LV scar | |
| Hypertrophic cardiomyopathy | |
| Dilated cardiomyopathy | |
| Infiltrative cardiomyopathy | |
| Tako-tsubo syndrome | |
| Myocardial infarction | |
| Myocarditis | |
| Mechanism | Impedance |
| Cardiac causes | Pericardial effusion |
| Constrictive pericarditis | |
| Pneumopericardium | |
| Non-cardiac causes | COPD |
| Obesity | |
| Pneumothorax | |
| Pleural effusion | |
| Pulmonary edoema | |
| Pneumomediastinum | |
| Peripheral edoema |
| Mechanism | Generation |
| Cardiac causes | Arrhythmogenic cardiomyopathy |
| Non-ischaemic LV scar | |
| Hypertrophic cardiomyopathy | |
| Dilated cardiomyopathy | |
| Infiltrative cardiomyopathy | |
| Tako-tsubo syndrome | |
| Myocardial infarction | |
| Myocarditis | |
| Mechanism | Impedance |
| Cardiac causes | Pericardial effusion |
| Constrictive pericarditis | |
| Pneumopericardium | |
| Non-cardiac causes | COPD |
| Obesity | |
| Pneumothorax | |
| Pleural effusion | |
| Pulmonary edoema | |
| Pneumomediastinum | |
| Peripheral edoema |
The causes are also divided according to the mechanism, i.e. defect of generation or impedance.
LV, left ventricular.
Conclusions
The interpretation of 12-lead resting ECG in patients with a definitive diagnosis or with the suspicion of a cardiomyopathy represents a cornerstone for the diagnosis and management of patients. Although LQRSV detected by 12-lead resting ECG have historically been acknowledged by physicians, in view of the recent evidence on the demonstration of myocardial scar by CMR and its relevance as a cause of SCD even in young individuals, a new interest has been raised about the utility of LQRSV in the clinical practice. The current evidence suggests that LQRSV can be crucial for the diagnosis, the differential diagnosis, and the prognosis of patients with cardiomyopathies, and particularly in individuals with ACM and NLVS.
Conflict of interest: none declared.
Comments