Contemporary understanding of cardiac morphology in hypertrophic cardiomyopathy (HCM) is rooted in the keen observations of Teare, a British forensic pathologist, who described the presence of left ventricular(LV) asymmetric hypertrophy, myocardial clefts, fiber disarray and myocardial fibrosis in cases of sudden death in young and apparently healthy adults in the 1950s and 1960s [1,2]. During the same period, pioneering cardiac surgeons began to have unwelcome encounters with idiopathic hypertrophic subaortic stenosis during cardiac surgery for supposed aortic valvular stenosis and began to report intraoperative resection of septal hypertrophy, based on the supposition that septal hypertrophy was the mechanism of outflow obstruction . Fortunately, patients often benefited, presumably because systolic anterior motion of the anterior mitral leaflet was reduced by septal myomectomy. Teare was aware of the familial occurrence of the disorder and of the early clinical research work of Braunwald et al. and of Pare et al. [4,5]. In 2015, we are now finally at a point in the development of noninvasive cardiac imaging at which it is possible to detect and quantify in vivo all of the cardiac structural properties of HCM that Teare noted on postmortem specimens some 57 years ago, using cardiac MRI (CMR). Initially, biplane invasive left ventriculography was required to visualize HCM in vivo. However, the emergence of M mode echocardiography in the late 1960s enabled first, noninvasive detection of systolic anterior motion of the mitral valve in obstructive HCM  and, a few years later, 2D echocardiographic characterization of asymmetric septal hypertrophy, and elucidation of the prevalence, familial forms and clinical behavior of HCM . Imaging research contributions made by investigators at the National Heart, Lung and Blood Institute, principally Walter Henry, Barry Maron, Robert Bonow and Julio Panza, were central to these advances. However, echocardiographic assessment of HCM in adults is often hampered by the limitations of thoracic acoustic windows, most of all in assessment of the apical HCM variant and of the overall segmental distribution of hypertrophy. In recent years advances in real time 3D echo applicable with both transthoracic and transesophageal echocardiography imaging have begun to overcome some of these limitations, but to date their impact has been relatively limited. Therefore, major recent advances in HCM imaging have largely been achieved using CMR. The first application of CMR to HCM came in 1985 from the Higgins lab at UCSF and demonstrated the ability of CMR to evaluate the distribution of segmental hypertrophy accurately throughout the LV . By the early 1990s, application of CMR to HCM had begun to extend and enhance understanding of the disorder, providing the earliest evaluations of segmental myocardial strain, including 3D strain, as well as evidence of abnormal energetics [10,11]. Over the 1990s and early 2000s the superior ability of CMR to detect and evaluate the apical variant of HCM and coexistant apical aneurysms when present was also described, as well as the earliest studies of myocardial perfusion abnormalities and their morphologic correlates [12,13]. By 2002, the demonstration of replacement fibrosis expressed as CMR late gadolinium enhancement (LGE) in HCM had been demonstrated and over the ensuing years, its association with adverse outcomes has been repeatedly reported [14,15]. In addition, the superior ability of CMR has enabled demonstration that global, as opposed to segmental, LVH is an additional important marker of increased risk of adverse outcomes . Given this long history, it is perhaps surprising that, over recent years, novel insights based on CMR imaging in HCM have continued to extend our understanding of this disorder. Nonetheless, that is certainly the case, and CMR findings on cardiac structure in HCM continue to be a driver of changes in management.
Among the themes that have been notable in recent years in CMR studies of cardiac structure in HCM have been:
- The role of quantitative assessment of LGE in risk stratification;
- Determination of myocardial extracellular volume as an index of interstitial fibrosis as opposed to replacement fibrosis in HCM;
- Recognition of additional phenotypic subtypes of HCM;
- Recognition of additional morphologic abnormalities of papillary muscles and of the mitral apparatus in HCM and the frequency of findings of noncompaction;
- CMR findings on myocardial structure in genotype positive, phenotype negative members of affected families in documented genetic HCM;
- The role of left atrial enlargement in HCM;
- Emerging methods for the assessment of fiber disarray.
In addition, the development of new methods for the evaluation of regional myocardial mechanical properties using elastography is highly relevant to HCM in terms of future understanding of cardiac mechanics in this disorder.
THE ROLE OF QUANTITATIVE ASSESSMENT OF LATE GADOLINIUM ENHANCEMENT IN RISK STRATIFICATION
In 2003, the first descriptions of LGE in HCM emerged in small studies from Bogaert et al.  from Leuven, Belgium and from the Brompton group in London . Associations between LGE presence and more severe segmental hyprtrophy and function were described, and correlations between LGE presence and extent and clinical markers predictive of adverse outcomes in HCM, including heart failure and sudden death, were described. These studies followed closely on the heels of the initial development of the ‘gold standard’ LGE method by Kim, Judd and Simonetti for the evaluation of myocardial infarction due to epicardial coronary artery disease [17,18]. Unfortunately, neither these early studies of LGE in HCM nor other subsequent studies that followed were sufficiently large and compelling to form a basis for changes in therapeutic decision-making, nor did they lead to early large-scale multicenter clinical trials. However, in 2014, Chan et al. [19▪▪] documented the quantitative relationship of LGE to sudden death, total mortality and development of end-stage HCM in 1293 HCM patients followed by a multicenter consortium for a median of 3.3 years (Fig. 1). There was a 3% incidence (37 events) of sudden death or appropriate defibrillator intervention, with a hazard ratio of 1.46 per 10% increase in LGE (P = 0.002), after adjustment for other disease variables. The study also reported a continuous relationship between LGE expressed as % LV mass and sudden death risk. Among patients who were low risk by conventional clinical HCM criteria, LGE of 15% LV mass or more was associated with a two-fold increase in sudden death events (Fig. 1). The net reclassification index was 12.9%. Among patients without LGE the hazard ratio for sudden death events was reduced to 0.39, P = 0.02. Moreover, the risk of development of end-stage disease with systolic dysfunction showed a hazard ratio 1.8 per 10% increase in LGE (P < 0.03). Although the total number of events was limited and another large confirmatory trial would be highly desirable, these data are compelling and entirely consistent with prior smaller studies. Thus, they can provide the basis for a reconsideration of risk stratification in HCM, with addition of a heavy weighting given to quantitative LGE.
MYOCARDIAL EXTRACELLULAR VOLUME AS AN INDEX OF INTERSTITIAL FIBROSIS IN HYPERTROPHIC CARDIOMYOPATHY
Although replacement fibrosis depicted by LGE is clearly an important process in HCM and a key correlate of adverse outcomes, it is not the whole story with regard to changes in myocardial composition in HCM. Much, and in some individuals all, myocardial fibrosis in this disorder and many others can be interstitial in distribution, microscopic in scale and invisible on CMR and other types of in vivo images. In recent years, the effects of gadolinium contrast on T1 relaxation of water protons in the myocardial extravascular interstitium has become a very useful index of myocardial composition. Initial studies focused on the partition coefficient of gadolinium between blood and the interstitium under equilibrium conditions using steady state infusion of gadolinium contrast . Subsequently, it was shown using steady state infusion that the combination of T1 change with contrast infusion, combined with the hematocrit, could be used to estimate myocardial extracellular volume (ECV) as an index of interstitial fibrosis. The technique was validated using histologic evaluation of myocardial biopsies obtained at cardiac surgery in valvular aortic stenosis, but the infusion duration required made the method impractical for routine clinical use . Subsequently, it has been shown that with proper timing of T1 mapping after contrast bolus administration for imaging LGE, ECV determination can be accurately performed without prolonged contrast infusion, and the bolus approach has also been validated in aortic stenosis and in HCM . Although the actual ECV in milliliters is not identical to the volume of interstitial collagen on quantitative histology, the correlations between the two obtained in these studies is quite high and consistent. In addition, ECV increases are associated with adverse outcomes . However, large-scale multicenter studies that incorporate evaluation of the optimal use of ECV determinations with LGE for the assessment of myocardial function, risk stratification and clinical decision-making in HCM are badly needed, and it will be some years before these issues have been rigorously clarified.
Recognition of additional phenotypic subtypes of hypertrophic cardiomyopathy
CMR demonstrated long ago that the segmental distribution of myocardial hypertrophy was more extensive and complex than had been inferred from 2D echocardiography. Although technical advances are potentially creating a larger role for 3D echocardiography in the assessment of HCM, there continue to be substantial limitations in applicability of 3D transthoracic echocardiography and a limited number of compelling indications for transesophageal echocardiography in HCM. Thus, CMR continues to be the principal tool in comprehensive evaluation of the distribution of segmental hypertrophy. Initially, the main consequence was improved recognition of the apical variant of HCM, which can be overlooked on TEE if the transducer position at which apical views of the LV can be obtained is higher than the true apex . Subsequently, it has become apparent that there is a greater range of variability of segmental hypertrophy in patients with apical HCM than previously thought. More recently, other potentially important phenotypic subsets of have been described. The first is based on the distinction between HCM patients with and those without true global LV hypertrophy, expressed as increased LV mass [16,23]. The subgroup with increased LV mass, which cannot be measured accurately using 2D echocardiography due to the marked segmental variability of wall thickness in HCM, clearly has increased outcome-risk relative to those with normal global LV mass. A second important phenotype comprises patients with a spiral pattern of segmental hypertrophy, beginning at the anteroseptal base and extending in a counterclockwise direction in the LV short axis, as viewed from the apex, extending first in midventricle into the mid, then inferior septum, and in some instances into the inferior and apical inferolateral segments ([24,25], Fig. 2). As noted by Florian et al. in the article that called attention to this pattern, this patient group tends to have little or no LGE and fewer adverse outcomes than the rest of the HCM population [25,26]. However, one does occasionally encounter such patients with substantial LGE and ventricular arrhythmias as well as patients with apical HCM who also have extensive segmental involvement throughout the LV.
Associations of papillary muscle and mitral apparatus abnormalities and frequency of noncompaction in hypertrophic cardiomyopathy
Increased attention is being paid to the prevalence of abnormal variations in papillary muscle architecture and location that may play a role in chamber function and intraventricular function in HCM . In addition, the role of excessive mitral leaflet length in mitral regurgitation and systolic anterior motion of the mitral valve has been emphasized . Finally, the rather counterintuitive presence of segmental areas of noncompaction in some individuals with HCM, detected by CMR, has also been stressed [28▪]. However, inquiry into these topics is still relatively early on.
The role of left atrial enlargement
The frequency of left atrial enlargement in HCM, often due to the presence of diastolic dysfunction and/or mitral regurgitation, is receiving increased attention as a correlate of the risk of atrial fibrillation, which in turn has emerged as an important risk factor for adverse outcomes in this disorder [29,30].
Phenotype negative genotype positive hypertrophic cardiomyopathy
It has become increasingly apparent that, in patients from kindreds with identifiable gene correlated HCM, genotype positive patients who do not have conventional clinical phenotype criteria for HCM may nonetheless show both structural abnormalities such as fibrosis by the LGE technique and functional abnormalities, myocardial and microvascular dysfunction [31,32▪▪]. These observations may well lead to improved early identification of individuals at risk for full blown HCM later in life and hopefully someday contribute to efforts at secondary prevention in this disorder.
Detection of fiber disarray
Myofiber disarray is one of the key histologic findings in HCM, but methods for in-vivo detection of disarray have been lacking. A long line of work, beginning with the contributions of van Wedeen working on in-vitro animal and later human postmortem hearts, has led to the development of methods for magnetic resonance diffusion tensor evaluation of myocardial fiber orientations in myocardium that can depict fiber disarray in HCM [32▪▪,33,34,35▪▪]. These measurements were relatively time consuming, but recent work at higher field strengths and using more advanced parallel imaging methods has made diffusion tensor evaluation fast enough to be more broadly applicable to human research in vivo. Differences between HCM and normal controls have been characterized, and more work is sure to shed further light on the problem.
There is a need to directly determine the stiffness of myocardium in humans in vivo in order to better relate cardiac structure to cardiac mechanical function. In static organs such as the liver, MRI elastography, in which an external pressure wave is imposed on tissue and changes in MR signal phase that result from tissue deformation by the imposed wave are obtained, has proven useful in assessing tissue stiffness. Liver elastography can be used to assess effects of right atrial hypertension on the liver already . But more importantly, in principle, such methods could be used to determine myocardial stiffness directly over the cardiac cycle. However, cardiac applications have faced formidable challenges in delivering such pressure waves and extracting interpretable data. Recently, an abstract presentation at the 2015 meeting of the Society for Cardiovascular Magnetic Resonance described an ingenious study that suggests it may be possible to use endogenous heart sounds in vivo as an energy source for cardiac elastography [36,37▪]. If this line of work develops well it can lead to exciting new insights into myocardial stiffness and its relationship to myocardial structure and function in many myocardial disorders.
Our understanding of myocardial structure, both macroscopic and microscopic, in HCM continues to evolve rapidly due to recent advances in CMR. Understanding of the role and prognostic significance of replacement fibrosis in HCM is far advanced and the role of interstitial fibrosis will be greatly clarified in the next few years. Insights into additional abnormalities in HCM, such as papillary muscle variants and abnormal mitral leaflet structure, as well as novel anatomic phenotypes such as spiral distribution of hypertrophy have also emerged. The role of left atrial abnormalities in determining atrial fibrillation risk and outcomes, subtle manifestations of genotype positive, phenotype negative HCM, and new methods for assessment of myocardial fiber disarray promise to continue, enhance and extend our ability to evaluate and select optimal therapy for patients with HCM for a long time to come.
The author's thanks to Dr Martin Maron for provision of Fig. 1 and to William Schapiro RT for preparation of Fig. 2.
Financial support and sponsorship
This work was supported by the Research and Education Department, St. Francis Hospital, The Heart Center, Roslyn, NY.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
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