Myocardial ischemia is an established pathophysiological feature of hypertrophic cardiomyopathy (HCM) that impacts various clinical features, including heart failure (HF) and sudden cardiac death (SCD). The major determinant of myocardial ischemia in HCM is coronary microvascular dysfunction (CMD) in the absence of epicardial coronary artery abnormalities. Despite the impossibility to directly visualize microcirculation in vivo, a multimodality approach can allow a detailed assessment of microvascular dysfunction and ischemia. Accordingly, the non-invasive assessment of CMD using transthoracic Doppler echocardiography, positron emission tomography, and cardiac magnetic resonance should now be considered mandatory in any HCM patient. Noteworthy, a complete diagnostic work-up for myocardial ischemia plays a major role in the approach of the patients with HCM and their risk stratification. Chronic and recurrent episodes of ischemia can contribute to fibrosis, culminating in LV remodeling and HF. Ischemia can potentially constitute an arrhythmic substrate and might prove to have an added value in risk stratification for SCD. Accordingly, strategies for the early diagnosis of CMD should now be considered an important challenge for the scientific community.

/pdf/microvascular-dysfunction-in-hypertrophic-cardiomyopathy-2tyrnqze.pdf

Microvascular Dysfunction in Hypertrophic Cardiomyopathy

To evaluate subclinical LV systolic dysfunction in obese patients by global myocardial work (MW).A total of 589 obese patients and 100 normal controls were enrolled in the study. The global longitudinal strain (GLS), global work index (GWI), global constructive work (GCW), global wasted work (GWW) and global work efficiency (GWE) were generated by a noninvasive pressure-strain loop (PSL) in apical 3-, 4- and 2-chamber views acquired by two-dimensional echocardiography. All obese patients were divided into three groups: class I obesity (mild) 30-35 kg/m2, class II obesity (moderate) 35-40 kg/m2 and class III obesity (severe) > 40 kg/m2. These values were compared among the three groups. The independent influencing factors of subclinical LV systolic dysfunction in obese patients were explored by constructing a multiple regression model. ROC analysis was performed to determine the performance of MW to detect subclinical LV systolic dysfunction in obese patients.The absolute value of GLS in obese patients was significantly lower than that in normal controls (P < 0.001). The values of GWI, GCW, GWE and GCW/GWW in obese patients were significantly lower than those in normal controls (P < 0.05), while GWW was significantly larger than that in normal controls (P < 0.001). Subgroup analysis and trend analysis showed that the values of GWI, GCW, GWE and GCW/GWW in severe obese patients were lower than those in moderate obese patients and lower than those in mild obese patients (P < 0.01), while GWW in severe obese patients was larger than that in moderate obese patients and larger than that in mild obese patients (P < 0.05). Female sex, BMI and SBP were independent influencing factors of impaired GWI (β = 0.15, P < 0.001) (β=-0.18, P < 0.001) (β = 0.50, P < 0.001) and GCW (β = 0.17, P < 0.001) (β=-0.19, P < 0.001) (β = 0.57, P < 0.001). ROC analysis showed that the AUC of the combined global MW was significantly higher than the AUCs of the individual indices (P < 0.05).In this study, we conclude that subclinical LV systolic dysfunction was detected by the novel global MW technique in obese patients. Elevated BMI in obese patients results in an increased risk of subclinical LV systolic dysfunction, although the LVEF is normal. Controlling BMI in obese patients may reduce the impairment to the LV myocardial systolic function. Global MW is a novel and reproducible technique that can be well applied in the clinical evaluation of subclinical LV systolic dysfunction. 

Evaluation of subclinical left ventricular systolic dysfunction in obese patients by global myocardial work

Pseudonormal T waves may be detected on stress electrocardiograms (ECGs) in hypertrophic cardiomyopathy (HCM). Either myocardial ischaemia or purely exercise-induced changes have been hypothesised to contribute to this phenomenon, but the precise electrophysiological mechanisms remain unknown. Computational models of human HCM ventricles (n = 20) with apical and asymmetric septal hypertrophy phenotypes with variable severities of repolarisation impairment were used to investigate the effects of acute myocardial ischaemia on ECGs with T wave inversions at baseline. Virtual 12-lead ECGs were derived from a total of 520 biventricular simulations, for cases with regionally ischaemic K+ accumulation in hypertrophied segments, global exercise-induced serum K+ increases, and/or increased pacing frequency, to analyse effects on ECG biomarkers including ST segments, T wave amplitudes, and QT intervals. Regional ischaemic K+ accumulation had a greater impact on T wave pseudonormalisation than exercise-induced serum K+ increases, due to larger reductions in repolarisation gradients. Increases in serum K+ and pacing rate partially corrected T waves in some anatomical and electrophysiological phenotypes. T wave morphology was more sensitive than ST segment elevation to regional K+ increases, suggesting that T wave pseudonormalisation may sometimes be an early, or the only, ECG feature of myocardial ischaemia in HCM. Ischaemia-induced T wave pseudonormalisation can occur on stress ECG testing in HCM before significant ST segment changes. Some anatomical and electrophysiological phenotypes may enable T wave pseudonormalisation due to exercise-induced increased serum K+ and pacing rate. Consideration of dynamic T wave abnormalities could improve the detection of myocardial ischaemia in HCM. 

Electrophysiological mechanisms underlying T wave pseudonormalisation on stress ECGs in hypertrophic cardiomyopathy

Abstract Despite the progress made in risk stratification, sudden cardiac death and heart failure remain dreaded complications for hypertrophic cardiomyopathy (HCM) patients. Myocardial ischaemia is widely acknowledged as a contributor to cardiovascular events, but the assessment of ischaemia is not yet included in HCM clinical guidelines. This review aims to evaluate the HCM-specific pro-ischaemic mechanisms and the potential prognostic value of imaging for myocardial ischaemia in HCM. A literature review was performed using PubMed to identify studies with non-invasive imaging of ischaemia (cardiovascular magnetic resonance, echocardiography, and nuclear imaging) in HCM, prioritising studies published after the last major review in 2009. Other studies, including invasive ischaemia assessment and post-mortem histology, were also considered for mechanistic or prognostic relevance. Pro-ischaemic mechanisms in HCM reviewed included the effects of sarcomeric mutations, microvascular remodelling, hypertrophy, extravascular compressive forces and left ventricular outflow tract obstruction. The relationship between ischaemia and fibrosis was re-appraised by considering segment-wise analyses in multimodal imaging studies. The prognostic significance of myocardial ischaemia in HCM was evaluated using longitudinal studies with composite endpoints, and reports of ischaemia-arrhythmia associations were further considered. The high prevalence of ischaemia in HCM is explained by several micro- and macrostructural pathological features, alongside mutation-associated energetic impairment. Ischaemia on imaging identifies a subgroup of HCM patients at higher risk of adverse cardiovascular outcomes. Ischaemic HCM phenotypes are a high-risk subgroup associated with more advanced left ventricular remodelling, but further studies are required to evaluate the independent prognostic value of non-invasive imaging for ischaemia. 

/pdf/mechanisms-and-prognostic-impact-of-myocardial-ischaemia-in-1ifnq106.pdf

Mechanisms and prognostic impact of myocardial ischaemia in hypertrophic cardiomyopathy.

Background: The pathophysiological impact of systemic vascular resistance (SVR) and pressure–strain loop-derived global myocardial work index (GWI) in hypertrophic cardiomyopathy (HCM) and transthyretin cardiac amyloidosis (ATTR) has been randomly investigated. Methods: Both SVR and GWI were assessed in outpatients consecutively referred at two Italian cardiology departments for heart failure with preserved left ventricular ejection fraction (LVEF), affected by either nonobstructive HCM or wild-type ATTR. Based on relevant cross-tabulations, the patients were gathered into 4 functional classes according to cut-off values of 1440 dyne/s/cm−5 for SVR, and 1576 mm Hg% for GWI, as suggested by previous studies. Results: A total of 60 patients, 30 in each group, aged 61 ± 16 years, with 78% males, were studied. HCM patients were younger than those with ATTR and in a better clinical condition (23% HCM vs. 77% ATTR were NYHA class II-III, p < 0.001). Overall, 51 patients (85%) showed a high SVR, 21/30 HCM (70%), and 30 ATTR (100%) (p < 0.005). Both SVR and GWI (expressions of ventricular–arterial coupling) were impaired in 43% of HCM patients (showing greater LV concentric hypertrophy) and 93% of ATTR patients (in advanced NYHA functional class) (p < 0.001). Conclusions: A substantial percentage of present study population showed impaired SVR and/or GWI, despite preserved LVEF. The proposed classification may shed further light on the pathophysiological and clinical characteristics of such hypertrophic phenotypes.

Systemic Vascular Resistance and Myocardial Work Analysis in Hypertrophic Cardiomyopathy and Transthyretin Cardiac Amyloidosis with Preserved Left Ventricular Ejection Fraction

Microvascular dysfunction is an often overlooked feature of hypertrophic cardiomyopathy (HCM). Our aim was to assess the association between microvascular dysfunction, wall thickness, tissue characteristics and myocardial deformation in HCM patients, by analyzing individual myocardial segments.Prospective assessment including cardiac magnetic resonance to assess wall thickness, T1 and T2 mapping, extracellular volume, late gadolinium enhancement (LGE) and stress perfusion. Results were stratified according to the 16 American Heart Association segments.Seventy-five patients were recruited (1200 segments), 63% male, mean age 54.6±14.8 years, maximal wall thickness of 20.22±4.6 mm. Among the 424 segments (35%) with perfusion defects, 24% had defects only in the endocardial layer and 12% in both endocardial and epicardial layers. Perfusion defects were more often detected in hypertrophied segments (64%). Among the 660 segments with normal wall thickness, 19% presented perfusion defects. Independently of wall thickness, segments with perfusion defects had a higher T1 (β-estimate 30.28, p<0.001), extracelluar volume (β-estimate 1.50, p<0.001) and T2 (β-estimate 0.73, p<0.001) and had late gadolinium enhancement more frequently (odds ratio 4.16, p<0.001). Higher values of circumferential strain (lower deformation) and lower values of radial strain were found in segments with perfusion defects (β-estimate 2.76, p<0.001; and β-estimate -10.39, p<0.001, circumferential and radial strain, respectively).While microvascular dysfunction was more prevalent in more hypertrophied segments, it also had a major presence in segments without hypertrophy. In this segmental analysis, we found an association between the presence of ischemia and tissue abnormalities, replacement fibrosis as well as impaired strain, independently of the segmental wall thickness. 

Associations between perfusion defects, tissue changes and myocardial deformation in hypertrophic cardiomyopathy, uncovered by a cardiac magnetic resonance segmental analysis.


 
 
 Type of funding sources: None.
 
 
 
 Left ventricular hypertrophy (LVH) and microvascular dysfunction are hallmarks of hypertrophic cardiomyopathy (HCM). We hypothesized that microvascular dysfunction contributes to LV myocardial deformation impairment.
 
 
 
 Prospective evaluation of adult patients with HCM (patients with "end-stage" HCM, prior septal reduction therapy or epicardial coronary artery disease were excluded). All underwent a cardiac magnetic resonance (CMR) protocol (1.5-T), from which the following parameters were analysed: maximal LV wall thickness (MLVWT), T1 and T2 mapping, extracellular volume, late gadolinium enhancement (LGE) and stress perfusion. Three-dimensional strain analysis was obtained by using feature-tracking from cine images. Results were stratified according to the 16 American Heart Association segments. Multivariate regression analyses for longitudinal, circumferential and radial strain were performed.
 
 
 
 A total of 1200 myocardial segments were analysed (Table 1) (75 patients, 63% male, age 54.6 ± 14.7 years) including 61% with asymmetric septal LVH, 29% with apical LVH, 8% with concentric LVH, 28% exhibiting LV outflow tract obstruction. The mean MLVWT was 20 ± 4.5mm.
 Higher values of longitudinal strain (lower deformation) were found in segments with MLVWT ≥15mm (β-estimate: 2.31, 95% CI 0.91-3.70, p < 0.001) and in patients with obstructive HCM (β-estimate: 2.44, 95% CI 1.15-3.72, p < 0.001]) (Table 2). No association was found between perfusion defects, LGE and longitudinal strain.
 Higher values of circumferential strain (lower deformation) were found in segments with MLVWT 12-14mm (β-estimate: 2.31, 95% CI 1.36-3.25, p < 0.001), MLVWT ≥15mm (β-estimate: 5.29, 95% CI 4.47-6.12, p < 0.001), with perfusion defects (β-estimate: 2.75, 95% CI 2.0-3.5, p < 0.001), with LGE (β-estimate: 2.49, 95% CI 1.77-3.22, p < 0.001) and in patients with obstructive HCM (β-estimate: 1.25, 95% CI 0.44-2.06, p = 0.003).
 Lower radial strain values were found in segments with MLVWT 12-14mm (β-estimate: -10.64, 95% CI -13.95 to -7.33, p < 0.001), with MLVWT ≥15mm (β-estimate: -20.67, 95% CI -23.36 to -17.97, p < 0.001), with perfusion defects (β-estimate: -10.60, 95% CI -13.08 to -8.13, p < 0.001), and with LGE (β-estimate: -10.49, 95% CI  -12.86 to -8.11) (table 2).
 Diabetes, hypertension and BMI > 25 kg/m2 were also associated with impaired myocardial deformation. Male gender correlated with worse radial and circumferential strain values.
 No association was found between parametric mapping values and LV myocardial deformation.
 
 
 
 In patients with HCM, three-dimensional speckle tracking parameters for LV systolic function were particularly impaired in segments with LVH, microvascular dysfunction or fibrosis. LVH was associated with abnormal longitudinal, circumferential and radial strain while perfusion defects and LGE correlated with impaired circumferential strain and radial strain. Abstract Table 1: Characteristics of AHA segments  Abstract Table 2: Multivariate analysis


Microvascular dysfunction and myocardial fibrosis impact on left ventricular myocardial deformation in hypertrophic cardiomyopathy: per segment analysis by magnetic resonance imaging


 
 
 Type of funding sources: None.
 
 
 
 While left ventricular hypertrophy (LVH) and myocardial fibrosis are frequently evaluated in hypertrophic cardiomyopathy (HCM), microvascular dysfunction is often overlooked. The aim of this study was to assess the association between wall thickness, microvascular dysfunction and tissue characteristics in HCM patients (P), comparing individual myocardial segments.
 
 
 
 Prospective evaluation of adult P with HCM (P with "end-stage" HCM, prior septal reduction therapy or epicardial coronary artery disease were excluded). All underwent a cardiac magnetic resonance (CMR) protocol (1.5-T), from which the following parameters were analysed: maximal LV wall thickness (MLVWT), T1 and T2 mapping, extracellular volume (ECV), late gadolinium enhancement (LGE) and stress perfusion. Results were stratified according to the 16 American Heart Association segments. Multivariate regression analyses for perfusion defects and tissue characteristics were performed.
 
 
 
 75 P (total of 1200 myocardial segments analysed), 63% male, mean age 55 ± 15 years, MLVWT of 20 ± 4.5mm (61% asymmetric septal LVH, 29% apical LVH and 8% concentric LVH). 28% presented LV outflow tract obstruction.
 MLVWT was greater in the basal and mid septum (table 1). Among the 424 segments (35.3%) with a perfusion defect, 286 (23.8%) had a defect only in the endocardial layer and 138 (11.5%) in both endocardial and epicardial layers with defects more often detected in hypertrophied segments. This association was verified in segments with MLVWT 12-14mm and MLVWT ≥15mm (OR 7.83, 95% CI 5.75-10.67, p < 0.001) (table 2). Among the 660 segments with normal MLVWT (≤11mm), 123 (19%) presented perfusion defects. A perfusion defect was more frequent in segments of obstructive HCM P (OR 1.48, 95% CI 1.13-1.92, p = 0.004).
 Microvascular dysfunction was associated with changes in tissue characteristics. For the same thickness, segments with perfusion defects had a higher T1 mapping (β-estimate 20.91, 95% CI 16.87-24.96, p < 0.001) and T2 mapping mean values than those without. Furthermore, regardless of MLVWT, segments with perfusion defects had LGE more often (OR 4.16, 95% CI 3.19-5.41, p < 0.001) and a higher ECV. On the other hand, among the 424 segments with a perfusion defect, 115 (27%) did not present LGE.
 MLVWT was associated with tissue characteristics. Comparing to non-hypertrophied segments, T1 mapping mean value was higher in segments with MLVWT 12-14mm and with ≥15mm (β-estimate 37.71, 95% CI 31.2-44.21, p < 0.001). Segments with MLVWT ≥15mm showed a significantly superior ECV mean value comparing to non-hypertrophied segments. LGE was more frequent in the more hypertrophied segments: MLVWT 12-14mm and ≥15mm (OR 9.02, 95% CI 6.42-12.67, p < 0.001) (Table 2).
 
 
 
 Microvascular dysfunction is more prevalent in obstructive HCM, particularly in the more hypertrophied segments. The presence of microvascular dysfunction is associated with diffuse tissue abnormalities and replacement fibrosis. Abstract Table 1: Characteristics of AHA segments  Abstract Table 2: Multivariable analyses


Segmental analysis of microvascular dysfunction and tissue characterization in hypertrophic cardiomyopathy by magnetic resonance imaging

Background Two‐dimensional speckle tracking echocardiography has been shown to correlate with microvascular dysfunction, a hallmark of hypertrophic cardiomyopathy (HCM). We hypothesized that there is an association between myocardial work and left ventricular ischemia, with incremental value to global longitudinal strain, in patients with HCM. Methods and Results We performed a prospective assessment of patients with HCM, undergoing 2‐dimensional speckle tracking echocardiography and stress perfusion cardiac magnetic resonance. Results were stratified according to obstructive or nonobstructive HCM and the presence of significant replacement fibrosis (late gadolinium enhancement ≥15% of left ventricular mass). Seventy‐five patients with HCM (63% men, age 55±15 years) were evaluated, 28% with obstructive HCM (mean gradient 89±60 mm Hg). Perfusion defects were found in 90.7%, involving 22.5±16.9% of left ventricular mass, and 38.7% had late gadolinium enhancement ≥15%. In a multivariable analysis, a lower global work index (r=−0.519, β‐estimate −10.822; P=0.001), lower global work efficiency (r=−0.379, β‐estimate −0.123; P=0.041), and impaired global constructive work (r=−0.532, β‐estimate −13.788; P<0.001) significantly correlated with ischemia. A segmental analysis supported these findings, albeit with lower correlation coefficients. A global work index cutoff ≤1755 mm Hg% was associated with hypoperfusion with a sensitivity of 88% and a specificity of 71%, while the best cutoff for global longitudinal strain (>−15.5%) had a sensitivity of 64% and a specificity of 57%. The association between myocardial work and perfusion defects was significant independently of late gadolinium enhancement ≥15% and obstructive HCM. Conclusions Impaired myocardial work was significantly correlated with the extent of ischemia in cardiac magnetic resonance, independently of the degree of left ventricular hypertrophy or fibrosis, with a higher predictive power than global longitudinal strain.

Microvascular Dysfunction Is Associated With Impaired Myocardial Work in Obstructive and Nonobstructive Hypertrophic Cardiomyopathy: A Multimodality Study

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Associations between perfusion defects, tissue changes and myocardial deformation in hypertrophic cardiomyopathy, uncovered by a cardiac magnetic resonance segmental analysis.

Microvascular dysfunction and myocardial fibrosis impact on left ventricular myocardial deformation in hypertrophic cardiomyopathy: per segment analysis by magnetic resonance imaging

Segmental analysis of microvascular dysfunction and tissue characterization in hypertrophic cardiomyopathy by magnetic resonance imaging

Microvascular Dysfunction Is Associated With Impaired Myocardial Work in Obstructive and Nonobstructive Hypertrophic Cardiomyopathy: A Multimodality Study